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Phase 2b FASCINATE-2 clinical trial of denifanstat in MASH

Denifanstat met all primary and multiple secondary endpoints in the Phase 2b FASCINATE-2 clinical trial evaluating denifanstat in 168 biopsy-confirmed MASH patients with stage F2 or F3 fibrosis compared to placebo at week 52. We announced topline results in January 2024 and published the trial results in The Lancet Gastroenterology & Hepatology in October 2024. Denifanstat also demonstrated anti-fibrotic activity, including in patients with advanced fibrosis, as seen in the F3 modified intention to treat (mITT) population and qF4 patients (qF4 patients are artificial intelligence (AI)-defined F4, based on the second harmonic generation (SGH) HistoIndex platform, which may encompass late stage F3 as well as F4 patients):

●Fibrosis improvement by ≥ 1 stage with no worsening of MASH (F3 mITT population: denifanstat 49% vs. placebo 13%, p=0.0032).

●Fibrosis improvement by ≥ 2 stages with no worsening of MASH (mITT population: denifanstat 20% vs. placebo 2%, p=0.0065; F3 mITT population: denifanstat 34% vs. placebo 4%, p=0.0065).

●A statistically significant difference in progression to cirrhosis (F4) (mITT population: denifanstat 5% vs. placebo 11%, p=0.0386).

●A statistically significant difference in fibrosis improvement by ≥ 1 stage with no worsening of MASH for patients on a stable background dose of a GLP-1 Receptor Agonist (mITT population: denifanstat 42% vs. placebo 0%, p=0.034).

●Decrease of 1 or 2 qFibrosis stages in 85% of qF4 patients as measured by AI-based pathology (SGH, HistoIndex).

●Statistically significant liver fibrosis regression in the portal and peri-portal regions (observed with AI-based digital pathology), which have been recently linked to major adverse liver outcomes (MALO) and mortality as measured by AI-based composite scores.

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As in prior studies, denifanstat was generally well tolerated. No treatment-related serious adverse events (SAEs) were observed, and the majority of adverse events (AEs) were mild to moderate in nature (Grades 1 and 2). There were no Grade ≥3 treatment-related AEs and no drug-induced liver injury (DILI) signal in the study. The most common treatment-related AEs by system organ class (observed in ≥5% of patients in the study) were eye disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders. The incidence of treatment emergent adverse events (TEAEs) leading to treatment discontinuation was 19.6% in the denifanstat group compared to 5.4% in placebo.

Combination of denifanstat and resmetirom for the treatment of MASH

We are developing a combination of our oral once-daily FASN inhibitor, denifanstat, and the thyroid hormone receptor beta (THR-β) agonist, resmetirom (commercially available as Rezdiffra), for cirrhotic patients living with F4-stage MASH.

Phase 1 pharmacokinetic (PK) clinical trial of a combination of denifanstat and resmetirom

In December 2025, we announced completion of our Phase 1 PK trial of a combination of denifanstat and resmetirom. The Phase 1 PK trial was an open-label, 2-cohort study that enrolled 40 healthy adult participants. The trial objectives were to evaluate multiple-dose and single-dose pharmacokinetics, identify any potential drug-drug interactions (DDI), and assess the safety and tolerability of the combination. The combination of denifanstat and resmetirom was generally well-tolerated over the duration of the study, with no safety signals. No SAEs were reported, and there were no clinically significant laboratory AEs and no treatment-related discontinuations.

Our combination program builds upon preclinical data we presented at the European Association for the Study of the Liver (EASL) Congress in 2024 for two mouse models of MASH, showing that the combination of a FASN inhibitor (TVB-3664, a surrogate for denifanstat) and resmetirom, had a synergistic effect on important liver disease markers, including improvement of NAS by histologic analysis and more robust improvement in hepatic collagen content compared to the single agents. Synergistic activity of the combination was demonstrated in the rate of histological improvement (NAS ≥2 points), which was 33% for FASN inhibitor monotherapy, 25% for resmetirom monotherapy, and 80% for the combination of the two, a level of improvement that greatly exceeds a simple addition of the activity of the two drugs.

We plan to use these data to advance the development of the combination into a Phase 2 proof-of-concept efficacy trial for patients living with MASH with F4 fibrosis, expected to initiate in the second half of 2026, subject to consultation with regulatory authorities.

Biomarker strategy

Given the inherent complexity of MASH and other diseases caused by dysregulated lipogenesis, our development strategy includes precision medicine approaches using non-invasive tests (NITs), which we also refer to as biomarkers, to identify indications that can be treated by denifanstat as well as patients who are most likely to respond to denifanstat. This approach includes the development of blood-based pharmacodynamic biomarkers, such as tripalmitin, to confirm FASN inhibition and pathway engagement by denifanstat, as well as predictive biomarkers incorporating metabolomic and single nucleotide polymorphism (SNP) blood profiling to identify a biomarker signature that predicts improvements in markers of MASH disease in patients taking denifanstat. Furthermore, we may apply such predictive tests complementary to therapeutic intervention with denifanstat to better understand the patients who partially respond to denifanstat. Identifying these potential non-responders may help clinicians determine if, for instance, a combination of denifanstat and another non-FASN inhibitor therapeutic may optimize clinical outcomes. We anticipate developing complementary diagnostic tools to benefit patients, clinicians and payors. Ultimately, we intend to leverage these non-invasive biomarkers to ensure FASN biology is informing both the diseases we investigate and the patients who receive treatment.

Acne

In addition to MASH, we are evaluating our FASN inhibitors in acne, a disorder in which dysregulation of fatty acid metabolism also plays a key role. Denifanstat is being developed for acne in China by our license partner for China, Ascletis BioScience Co. Ltd. (Ascletis), a subsidiary of Ascletis Pharma Inc. (Ascletis Pharma). Our potent and selective small molecule FASN inhibitor, TVB-3567, is currently in a first-in-human Phase 1 clinical trial for development of an acne indication. Acne is a promising therapeutic area for application of FASN inhibitors because FASN is required for sebum production, which is upregulated in acne and leads to exacerbation of acne lesions including development of nodules and cysts.

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Phase 3 clinical trial of denifanstat in acne

In January 2026, Ascletis reported positive topline results in the open-label Phase 3 trial evaluating the long-term safety of ASC40 (denifanstat) tablets in patients with moderate to severe acne in China.

In December 2025, Ascletis announced that the China National Medical Products Administration (NMPA) accepted its New Drug Application (NDA) for denifanstat for the treatment of moderate to severe acne.

In June 2025, Ascletis announced that denifanstat met all primary and secondary endpoints in its Phase 3 trial in moderate to severe acne vulgaris in China. The Phase 3 clinical trial was a randomized, double-blind, placebo-controlled, multicenter clinical trial of 480 enrolled patients randomized 1:1 to receive denifanstat 50mg or placebo, once daily for 12 weeks.

Ascletis reported the following efficacy data from the Phase 3 trial:

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●All primary endpoints were met, including:

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●the percentage of treatment success (defined as an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-point decrease from baseline) (denifanstat 33.2% vs. placebo 14.6%, p<0.0001).

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●the percentage change in total lesion count (denifanstat -57.4% vs. placebo -35.4%, p<0.0001).

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●the percentage change in inflammatory lesion count (denifanstat -63.5% vs. placebo -43.2%, p<0.0001).

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●The secondary endpoint of change in non-inflammatory lesion count was also met (denifanstat -51.9% vs. placebo -28.9%, p<0.0001).

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Ascletis reported that denifanstat was generally well-tolerated. Following 12 weeks of once-daily oral administration at 50mg, the incidence rates of TEAEs were comparable between denifanstat and placebo.

Phase 1 clinical trial of TVB-3567

In June 2025, we initiated a first-in-human Phase 1 clinical trial of our potent and selective small molecule FASN inhibitor, TVB-3567, for development of an acne indication. The Phase 1 clinical trial is a randomized double-blind placebo-controlled trial designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TVB-3567 in healthy participants with or without acne. The trial is comprised of several parts, including single ascending dose cohorts and multiple ascending dose cohorts in participants without acne, followed by testing in participants with acne including evaluation of pharmacodynamic biomarkers.

Subject to consultation with regulatory authorities, and contingent on the results of the Phase 1 trial, we anticipate initiating the Phase 2 trial of TVB-3567 in 2026.

Our FASN inhibitor pipeline

The critical role of FASN overactivity in MASH, acne and cancer has made it an attractive target for drug therapy. Early generations of FASN inhibitor compounds made by others were limited by their off-target activities, inappropriate localization to the brain and poor pharmaceutical properties. Most of these compounds never entered clinical development, and the few that did, failed in early-stage clinical trials due to these limitations. We selected denifanstat and TVB-3567 from our library of over 1,200 internally discovered and wholly owned FASN inhibitors after a rigorous medicinal chemistry and preclinical development effort. We advanced denifanstat and TVB-3567 into clinical development, based upon their oral administration, high selectivity for FASN, and excellent pharmacokinetic and pharmaceutical properties, including restricted penetration of the blood-brain barrier. FASN is a large protein with six different enzymatic domains. The selectivity of denifanstat and TVB-3567 is a consequence of binding to the protein in an area that is not an

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enzymatic active site and unique to the structure of FASN. This selectivity is critical for preventing off-target effects that plagued earlier generations of FASN inhibitor compounds.

The following table summarizes our development programs for multiple diseases with high unmet need:

*Trials conducted in China by Ascletis, who has licensed development and commercialization rights to all indications in Greater China.

**First-in-human (FIH).

Figure 1. Development pipeline​

Our strategy

Our goal is to develop and commercialize our selective FASN inhibitors in therapeutic areas where upregulation of FASN plays a central role in the development or progression of disease. We intend to achieve this goal by pursuing the following key strategic objectives:

●Progress the combination of denifanstat and resmetirom through clinical development for the treatment of MASH. We have tested a combination of a FASN inhibitor (TVB-3664, a surrogate for denifanstat) and a THR-ß agonist in two in vivo preclinical MASH models, and data showed that the combination of a FASN inhibitor and resmetirom had a synergistic effect on important liver disease markers, including improvement of NAS (NAFLD Activity Score) by histologic analysis and more robust improvement in hepatic collagen content compared to the single agents. We hypothesize that the complementary mechanisms of denifanstat (inhibiting fat synthesis) and THR-ß (increasing fat removal) may normalize liver fat in MASH patients and may improve clinical activity on fibrosis endpoints. In December 2025, we announced completion of our Phase 1 PK trial of a combination of denifanstat and the THR-β agonist resmetirom. We plan to advance the development of the combination into a Phase 2 proof-of-concept efficacy trial for patients living with MASH with F4 fibrosis, expected to initiate in the second half of 2026, subject to consultation with regulatory authorities.

●Establish the combination of denifanstat and resmetirom as a potential backbone therapy for the treatment of MASH. Given the disease complexity of MASH, as well as the heterogeneity and large size of the MASH patient population, we believe a combination of denifanstat and resmetirom has the potential to address multiple MASH indications. Subject to data from our clinical trials, we intend to seek approval of the combination of denifanstat and resmetirom for the treatment of cirrhotic MASH (F4) and pediatric MASH to maximize denifanstat’s full clinical and commercial potential.

●Advance our precision medicine strategy to identify patients who will benefit from denifanstat. Given that MASH is a complex, progressive disease for which there are two recently approved treatments in the United States and only one currently

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approved treatment in Europe, our precision medicine strategy to develop non-invasive biomarkers complements our clinical development efforts for denifanstat. This includes the development and application of pharmacodynamic biomarkers to confirm drug response to denifanstat and predictive biomarkers to select the patients most likely to have a clinical response. We expect to continue to validate these biomarkers with results emerging from our ongoing clinical development, including our planned Phase 2 proof-of-concept efficacy trial for patients living with MASH with F4 fibrosis, expected to initiate in the second half of 2026, subject to consultation with regulatory authorities.

●Advance TVB-3567 clinical development for the treatment of moderate to severe acne. In June 2025, we initiated a first-in-human Phase 1 clinical trial of TVB-3567, a potent and selective small molecule FASN inhibitor, for development of an acne indication. This builds upon the clinical trial results of denifanstat in acne reported by our license partner for China, Ascletis. In June 2025, Ascletis announced that denifanstat met all primary and secondary endpoints in its Phase 3 trial in moderate to severe acne vulgaris in China. In December 2025, Ascletis announced that the China NMPA has accepted its NDA for denifanstat for the treatment of moderate to severe acne. In January 2026, Ascletis reported positive topline results in the open-label Phase 3 trial evaluating the long-term safety of ASC40 (denifanstat) tablets in patients with moderate to severe acne in China. Subject to consultation with regulatory authorities, and contingent on the results of our Phase 1 trial, we anticipate initiating the Phase 2 trial of TVB-3567 in 2026.

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●Expand pipeline in indications beyond MASH and acne, where FASN plays a central role in disease pathogenesis. Based on our seminal work around FASN biology and the broad potential of this mechanism in diseases beyond MASH and acne, we have also prioritized oncology in our initial development pursuits for denifanstat. In oncology, we are developing FASN inhibitors to treat specific subsets of solid tumors that are FASN-dependent. We are exploring the potential of denifanstat in combination with other classes of oncology drugs. We conducted our first-in-human Phase 1 clinical trial for denifanstat in patients with advanced solid tumors. We will maintain a focused and disciplined strategy in evaluating potential indications beyond MASH and acne that may merit further advancement.

●Develop and commercialize our drug candidates independently in indications and geographies where we believe we can maximize value and benefit to patients. Because we believe our FASN platform and drug candidates have the potential to treat a broad range of diseases, we will independently develop drug candidates in indications and geographies where we believe we can successfully commercialize on our own if they are approved. We will collaborate on drug candidates that we believe have promising utility in disease areas, patient populations or geographies that are better served by the resources or specific expertise of other biopharmaceutical companies. Our license agreement with Ascletis for the development, manufacturing and commercialization of denifanstat in Greater China is an example of this strategy.

Overview of MASH

MASH is an aggressive form of MASLD, a condition where an abnormal buildup of excess fat (known as steatosis) occurs in the liver unrelated to the consumption of alcohol. MASLD encompasses a progressive and histologically-defined range of liver diseases including simple steatosis (the presence of excess liver fat without inflammation or fibrosis) to MASH without fibrosis (excess liver fat with inflammation), to MASH with fibrosis and may ultimately lead to cirrhosis or cancer of the liver. Patients with moderate to severe disease, who have advanced fibrosis (F3) or cirrhosis (F4), have the highest risk of liver-related outcomes such as decompensation, hepatocellular carcinoma, and liver transplantation. There are few approved treatments for non-cirrhotic MASH (stages F1, F2 and F3 fibrosis) and no approved treatments for cirrhotic MASH (F4).

MASH is initiated and propagated through several processes driven by excess fat in liver cells.

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Figure 2. Excess liver fat drives three key diseases processes​

Excess intracellular fat damages hepatocytes, the predominant cell type in the liver, leading to apoptosis, or cell death. Hepatocyte apoptosis triggers the stimulation of specialized immune cells. The increased activity of these cells drives inflammation in the liver. Additionally, as more hepatocytes are destroyed and inflammation increases, hepatic stellate cells are stimulated and induce fibrotic scarring. As this progressive cycle continues, the functions of the liver become compromised, potentially necessitating transplantation.

The diagnosis and severity of the disease can be assessed by histological analyses of liver tissue taken by biopsy which examine the degree of steatosis, inflammation and fibrosis using a microscope. For example, NAS is the most widely used histological grading and staging score and is a compilation of scores measuring steatosis, ballooning and inflammation. Additionally, the severity of fibrosis is scored on a 5-level scale of F0 (no fibrosis) to F4 (cirrhosis). NAS, along with the fibrosis stage, indicate the degree of progression of an individual’s disease. In addition to liver biopsy, non-invasive approaches for the diagnosis of MASH are becoming increasingly prevalent and may eventually replace liver biopsy as further data becomes available. As part of its December 2018 MASH draft guidance, the U.S. Food and Drug Administration (FDA) emphasized the importance of non-invasive biomarkers in accurately diagnosing and assessing various degrees of MASH. The FDA encouraged sponsors to include non-invasive biomarkers in clinical trials for MASH with the goal of ultimately supplanting liver biopsy. Recently, in August 2025, the FDA accepted a Letter of Intent (LOI) for vibration-controlled transient elastography (VCTE) as a reasonable surrogate endpoint for assessing response to investigational drugs in non-cirrhotic MASH.

MASLD is a growing epidemic. According to a study published in 2023, MASLD affected more than 1.6 billion people worldwide as of 2019, 265 million of whom had MASH. In a separate study published in 2018, the prevalence of MASH in the United States was estimated at 17.3 million in 2016 and expected to grow to 27.0 million by 2030. Of the MASH patients in the United States, 1.4 million had cirrhotic MASH (F4) in 2016, which is our initial target patient population for the combination of denifanstat and resmetirom, if approved. The number of cirrhotic MASH (F4) patients is expected to grow to 3.5 million in 2030. According to a study published in 2022, when MASH is left unchecked, over time approximately 10%-20% of patients with MASH will progress to liver cirrhosis (histological stage F4). Once cirrhosis has developed, the risk of developing a major complication is 17%, 23%, and 52% at one, three, and 10 years, respectively. The survival of patients with MASH cirrhosis falls markedly once decompensation occurs, with a median survival of approximately two years. Conversely, histological regression of cirrhosis has been shown to reduce the risk of cirrhosis-related complications by six-fold. According to a study published in 2022, in the United States alone, the economic burden of MASH has been estimated to be over $222 billion.

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Figure 3. MASLD disease progression and epidemiology​

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MASH treatment landscape

MASH is characterized by the build-up of fat in the liver and various degrees of inflammation and fibrosis along with systemic metabolic changes including dyslipidemia (increased fat levels in blood) and insulin resistance. These parameters provide a framework to classify the various treatments under development and their mechanisms of action, many of which have significant limitations or address only a subset of MASH patients. Treatments that primarily address the build-up of fat in the liver and systemic metabolic changes include enzyme-specific inhibitors, nuclear receptor modulators, gene expression modulators, growth factor analogs and drugs that induce weight loss. Other approaches attempt to directly target only inflammation and fibrosis.

Enzyme-specific inhibitors in the lipid synthesis pathway target an enzyme in the de novo lipogenesis (DNL) pathway to return lipid synthesis to a normal level, reduce liver fat, and minimize the ongoing inflammation and fibrosis in MASLD and MASH patients, ultimately allowing the liver tissue to regain its normal cellular structure and function. FASN and acetyl-CoA carboxylase (ACC) are examples of enzyme inhibitors, both of which have shown significant clinical improvements in fat reduction, and improvements in biomarkers of liver enzymes, inflammation and fibrosis. ACC inhibitors, unlike FASN inhibitors, have also been shown to increase plasma triglyceride levels in MASH patients. This is particularly problematic for MASH patients who typically have an elevated risk for cardiovascular disease.

Nuclear receptor modulators alter the gene expression pattern of cells, affecting multiple biochemical pathways, which can lead to unintended changes beyond the target pathway of interest. Examples of nuclear receptor modulators studied as therapeutic targets in MASH include farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, and thyroid hormone receptor beta (THR-ß) agonists. FXR is expressed in a number of tissues throughout the body, including the liver. It serves as a receptor for bile acids and participates in regulating their metabolism, including synthesis, conjugation, absorption, and secretion. The PPAR family of receptors modulate fatty acid metabolism and energy homeostasis. FXR and PPAR agonists have had mixed clinical results to date. The FDA approval of THR-ß agonist Rezdiffra (resmetirom) in March 2024 and by the European Commission in August 2025 for the treatment of MASH in patients with moderate to advanced liver fibrosis represents a significant advancement in the MASH space. Activation of hepatic THR-ß is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. These results suggest that directly targeting liver fat metabolism can be a successful therapeutic strategy in MASH. However, it should be noted that therapeutic nuclear receptor modulation is not without safety risk. FXR agonists can affect pathways leading to excess bile acids, which have long been shown to be toxic. This can cause pruritus, or itching of the skin. PPAR agonists have been associated with weight gain. THR-ß agonists need to be highly selective for the beta isoform of this receptor and avoid binding the alpha isoform, which exists in the heart and kidneys. If not highly selective, they can result in significant, potentially life-threatening complications.

Growth factor analogs attempt to mimic natural proteins, such as FGF21, to bring several disordered systems back to normal levels. In two clinical trials in patients with F2-F3 fibrosis, FGF21 analogs showed evidence of MASH resolution and improvement in liver fibrosis after 48 or 96 weeks of treatment, respectively. Data showed that an FGF21 analog administered for 96 weeks induced regression

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of histological cirrhosis (F4). Gastrointestinal side effects are common with injected FGF21, nausea and diarrhea being the most common. Data from two clinical trials, one in patients with F2-F3 fibrosis and the other in patients with F4 fibrosis, demonstrated that an FGF21 analog was associated with a decrease in bone density that can potentially lead to an increased risk of fractures. Because of the large size of proteins, the mode of delivery is typically limited to injection. Growth factor analogs are also more expensive to manufacture compared to small molecules. We believe there is a possibility that patients will develop neutralizing antibodies against these therapeutics with chronic treatment.

Glucagon-like peptide 1 (GLP-1) analogs are approved to treat diabetes and obesity; and one GLP-1 analog is approved for the treatment of MASH in adult patients with moderate to advanced liver fibrosis in the United States. In Phase 2 and Phase 3 clinical trials in F2-F3 fibrosis, treatment with a GLP-1 analog or GLP-1-containing medications, reduced body weight, demonstrated histological MASH resolution, reduced biomarkers associated with MASH and achieved improvement in fibrosis compared to placebo. In addition, a Phase 2 clinical trial with a GLP-1 receptor agonist failed to demonstrate improvement in F4 fibrosis. Gastrointestinal side effects are common with injected or oral GLP-1 medications, with nausea and vomiting being the most common.

Our lead drug candidate—denifanstat in MASH

Denifanstat, formerly known as TVB-2640, an oral, once-daily pill, is our selective FASN inhibitor currently being developed for the treatment of MASH. Following a robust translational research program in multiple preclinical models that demonstrated FASN inhibition reduced liver fat, decreased inflammatory cells and molecules and blunted fibrosis and a proof-of-mechanism Phase 1b clinical trial that demonstrated inhibition of hepatic DNL in humans, we initiated two Phase 2 clinical trials in patients with MASH: FASCINATE-1 and FASCINATE-2. Treatment with denifanstat favorably altered biomarkers of MASH in our Phase 2 clinical trials as shown in the figure below.

Figure 4. Comprehensive improvement across biomarkers​​

The Phase 2 FASCINATE-1 clinical trial examined multiple doses of denifanstat, ranging from 25mg to 75mg daily, administered for 12 weeks compared to placebo in 142 patients in the United States and China. Denifanstat caused a rapid and robust reduction in liver fat that was statistically significant in the 50mg cohort, as well as improvements in inflammatory, fibrotic and cardiometabolic components of the disease in this short time period and was generally well tolerated at dose levels of 25mg and 50mg once-daily in these diverse populations. The 50mg dose was selected for further study.

Our Phase 2b FASCINATE-2 clinical trial examined the impact of 50mg denifanstat for one year on the livers of biopsy confirmed MASH patients with moderate to advanced fibrosis (F2-F3). In January 2024, we announced that denifanstat had met both primary endpoints and multiple secondary endpoints in the Phase 2b FASCINATE-2 clinical trial evaluating denifanstat in 168 biopsy-confirmed MASH patients with stage F2 or F3 fibrosis compared to placebo at week 52. The trial results were published in October 2024 in The Lancet Gastroenterology & Hepatology.

●Both primary endpoints were met:

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●A ≥2-point reduction in NAS (NAFLD Activity Score) without worsening of fibrosis in both modified intention to treat (mITT) and intention to treat (ITT) populations (mITT population: denifanstat 52% vs. placebo 20%, p=0.0003; ITT population: denifanstat 38% vs. placebo 16%, p=0.0035), and

●MASH resolution without worsening of fibrosis with ≥2-point reduction in NAS (mITT population: denifanstat 36% vs. placebo 13%, p=0.0044; ITT population: denifanstat 26% vs. placebo 11%, p=0.0173).

●Multiple secondary endpoints were met, including:

●The 2 histology endpoints used by the FDA for accelerated approval in Phase 3 programs; fibrosis improvement by ≥ 1 stage with no worsening of MASH (mITT population: denifanstat 41% vs. placebo 18%, p=0.0102) and MASH resolution with no worsening of fibrosis (mITT population: denifanstat 38% vs. placebo 16%, p=0.0043). MRI-derived proton density fat fraction (MRI-PDFF) response relative to placebo (mITT population: denifanstat 65% vs. placebo 21%, p<0.0001). MRI-PDFF responders are patients with ≥8% liver fat content at baseline who achieve a ≥30% relative reduction of liver fat at the end of treatment.

Denifanstat demonstrated anti-fibrotic activity, including in patients with advanced fibrosis, based on results in the F3 mITT population and qF4 patients (qF4 patients are AI-defined F4, based on the second harmonic generation (SGH) HistoIndex platform, which may encompass late stage F3 as well as F4 patients):

●Fibrosis improvement by ≥ 1 stage with no worsening of MASH (F3 mITT population: denifanstat 49% vs. placebo 13%, p=0.0032).

●Fibrosis improvement by ≥ 2 stages with no worsening of MASH (mITT population: denifanstat 20% vs. placebo 2%, p=0.0065; F3 mITT population: denifanstat 34% vs. placebo 4%, p=0.0065).

●A statistically significant difference in progression to cirrhosis (F4) (mITT population: denifanstat 5% vs. placebo 11%, p=0.0386).

●A statistically significant difference in fibrosis improvement by ≥ 1 stage with no worsening of MASH for patients on a stable background dose of a GLP-1 Receptor Agonist (mITT population: denifanstat 42% vs. placebo 0%, p=0.034).

●Decrease of 1 or 2 qFibrosis stages in 85% of qF4 patients as measured by AI-based pathology (SGH, HistoIndex).

●Statistically significant liver fibrosis regression in the portal and peri-portal regions (observed with AI-based digital pathology), which have been recently linked to MALO and mortality as measured by AI-based composite scores.

●A statistically significant VCTE improvement (VCTE <= -30% and VCTE < 10KPa) at week 26 (mITT population: denifanstat 32% vs. placebo 13%, p=0.02) and at week 52 (mITT population: denifanstat 42% vs. placebo 13%, p=0.0009).

Other key results of the Phase 2b FASCINATE-2 clinical trial included:

●A statistically significant increase in polyunsaturated triglycerides (potential for cardiovascular benefit) at the end of 52 weeks of treatment (mITT population: +42% denifanstat vs. -4% placebo, p<0.001).

●A biomarker of denifanstat activity (tripalmitin) showed an early and sustained reduction in de novo lipogenesis at 4-weeks (-2.4ug/mL with denifanstat vs. -0.4ug/mL placebo, p=0.001) and 13-weeks (-2.2ug/mL with denifanstat vs. -0.1ug/mL placebo, p=0.005) in the ITT population.

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Figure 5. FASCINATE-2 liver biopsy analysis at Week 52, primary and secondary endpoints

Cochran-Mantel-Haenszel Test – two sided at the 0.05 significance level. * ≥1-point improvement in ballooning or inflammation.

Loomba R, et al. Lancet Gastroenterol Hepatol. 2024;9(12):1090-1100

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Figure 6. FASCINATE-2 liver biopsy analysis at Week 52, secondary endpoints

In the study, the ITT definition was consistent with the FDA’s historical recommendation that patients without a second biopsy be considered treatment failures.

As in prior studies, denifanstat was generally well tolerated. No treatment-related SAEs were observed, and the majority of AEs were mild to moderate in nature (Grades 1 and 2). There were no Grade ≥3 treatment-related AEs and no drug-induced liver injury (DILI) signal in the study. The most common treatment-related AEs by system organ class (observed in ≥5% of patients in the study) were eye disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders. The incidence of TEAEs leading to treatment discontinuation was 19.6% in the denifanstat group compared to 5.4% in placebo.

In October 2024, the FDA granted Breakthrough Therapy designation to denifanstat for the treatment of non-cirrhotic MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Treatments that receive Breakthrough Therapy designation must target a serious or life-threatening disease and preliminary clinical evidence must indicate that the drug may demonstrate a substantial improvement over existing therapies on one or more clinically significant endpoints. Breakthrough Therapy designation of denifanstat was supported by positive data from the Phase 2b FASCINATE-2 clinical trial in biopsy-confirmed MASH patients with stage 2 or stage 3 fibrosis. In October 2024, we completed successful end-of-Phase 2 interactions with the FDA.

Mechanisms of action in MASH

FASN is a key enzyme in the DNL pathway that converts metabolites of dietary sugars such as fructose into palmitate, a saturated fatty acid. Excess DNL activity and palmitate drive the hallmarks of MASH through accumulation of triglyceride in hepatocytes, and induction of inflammatory responses. The amount of FASN expressed and the DNL pathway activity are increased in the livers of patients with metabolic syndrome or MASLD compared to healthy individuals. Increased DNL activity in hepatocytes leads to the

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accumulation of excess fat (steatosis) in the liver. This initiating event drives MASH, and causes liver inflammation, tissue damage, and fibrosis. In addition, inflammatory cells require DNL for pro-inflammatory function, and hepatic stellate cells, which generate fibrotic scar tissue in the liver, require DNL to express profibrotic genes including procollagen. Furthermore, palmitate, the product of FASN, is used to synthesize pro-inflammatory and pro-fibrotic molecules called lipotoxins which contribute to the mechanisms driving the progressive nature of MASH. This places FASN at the nexus of three major drivers of liver damage in MASH: excess intracellular fat synthesis, inflammation and fibrosis.

We believe that inhibiting FASN has the potential to minimize side effects in MASH patients for several reasons. First, the enzymatic inhibition of FASN is targeted and directly acts within the DNL pathway, unlike nuclear receptor modulators such as THR-ß or FXR agonists that activate multiple transcription pathways. Second, FASN is aberrantly overactivated in the liver in MASH, and normalizing activity through inhibition of FASN may avoid side effects. Furthermore, mice genetically engineered to have the FASN gene knocked-out in their livers appear normal, whereas mice with the ACC gene, an enzyme one step earlier in the lipid synthesis pathway, knocked-out have high liver and plasma triglycerides.

Figure 7. Denifanstat impacts key drivers of MASH​

We believe that denifanstat has the potential to alleviate MASH by inhibiting FASN and thereby impacting key drivers of MASH by:

1.Blocking liver fat accumulation (steatosis) by reducing liver fat synthesis in hepatocytes;

2.Minimizing inflammation by blocking the activation and cytokine secretion by inflammatory cells; and

3.Reducing fibrosis by blocking the activation and fibrogenic activity of stellate cells.

Figure 8. The cycle of MASH pathogenesis​

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The diagram above of the cycle of MASH pathogenesis shows how excess dietary sugar, particularly in someone with decreased sensitivity to insulin, produces excess palmitate in hepatocytes leading to fatty hepatocytes. The high level of palmitate, a lipotoxin, creates metabolic stress in these cells, leading to ballooned hepatocytes, which is evidence of cellular damage. These damaged hepatocytes undergo apoptosis. The cellular debris resulting from apoptosis stimulates inflammatory cells in the liver, eliciting an inflammatory response. This damage and inflammation in the liver stimulates hepatic stellate cells, which trigger fibrotic responses. As additional excess sugars come in via the diet, this process continues, leading to build up of fibrotic scar tissue. If the damaging environment is removed, the liver has the potential to regenerate healthy tissue over time. However, if the damaging environment continues to persist, some patients will progress to cirrhosis and may develop hepatocellular carcinoma.

Recent studies, including evidence presented at the European Association for the Study of the Liver in Paris, France in 2018 and a clinical trial that measured DNL in MASH patients with cirrhosis (2022; Lawitz et al.), have shown that the liver also continues to produce fat in the later stages of MASLD, including in patients with early stages of cirrhosis. This broadens the number of patients who could benefit from FASN inhibition. These late-stage patients can progress to liver cirrhosis, which can lead to acute liver decompensation events that can be life threatening, require hospitalization, and in the case of decompensated cirrhosis, liver transplant. We believe the three-pronged potential mechanism of action of denifanstat could address these patients with MASH cirrhosis, preventing further liver damage.

Combination therapy for MASH treatment

Currently there are few approved treatments for non-cirrhotic MASH (stages F1, F2 and F3 fibrosis) and no approved treatments for cirrhotic MASH (F4). Clinical results of single agent trials have often been modest, with the majority of patients not responding. Combination therapy may increase the depth and breadth of clinical response across patient populations and decrease tolerability concerns for the treatment of MASH. The magnitude of patients combined with the disease complexity support the concept that multiple combinations of drugs targeting different mechanisms will be required to effectively manage this disease in a large, diverse population.

Based on its proposed mechanism of action, we believe that denifanstat, if successfully developed and approved, has the potential to be a backbone therapy and improve clinical activity in combination with a broad set of other drugs. Denifanstat’s convenient once-a-day oral administration and tolerability profile make it a potentially desirable combination partner. The activity of denifanstat may be further empowered by additional drugs targeting other aspects of MASH or metabolic disease.

Our combination strategy is to use preclinical models to mechanistically evaluate the combination potential prior to considering clinical studies with the combination. We focused on combination partners that have clinical validation in MASH, and complementary mechanism of action to denifanstat. We have experience with models of human liver microtissues, human liver slices, and murine models; these models and others continue to be refined in order to provide information that guides identification of mechanisms and drugs that would exhibit a significant benefit for combination therapy.

We have tested a combination of a FASN inhibitor (TVB-3664, a surrogate for denifanstat) and a THR-ß agonist in two in vivo preclinical MASH models, and data showed that the combination of a FASN inhibitor and resmetirom had a synergistic effect on important liver disease markers, including improvement of NAS (NAFLD Activity Score) by histologic analysis and more robust improvement in hepatic collagen content compared to the single agents. Synergistic activity of the combination was demonstrated in the rate of histological improvement (NAS ≥2 points). The FASN inhibitor monotherapy showed 33% improvement, resmetirom monotherapy showed 25% improvement, and the combination of the two showed an 80% improvement, a level of improvement that greatly exceeds a simple addition of the activity of the two drugs. Therefore, the complementary mechanisms of denifanstat (inhibiting fat synthesis) and THR-ß (increasing fat removal) might further normalize liver fat in MASH patients and might improve clinical activity on fibrosis endpoints. Building on the combination data, we initiated in October 2025 a Phase 1 clinical trial to evaluate the PK of a combination of denifanstat and resmetirom. The Phase 1 PK trial of denifanstat and resmetirom was an open-label, 2-cohort study that enrolled 40 healthy adult participants. The objectives were to evaluate multiple-dose and single-dose pharmacokinetics, identify any potential DDIs, and assess the safety and tolerability of the combination. In December 2025, we announced the completion of the Phase 1 PK trial. The combination of denifanstat and resmetirom was generally well-tolerated over the duration of the study, with no safety signals. No SAEs occurred, and there were no clinically significant laboratory AEs, and no treatment-related discontinuations. We plan to use these data to advance the development of the combination into a Phase 2 proof-of-concept efficacy trial for patients living with MASH with F4 fibrosis, subject to consultation with regulatory authorities.

We have also evaluated a GLP-1 agonist in a preclinical mouse combination study. In November 2023, at the 7th Obesity and NASH Drug Development Summit, we presented the results of a study assessing treatment with FASN inhibitor alone, semaglutide alone, or combination of FASN inhibitor with semaglutide for 12 weeks in a MASH mouse model. FASN inhibitor or semaglutide alone improved

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NAS and decreased several biomarkers associated with MASH. Only the FASN inhibitor, but not semaglutide, showed significant reduction of liver fibrosis by a digital AI pathology assessment. FASN inhibitor and semaglutide in combination showed further histological improvement of NAS and liver fibrosis compared to treatment with FASN inhibitor alone or semaglutide alone. In addition, data from the Phase 2b FASCINATE-2 trial in a small subset of patients on a stable GLP-1 dose showed a statistically significant superior response in liver fibrosis improvement by more than one stage without worsening of MASH when patients received denifanstat in addition to GLP-1 therapy, versus with placebo. We believe such data support further clinical evaluation of denifanstat and GLP-1 combination therapy for MASH.

We may conduct exploratory clinical trials with relatively short durations to evaluate combinations of denifanstat and other complementary mechanisms. These trials would allow us to evaluate potential improvements in non-invasive biomarkers directly in MASH patients and select combinations for further development.

MASH clinical program

Denifanstat has been studied in over 1,200 people to date including healthy volunteers, patients with solid tumors, patients with acne, and patients with MASH. In MASH, we completed a Phase 2 clinical trial, FASCINATE-1, which examined multiple doses of denifanstat from patients in both the United States and China. We completed a Phase 2b trial, FASCINATE-2, in patients with biopsy-confirmed MASH with moderate to advanced fibrosis (F2-F3). FASCINATE-1 examined doses ranging from 25mg to 75mg daily for 12 weeks and demonstrated improvement in non-invasive measurements of steatosis, inflammation, fibrotic and metabolic parameters. FASCINATE-2 evaluated the 50mg dose daily for one year. In January 2024, we announced positive topline results at week 52 from our Phase 2b FASCINATE-2 clinical trial. The Phase 2b FASCINATE-2 clinical trial achieved statistically significant results on primary and multiple secondary endpoints at week 52 in 168 biopsy-confirmed MASH patients. Further, in December 2025, we announced completion of our Phase 1 PK trial of a combination of denifanstat and a THR-β agonist, resmetirom.

Phase 1 PK clinical trial of a combination of denifanstat and resmetirom

In December 2025, we announced the completion of the Phase 1 PK trial of a combination of denifanstat and a THR-β agonist, resmetirom. The Phase 1 PK trial of denifanstat and resmetirom was an open-label, 2-cohort study that enrolled 40 healthy adult participants. The trial objectives were to evaluate multiple-dose and single-dose pharmacokinetics, identify any potential DDI, and assess the safety and tolerability of the combination. The combination of denifanstat and resmetirom was generally well-tolerated over the duration of the study, with no safety signals. No SAEs occurred, and there were no clinically significant laboratory AEs, and no treatment-related discontinuations.

Our combination program builds upon preclinical data we presented at the EASL Congress in 2024 for two mouse models of MASH, showing that the combination of a FASN inhibitor (TVB-3664, a surrogate for denifanstat) and resmetirom had a synergistic effect on important liver disease markers, including improvement of NAS by histologic analysis and more robust improvement in hepatic collagen content compared to the single agents. Synergistic activity of the combination was demonstrated in the rate of histological improvement (NAS ≥2 points), which was 33% for FASN inhibitor monotherapy, 25% for resmetirom monotherapy, and 80% for the combination of the two, a level of improvement that greatly exceeds a simple addition of the activity of the two drugs.

We plan to use these data to advance the development of the combination into a Phase 2 proof-of-concept efficacy trial for patients living with MASH with F4 fibrosis, subject to consultation with regulatory authorities.

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Phase 2b FASCINATE-2 clinical trial

Phase 2b FASCINATE-2 clinical trial design

Figure 9. Phase 2b FASCINATE-2 clinical trial design​

The Phase 2b FASCINATE-2 clinical trial was a randomized, placebo-controlled, double-blind clinical trial, which enrolled 168 biopsy-confirmed MASH patients with F2-F3 fibrosis confirmed by liver biopsy and randomized overall 2:1 to receive 50mg of denifanstat or placebo for 52 weeks. Following 52 weeks of therapy, a second liver biopsy was obtained. A central pathologist who is unaware of the patients’ assignment to denifanstat or placebo cohorts evaluated these biopsies. Patients were followed for an additional four weeks after the biopsy for safety. The primary efficacy endpoints were histological improvement at week 52 in NAS ≥2 points (with ≥1 point improvement in ballooning or inflammation) and without worsening of fibrosis (by NASH Clinical Research Network (CRN) fibrosis score); OR resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis score) and ≥2 points improvement in NAS at Week 52. Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. The study also had multiple secondary endpoints including fibrosis improvement without worsening of MASH and MASH resolution without worsening of fibrosis, as well as AI-based digital pathology assessment of liver biopsies.

Phase 2b FASCINATE-2 clinical trial results

In January 2024, we announced positive topline results at week 52 from our Phase 2b FASCINATE-2 clinical trial. The Phase 2b FASCINATE-2 clinical trial achieved statistically significant results on primary and multiple secondary endpoints in 168 biopsy-confirmed MASH patients with stage F2 or F3 fibrosis compared to placebo at week 52, including statistically significant improvements in MASH resolution without worsening of fibrosis with ≥2-point reduction in NAS (denifanstat 36% vs. placebo 13%, p=0.0044), and ≥2-point reduction in NAS without worsening of fibrosis (denifanstat 52% vs. placebo 20%, p=0.0003). Denifanstat-treated patients showed statistically significant fibrosis improvement by ≥ 1 stage with no worsening of MASH (denifanstat 41% vs. placebo 18%, p=0.0102) showed statistical significance in fibrosis improvement as measured by an AI digital pathology-based qFibrosis assessment. Analyses of liver fat showed a greater proportion of MRI-PDFF ≥30% responders relative to placebo (denifanstat 65% vs. placebo 21%, p<0.0001).

The p-value is a measure that states the probability that a comparable or better result would be produced purely by chance. Differences with a p-value of <0.05 are generally considered statistically significant, indicating a high degree of confidence that the measured result was due to administration of the drug and not due to chance.

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Liver fibrosis and MASH resolution

Figure 10. Liver fibrosis and MASH resolution

Liver fibrosis is associated with prognosis in MASH. As shown in Figure 11 below, denifanstat demonstrated a decrease of 0.3 (p=0.0023) in qFibrosis Continuous Value (HistoIndex, plc) versus an increase of 0.1 in placebo at week 52. AI-based digital pathology further corroborates and expand the findings from conventional pathology.

Figure 11. Fibrosis analysis using AI-based digital pathology

Vibration-controlled transient elastography

Figure 12. Vibration-controlled transient elastography

Treatment with denifanstat resulted in 32% (p=0.02) of patients becoming VCTE responders compared with 13% in placebo at week 26, and 42% (p=0.0009) of patients becoming VCTE responders compared with 13% in placebo at week 52. VCTE measures liver stiffness and responders above are defined as patients who achieve ≥30% relative reduction of VCTE score from baseline, and a score

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of <10kPa. Longitudinal data supports the use of liver stiffness measured by VCTE as a pragmatic noninvasive indicator of treatment response in MASH. A >=30% reduction in VCTE has been associated with improved clinical outcomes, while an achievement of an absolute VCTE <10 KPa corresponds to regression into a lower risk disease category.

Liver fat biomarker: MRI-PDFF imaging

Figure 13. Liver fat biomarkers

Treatment with denifanstat resulted in 65% (p<0.0001) of patients becoming MRI-PDFF responders compared with 21% in placebo. MRI-PDFF responders achieve ≥30% relative reduction of liver fat. A meta-analysis of several clinical trials showed that patients who experience a ≥30% relative reduction of liver fat had a 7-fold higher likelihood that the biopsied liver tissue in these responders would show a ≥2 point improvement in NAS and a 5-fold higher rate of MASH resolution.

In addition to liver fat, several inflammation/lipotoxicity, fibrosis and metabolic health biomarkers that are important to MASH were assessed.

Inflammation biomarkers

Figure 14. ALT and AST

●ALT. Denifanstat showed a statistically significant decrease of ALT by 30.6% (p=0.03) versus 16.2% for placebo at week 52. ALT is a liver enzyme often elevated in MASH patients and indicative of hepatic inflammation and damage. Decreasing ALT levels in MASH patients has been shown to correlate with improvements in liver health.

●AST. Denifanstat showed a statistically significant decrease of AST by 26.8% (p=0.027) versus 12% for placebo at week 52. AST is a liver enzyme often elevated in MASH patients and indicative of hepatocyte injury and is associated with fibrosis.

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Fibrosis biomarkers

Figure 15. FAST score

●FAST score. Denifanstat showed a statistically significant decrease of 0.3 (p<0.0001) versus 0.1 in placebo at week 52. The FAST score combines liver stiffness and fat content by Fibroscan® with AST, and is a validated noninvasive marker of fibrosis.

Lipid biomarkers

Figure 16. Lipid biomarkers

●LDL-cholesterol. Denifanstat showed a decrease in LDL-cholesterol levels of 23.1 mg/dL (p>0.05), compared to a decrease of 9.1 mg/dL, with placebo at week 52 in the subset of patients with baseline LDL-c greater than 100 mg/dL. Elevated LDL-cholesterol levels are associated with increased risk of cardiovascular disease and often elevated in MASH patients.

●Total plasma triglycerides. Denifanstat showed a statistically significant increase in polyunsaturated triglycerides of 42%, compared to a decrease of 4.0% with placebo at week 52. Polyunsaturated fatty acids are a class of fatty acids that include omega-3 and omega-6 fatty acids that have been shown to reduce the risk of cardiovascular disease.

We also assessed other laboratory values in patients in the interim cohort as described below:

●Tripalmitin. Denifanstat decreased tripalmitin levels by 2.2 µg/mL (p=0.005) after 13 weeks of treatment compared to -0.1 µg/mL with placebo. Tripalmitin is a triglyceride in which all three fatty acid chains are palmitate. We believe this reduction reflects the reduction of excess palmitate resulting from the inhibition of FASN.

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Safety data

In the FASCINATE-2 clinical trial, the safety population included all 168 subjects enrolled. As in prior clinical trials of denifanstat, no treatment-related SAEs were observed, and the majority of AEs were mild to moderate in nature (Grades 1 and 2). There were no Grade ≥3 treatment-related AEs. The most common treatment-related AEs by system organ class (observed in ≥5% of patients in the study) were eye disorders (denifanstat 15.2%, placebo 16.1%), gastrointestinal disorders (denifanstat 11.6%, placebo 8.9%), and skin and subcutaneous tissue disorders (denifanstat 22.3%, placebo 7.1%). The incidence of TEAEs leading to treatment discontinuation was 19.6% in the denifanstat group compared to 5.4% in placebo. None of the SAEs (denifanstat 12%, placebo 5%) were considered drug-related. Additionally, there was no evidence of DILI and no deaths in the trial.

Phase 2 FASCINATE-1 clinical trial

We completed our Phase 2 FASCINATE-1 clinical trial in 2021 and demonstrated that a once-daily oral dose of 50mg denifanstat for 12 weeks was well tolerated and led to a statistically significant reduction in excess liver fat in patients with MASH, the study’s primary and key secondary endpoints. The 25mg dose level was also well tolerated, and led to non-statistically significant improvements in comparison to placebo. The 75mg dose level was a small, open-label, non-randomized cohort, which was not powered to show statistical significance.

​

Denifanstat demonstrated improvements in biomarkers across all three hallmarks of MASH:

●Liver fat (steatosis): MRI-PDFF

●Inflammation/lipotoxicity: alanine transaminase (ALT), ceramides, CK-18

●Fibrosis: PRO-C3, ELF

Denifanstat also improved multiple biomarkers of metabolic health, including LDL-cholesterol and FGF21. We believe the concordance of improvements observed across multiple parameters in this relatively short time frame supports the potential of denifanstat to treat MASH patients.

Phase 2 FASCINATE-1 clinical trial design

Figure 17. Phase 2 FASCINATE-1 trial design

The Phase 2 trial was conducted over three cohorts. Cohort 1 and Cohort 2 were randomized, placebo-controlled, single-blind, dose escalation clinical trials based in the United States and China. Cohort 3 was a small, open-label, non-randomized trial in the United States to evaluate a higher 75mg dose level which did not demonstrate a discernable benefit and was less well tolerated. Based on these results, we selected the 50mg dose to advance into further clinical development.

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Key enrollment criteria included male and female subjects aged ≥18 years with either biopsy-proven MASH within two years before randomization or magnetic resonance elastography (MRE) ≥2.5 kPa (Cohorts 1 and 2 only); and MRI-PDFF ≥8%. A total of 142 patients were enrolled across the three cohorts, with 112 patients enrolled in the United States and 30 patients enrolled in China.

Cohort 1 clinical activity—United States

Baseline demographics. The median age of patients in Cohort 1 was 55 years, 46% were female, and 93% were white with 72% identifying as Hispanic or Latino. As expected for a MASH population, the median liver fat was 15.6%, the majority of patients had type 2 diabetes and the median body mass index (BMI) was 32.6 kg/m2. Safety data was reported for all 99 patients enrolled in the clinical trial. The primary analysis of clinical activity was performed on 85 patients that had an end-of-treatment MRI-PDFF. Two patients discontinued the trial early due to a TEAE and five patients had an end of treatment MRI-PDFF later than planned between 12 and 16 weeks of treatment as a result of COVID-19 visit restrictions; they were not included in the primary efficacy analysis.

Liver fat biomarker: MRI-PDFF imaging

The primary endpoint of this clinical trial was the percent change in relative liver fat following 12 weeks of treatment, and was statistically significant at 50mg of denifanstat. The patients in the placebo group, on average, had a 4.5% relative increase in liver fat over 12 weeks. In contrast, there was a dose-dependent relative reduction of liver fat of 9.6% (p=0.053) in patients treated with 25mg of denifanstat and of 28.1% (p<0.01) in patients treated with 50mg.

The secondary endpoint of this clinical trial was percentage of subjects with at least a 30% reduction in liver fat at week 12, and was statistically significant at 50mg of denifanstat; 23% of patients in the 25mg arm achieved an MRI-PDFF response (p=ns), defined as ≥30% relative reduction of liver fat, and 61% of patients treated with 50mg of denifanstat achieved a response (p<0.001), compared with 11% of the placebo group, as depicted below.

Figure 18. Liver fat biomarkers. **p<0.01, *** p<0.001​

MRI-PDFF images for one patient treated with 50mg of denifanstat are shown below. The two images were taken 12 weeks apart from one another at the same horizontal position in the patient’s body. The image on the left shows substantial liver fat content, represented by the yellow-green colored portion of the image. After 12 weeks of treatment, this same area no longer had a substantial amount of liver fat, as shown by the lack of yellow-green coloration and presence of the blue background color in the image on the right.

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Figure 19. MRI-PDFF images for one patient treated with 50mg denifanstat​

In addition to liver fat, several inflammation/lipotoxicity, fibrosis and metabolic health biomarkers that are important to MASH were assessed in this clinical trial.

Inflammation/lipotoxicity biomarkers

Figure 20. Inflammation / lipotoxicity biomarkers. *p<0.05, **p≤0.01​

●ALT. Denifanstat showed a statistically significant decrease of ALT up to 22.3% (p<0.01) in a dose-dependent manner. Approximately one-third of the patients in each arm had abnormal ALT levels at baseline. In this subgroup, 33% of placebo patients normalized ALT post-treatment compared to 60% of the patients treated with 50mg of denifanstat.

●CK-18(M30). Denifanstat showed a statistically significant decrease of CK-18(M30) up to 11.7% (p<0.01) in a dose-dependent manner.

●Ceramides. Denifanstat showed a statistically significant decrease in multiple ceramides. Excess accumulation of ceramides, a type of fat often increased in MASH patients, is toxic and leads to inflammation and fibrosis. The decrease in ceramide levels likely reflects the reduction of excess palmitate and suggests an improved inflammatory environment.

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Fibrosis biomarkers

Figure 21. Fibrosis biomarkers. *p<0.05​

●PRO-C3. Denifanstat showed a statistically significant decrease in PRO-C3 levels (measured by ELISA) in a dose-dependent manner. PRO-C3 levels increased in the placebo group by 8.5% and decreased in the denifanstat 50mg-treated group by 8.1% (p < 0.05).

●ELF Score. Denifanstat showed a 0.25 decrease in ELF score compared to a decrease of 0.1 with placebo (p = ns).

Metabolic/lipid biomarkers

Figure 22. Metabolic / lipid biomarkers. *p<0.05 **p<0.01​

●LDL-cholesterol. Denifanstat showed a statistically significant decrease in LDL-cholesterol levels up to 11% (p<0.05) in a dose- dependent manner.

●FGF-21. Denifanstat showed a statistically significant increase in FGF-21 levels up to 57% (p<0.01) in a dose-dependent manner.

Over the course of the clinical trial, we also assessed other laboratory values in the patients as described below:

●Tripalmitin. Denifanstat decreased tripalmitin levels up to 40% (p<0.0001) in a dose-dependent manner.

●Total plasma triglycerides. There were minor elevations of triglyceride levels of 22mg/dL (p=ns) and 13mg/dL (p=ns) in the 25mg and 50mg arms, respectively. In FASCINATE-2, it was observed that the increase in triglycerides was due to a change in composition towards a beneficial polyunsaturated content in the pool of triglycerides.

●Total and HDL cholesterol. Denifanstat decreased total cholesterol levels up to 5.1% (p<0.05) and HDL-cholesterol up to 4.4% (p<0.01) in a dose dependent manner. The ratio of total-cholesterol and HDL-cholesterol (4.4-4.6) did not change in any

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arm in the clinical trial during 12 weeks of treatment, suggesting that the reduction of HDL-cholesterol was indicative of lowered total-cholesterol levels in the blood.

Cohorts 2 and 3

Cohort 2—China. As part of our collaboration with our license partner Ascletis, we evaluated the profile of denifanstat (designated ASC-40 in China) in a small cohort of MASH patients under our FASCINATE-1 protocol in China. We enrolled 30 MASH patients who received either 50mg of ASC40 (n=21) or placebo (n=9) once-daily for 12 weeks. The median age of patients in the China cohort in this clinical trial was 34 years, 23.3% were female, 100% were Asian, median liver fat was 18.0%, and the median BMI was 28.9 kg/m2. In March 2021, we and Ascletis announced results showing ASC40 reduced liver fat with a 50% responder rate in patients treated with ASC40. ASC40 also demonstrated a decrease of ALT by 28% (p=ns) (mean decrease of 31 U/L at week 12). 63% of patients had at least a 17 unit decrease in ALT, a threshold that has been associated with liver fibrosis biopsy response.

Cohort 3—75mg Open-Label. A small, open-label 75mg once-daily cohort was conducted in the United States (N=13 patients) to explore the safety and efficacy of denifanstat at this dose level. The median age of Cohort 3 in this clinical trial was 48 years, 38.5% were female, 100% were Hispanic/Latino, median liver fat was 14.0%, and the median BMI was 28.4 kg/m2. At the end of 12 weeks of treatment, denifanstat 75mg led to a mean relative decline of liver fat content by MRI-PDFF of 35.8% and a responder rate of 57.1%. The liver fat decline was mostly driven by one single patient that had a decline of 82.6%. Denifanstat 75mg once-daily also decreased ALT by 3.2% (9.6 U/L) and LDL cholesterol by 13.5%.

Safety data

Figure 23. FASCINATE-1 safety summary​

Denifanstat was considered well tolerated in the Phase 2 FASCINATE-1 trial at the 25mg and 50mg dose levels, with AEs that were mostly mild and similar among the cohorts. Safety data were collected from all 99 patients, of whom 68 were treated with denifanstat. Overall, 62 (63%) patients experienced at least one TEAE, all of which were assessed by the investigator as Grade 1 or mild except one incidence of Grade 2 urinary tract infection, one incidence of Grade 2 increased appetite at 25mg, and one incidence of Grade 2 shortness of breath at 50mg. All three of these Grade 2 TEAEs resolved without dose adjustment. No denifanstat-related SAEs occurred in any dose group. Overall, the most common TEAEs, regardless of drug-relatedness, among denifanstat-treated patients included headache (six patients; 9%), peripheral edema, rash, and upper respiratory tract infection (four patients; 6%); bronchitis, diarrhea, nausea, and urinary tract infection (four patients; 6%); and hypertriglyceridemia (noted as unrelated to treatment; two patients; 5.7%). Two (3%) patients discontinued denifanstat due to a TEAE: (1) mild eye allergy on day two of the clinical trial and (2) mild conjunctivitis. Both events occurred at the 25mg dose and resolved following discontinuation. No discontinuations for a TEAE were observed in the 50mg dose cohort.

In the Chinese cohort of 30 patients, 21 and nine of whom were treated with denifanstat and placebo, respectively, the 50mg denifanstat daily dose was well tolerated with a benign adverse event profile and no SAEs. Most TEAEs were Grade 1 (11 patients: 52% on denifanstat and 3 patients; 33% on placebo) or Grade 2 (four patients; 19% on denifanstat and two patients; 22% on placebo). No patients in the China cohort discontinued due to a TEAE. Treatment-related AEs, as determined by the investigator, were observed in 13 patients (62%) on denifanstat.

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In the 75mg open-label cohort of 13 patients, there was an increased incidence of TEAEs compared to U.S. patients who received 25mg or 50mg, 23% of TEAES were Grade 1 and 46% of TEAES were Grade 2, including four cases of dry skin (30.8%, including possible palmar-plantar erythrodysesthesia (PPE) syndrome), five cases of dry eye (38.5%) and four cases of hair thinning (30.8%). Hair thinning was not observed in the 25mg or 50mg cohorts. The 75mg cohort had an overall discontinuation rate of 46.2% (N=6) due to AEs. Four patients discontinued treatment due to more than one on-target AE; hair thinning (N=4; 30.8%), dry skin (N=4; 30.8%, including possible PPE syndrome), dry eye (N=2; 15.4%). Two patients (15.4%) discontinued due to one or more AEs of headache, lower abdominal pain, constipation, and diarrhea. All TEAEs were Grades 1 or 2, and there were no SAEs. While the 75mg dose demonstrated clinical activity, the adverse effects, which were reversible, were not balanced by the clinical activity observed. As such, this dose level was not pursued in the Phase 2b FASCINATE-2 trial.

The results from the Phase 2 FASCINATE-1 trial showed that a once-daily, oral dose of 25mg or 50mg of denifanstat for 12 weeks was well tolerated and led to rapid and robust reduction in excess liver fat in patients with MASH, which was statistically significant in the 50mg cohort, in a dose-dependent manner. Additionally, these data showed improvements across steatosis, inflammation/lipotoxicity and fibrosis biomarkers associated with MASH and multiple biomarkers of metabolic health. Based on the results, we elected to use the once-daily, oral 50mg dose in the Phase 2b FASCINATE-2 trial.

Phase 1 DNL clinical trial results

To evaluate the impact of denifanstat on liver fat synthesis in 12 healthy male adults with characteristics of metabolic syndrome, we collaborated with the University of Missouri. Liver fat synthesis was quantified by measuring the conversion of acetate into the product of FASN, palmitate. This measurement was done in each subject once before the subject received denifanstat and again after 10 days of taking a once-daily oral dose of either 50mg, 100mg or 150mg of denifanstat. This second measurement was taken approximately 10 hours after the last dose in order to measure the impact of steady-state drug levels on liver fat synthesis. This trial showed there was a significant reduction of liver fat synthesis at all doses and such reduction occurred in a dose-dependent manner. The 50mg dose reduced peak liver fat synthesis by approximately 26% and the 150mg dose inhibited liver fat synthesis by 78%, as shown in the graphic below. The drug was well-tolerated; one of the four subjects given 100mg and one of the two subjects given 150mg of denifanstat experienced some hair thinning that returned to normal after the drug was stopped. These changes correlated with significant reduction of their skin sebum while on treatment, which returned to normal after drug was stopped.

Denifanstat inhibited DNL in human volunteers

Figure 24. Inhibition of liver fat synthesis in Phase 1 DNL trial​

We believe the results from this clinical trial established the clinical proof of mechanism for denifanstat. The results showed that an oral dose of denifanstat reached the liver of adults who were overweight. By inhibiting FASN, fat synthesis was reduced in the liver. Prior studies have shown subjects with increased amounts of liver fat have an approximately 3-fold higher rate of FASN-mediated DNL compared to subjects with lower liver fat. The conceptual goal of denifanstat treatment in MASH patients is to normalize the rate of DNL; the goal does not include ablation of the pathway. The data from this Phase 1 trial suggested that doses below 100mg should be evaluated for their ability to reduce liver fat by reducing the rate of DNL.

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Phase 1 open-label study in subjects with hepatic impairment

In March 2024, we announced completion of our Phase 1, open-label, pharmacokinetic study of denifanstat in subjects with mild, moderate, or severe hepatic impairment compared to subjects with normal hepatic function.

This Phase 1 hepatic impairment study was designed to test the safety and pharmacokinetics of denifanstat in subjects with hepatic impairment, a standard requirement of the ongoing development program in MASH. This was a non-randomized parallel group study in which 38 subjects were enrolled and completed the study. The study population comprised 8 subjects in each category of mild, moderate or severe hepatic impairment, and 14 healthy subjects with normal hepatic function demographically matched to the hepatic impaired subjects for age, body weight and gender. Subjects received oral denifanstat 50mg a day for 4 days. Denifanstat was generally well-tolerated, and no safety signals were reported. The pharmacokinetic results from the study demonstrated that denifanstat can be studied with patients with F4 fibrosis.

Preclinical studies in MASH models

We characterized the effect of FASN inhibitors in preclinical models of MASH using a comprehensive strategy. We performed mechanistic in vitro studies in isolated human cell types to confirm the mode of action of FASN inhibitors. The in vitro results demonstrated that FASN inhibition via DNL pathway directly targets a) liver fat accumulation in hepatocytes, the initiating event of MASH, b) pro-inflammatory signaling in immune cells, and c) fibrogenesis by hepatic stellate cells, as described below. We used several different in vivo mouse models of MASH that encompass the full physiology of diet induced MASH and liver histology. These models showed consistently that FASN inhibitors had in vivo activity and improved liver health biomarkers including ALT, pro-inflammatory cytokines, and liver histology endpoints of steatosis, inflammation and fibrosis. Collectively, these preclinical results suggest that FASN inhibitors effect change in the histologic parameters of MASH resolution and fibrosis improvement in two distinct ways. Not only do they act by preventing inflammation and fibrosis secondary to the excess accumulation of fat, but they also act by inhibiting inflammation and fibrosis mechanisms directly. In preclinical models of MASH we have also tested FASN inhibitors in combination with other drug classes including a THR- β agonist (resmetirom) and GLP-1 agonist (semaglutide), to evaluate the potential for additive or synergistic effect.

Disease models—direct impact on steatosis, inflammation and fibrosis

Steatosis—FASN inhibition directly reduced lipid accumulation in liver models. In human liver microtissues, denifanstat decreased cellular triglycerides, a marker of lipid accumulation or steatosis. This is a consequence of FASN inhibition leading to decreased hepatic DNL. These findings were extended in animal models where decreased lipid content was observed after FASN inhibitor treatment by Oil Red staining or steatosis by histology.

Inflammation—FASN inhibition directly reduced pro-inflammatory activity in immune cells. Two types of immune cells relevant for inflammation in the liver were used to test the effect of FASN inhibitors on pro-inflammatory activity: human white blood cells and human primary CD4+ T-cells. Human white blood cells were activated with lipopolysaccharide (LPS) or related stimulants, treatment with FASN inhibitors dramatically decreased production of interleukin-1 beta, a pro-inflammatory cytokine. A similar effect was observed in mice fed with a high fat, high cholesterol diet where interleukin-1 beta plus several other pro-inflammatory cytokines and chemokines were reduced. Th17 cells are immune cells that can cause pro-inflammatory damage in the liver and the DNL pathway is important for Th17 cell differentiation and function. In human primary CD4+ T cells, denifanstat significantly reduced the number of Th17 cells and increased the number of regulatory T-cells (Treg). Treg cells are more common in healthy livers and expected to blunt the damage caused by the inflammation producing Th17 and other immune cells.

Fibrosis—FASN inhibition directly reduced activation and fibrogenic activity of human hepatic stellate cells (HSCs). HSCs are the main cell type responsible for fibrosis and the deposition of scar tissue in the liver. HSCs need the DNL pathway to become activated to accomplish fibrogenic activity, which leads to production of fibrotic scar. In the human HSC cell line LX-2, FASN inhibitor decreased expression of several fibrogenic genes, as seen below. This includes the genes encoding collagen 1α1, αSMA, two important markers of HSC activation and pro-fibrogenic activity. The protein levels of collagen 1α1 and SMA were also decreased by FASN inhibitor treatment. These results provide mechanistic evidence that FASN inhibition can directly reduce fibrogenic activity in HSCs. We believe that this would be expected to reduce fibrosis. In more complex disease models such as mice with MASH, decreased expression of fibrogenic markers was also observed after FASN inhibitor treatment.

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Figure 25. Expression of fibrogenic genes

in a human stellate cell line. *p<0.01, **p<0.05, ****p<0.0001​

FASN inhibition not only directly inhibits the fibrogenic activity of stellate cells, but it also removes the fibrogenic stimuli required to activate these cells. These stimuli result from excess fat in hepatocytes. By reducing liver fat via FASN inhibition, the levels of fibrogenic stimuli, including lipotoxins, are reduced. We believe this is an important and unique facet of using FASN inhibition to treat MASH.

Disease models—in vivo activity in MASH

We evaluated the effect of FASN inhibitors in three different mouse models of MASH spanning the spectrum of disease severity: a prevention model, a therapeutic model with diet-induced MASH, and a therapeutic model with diet-induced MASH and advanced fibrosis and tumor formation (FAT-MASH) and also in a MASH model with atherosclerosis. The results showed that FASN inhibition alleviated established features of MASH. For mouse models, we used the FASN inhibitor, TVB-3664, as a surrogate for denifanstat in these experiments due to TVB-3664’s pharmacokinetics in mice. TVB-3664 has a chemical structure highly related to denifanstat and has been shown to inhibit FASN with similar potency.

FASN inhibition ameliorated disease progression in diet-induced MASH mouse model (a therapeutic model). After 44 weeks on a high-fat/fructose/cholesterol diet, mice developed obesity, steatohepatitis and liver fibrosis before FASN inhibitor treatment was initiated for eight additional weeks, while the mice continued the same diet. After treatment with the FASN inhibitor, livers showed reduced steatosis and NAS score, despite being on a diet high in fat, fructose and cholesterol. FASN inhibition also improved biomarkers of liver inflammation, diminished liver triglyceride and cholesterol, and reduced expression of fibrosis biomarkers and fibrosis severity.

A combination of FASN inhibitor with resmetirom was tested in this diet-induced MASH model. After 38 weeks on a high-fat/fructose/cholesterol diet, mice developed obesity, steatohepatitis and liver fibrosis before drug treatment was initiated for up to 12 additional weeks, while the mice continued the same diet. The combination decreased liver fat dramatically within 6 weeks, to resemble that of mice on a normal chow diet, and to a greater extent than FASN inhibitor or resmetirom alone. The combination had a synergistic effect on important liver disease markers, including improvement of NAS (NAFLD Activity Score) by histologic analysis and more robust improvement in hepatic collagen content compared to the single agents. Synergistic activity of the combination was demonstrated in the rate of histological improvement (NAS ≥2 points). The FASN inhibitor monotherapy showed 33% improvement, resmetirom monotherapy showed 25% improvement, and the combination of the two showed an 80% improvement, a level of improvement that greatly exceeds a simple addition of the activity of the two drugs.

A combination of FASN inhibitor with semaglutide was also tested in this diet-induced MASH model. After 38 weeks on a high-fat/fructose/cholesterol diet, mice developed obesity, steatohepatitis and liver fibrosis before drug treatment was initiated for up to 12 additional weeks, while the mice continued the same diet. FASN inhibitor or semaglutide alone improved NAS and decreased several biomarkers associated with MASH. Only the FASN inhibitor, but not semaglutide, showed significant reduction of liver fibrosis by a digital AI pathology assessment. FASN inhibitor and semaglutide in combination showed further histological improvement of NAS and liver fibrosis compared to treatment with FASN inhibitor alone or semaglutide alone. Liver transcriptomic analysis indicated that the FASN inhibitor and semaglutide altered different gene expression pathways, with only FASN inhibitor modifying fibrosis pathways, while the combination had some unique effects on gene expression.

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FASN inhibition had in vivo activity in the diet induced FAT-MASH model with established liver fibrosis and liver cancer (a therapeutic model). In a study performed by our collaborator Professor Scott Friedman at the Icahn School of Medicine at Mt. Sinai Hospital in New York, mice were fed a high-fat, high-sugar diet and given a once weekly injection of carbon tetrachloride, for six months. This toxic chemical causes liver fibrosis in rodent models of MASH. Mice received either placebo or FASN inhibitor for the last three months. After six months, mice in the placebo group had extensive fibrosis evidenced by scar tissue and collagen deposition in their livers as well as liver tumors. This was visualized by the picrosirius red staining of liver slices as shown below (left panel). In contrast, mice that received the FASN inhibitor (middle and right panels) for 12 weeks had significantly less scar tissue and collagen deposition in their livers and, in most cases, less than observed before the drug was started, indicating that FASN inhibition reversed fibrosis despite continued insult to the liver as shown in the figure below. Quantitation of collagen content by digital pathology showed that this decrease is statistically significant, as shown in the graph below. Additionally, animals receiving the FASN inhibitor had overall 85% fewer liver tumors than those receiving placebo and several drug-treated animals had no tumors in their livers at the end of the study. These results were consistent with the documented role of FASN and the DNL pathway in liver fat accumulation, inflammation and fibrogenesis.

Figure 26. FASN inhibitor decreased liver fibrosis in mouse model of MASH. * p<0.05​

FASN inhibition reduced atherosclerosis development in the LDL receptor knockout mouse model of diet-induced MASH with dyslipidemia (a therapeutic model). This MASH model incorporates features of human atherosclerosis. Mice were administered a fast-food diet for 18 weeks to allow development of dyslipidemia, atherosclerosis, and features of MASH including steatohepatitis and liver fibrosis, before FASN inhibitor treatment was initiated at that point in time for 10 additional weeks, while the mice continued the same diet. After treatment with the FASN inhibitor, a reduction in circulating cholesterol and triglycerides was apparent. Histology analysis showed that FASN inhibitor treatment reduced the total atherosclerotic lesion area per cross-section of aortic root. This was accompanied by reduction in several circulating inflammatory markers associated with atherosclerosis such as CCL4 and CXCL2. Liver histology steatosis inflammation and fibrosis also improved with FASN inhibitor treatment. These results show the potential cardiovascular and liver impacts of treatment with a FASN inhibitor, and are consistent with the decreased LDL cholesterol observed with denifanstat versus placebo in FASCINATE-1 and FASCINATE-2 clinical studies in MASH.

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Combination of FASN inhibitor treatment with resmetirom treatment was also tested in this LDL receptor knockout model of diet induced MASH. The combination treatment normalized liver fat levels to that observed in mice on a normal chow diet and decreased both macrovesicular and microvesicular steatosis. The combination significantly decreased collagen production. In addition, the beneficial effect of FASN inhibition on markers of dyslipidemia described above as monotherapy was further improved by combination with resmetirom.

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Precision medicine—enabling the right intervention for MASH patients

We have initiated a comprehensive biomarker program as part of our denifanstat development program. Biomarkers are indicators of the disease state and/or response to treatment, and typically measured using convenient, non-invasive approaches. In addition to disease-associated biomarkers, we are developing two types of biomarkers specific to denifanstat and FASN. We believe the identification of these biomarkers has the potential to prospectively identify appropriate patients that will respond to therapy with denifanstat alone or in combination, monitor treatment response to drive clinical outcomes for MASH patients, and help differentiate denifanstat as a potential therapy for MASH.

MASH, the hepatic manifestation of metabolic syndrome, is a complex, progressive disease, with few approved treatments for non-cirrhotic MASH (stages F1, F2 and F3 fibrosis) and no approved treatments for cirrhotic MASH (F4). With the large and growing global

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MASH population, we believe that it would be beneficial to develop precision medicine approaches to confirm that the drug is having a positive impact based on biomarker assessments, and match MASH patients prior to initiation with the most appropriate treatment for their disease. These approaches potentially provide physicians with a helpful tool to better manage their patients, and increase the market opportunity for denifanstat and for combination treatments that include denifanstat.

Figure 27. Precision medicine strategy​

Drug response biomarkers

Pharmacodynamic (PD) biomarkers are drug response markers and provide evidence that a drug has modulated its target. This is important to test in clinical trials because lack of sufficient target modulation can cause lack of clinical activity. Over the past several years, we identified tripalmitin as a PD biomarker for FASN inhibition in several clinical trials and developed a reliable assay to measure serum tripalmitin in patients. Tripalmitin is a triglyceride with palmitate, a fatty acid produced by FASN, at each of the acyl moieties; therefore, a decrease of tripalmitin confirms FASN inhibition. In the Phase 2b FASCINATE-2 clinical trial, at 50mg denifanstat, tripalmitin showed an early and sustained reduction in de novo lipogenesis at 4-weeks (-2.4ug/mL with denifanstat vs. -0.4ug/mL placebo, p=0.001) and 13-weeks (-2.2ug/mL with denifanstat vs. -0.1ug/mL placebo, p=0.005) in the ITT population.

Figure 28. Tripalmitin levels at 4 and 13 weeks of dosing in Phase 2b FASCINATE-2 ​

We anticipate that other biomarkers may be used in conjunction with PD biomarkers such as tripalmitin to refine and enhance the robustness of demonstrating drug response in treated patients. These markers may include ALT, AST or other parameters that change upon denifanstat treatment.

Predictive biomarkers

We also plan to develop a predictive test to select MASH patients most likely to have an efficacious clinical response.

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This program includes two distinct technical approaches, both using blood samples to identify biomarkers or biomarker panels that may predict clinical response to denifanstat: metabolomic profiling to measure metabolic state, and SNP profiling to incorporate genetic markers associated with metabolic disease. From the FASCINATE-1 clinical trial, we identified a preliminary biomarker signature (termed Sig-A) that predicts liver fat response to denifanstat, based on the metabolomic profile of patient blood samples collected before treatment. We plan to conduct a similar process across clinical trials, including the FASCINATE-2 clinical trial, incorporating data from biomarkers panels with broad metabolomic and proteomic analyses of patient blood samples. Machine learning algorithms will be applied to identify biomarker panels of response.

Additional MASH indications

Non-cirrhotic MASH (F2-F3). According to a study published in 2018, the prevalence of MASH in the United States was estimated at 17.3 million in 2016 and expected to grow to 27.0 million by 2030. Of the MASH patients in the United States, 5.7 million had MASH with advanced fibrosis (F2-F3) in 2016. The number of MASH patients with advanced fibrosis (F2-F3) is expected to grow to 10.6 million in 2030. According to two studies published in 2021 and 2023, when left untreated, MASH can lead to liver cirrhosis, which is currently on par with alcohol as the leading indication for liver transplantation and is expected to surpass alcohol in the coming years. In January 2024, we announced that denifanstat had met both primary endpoints and multiple secondary endpoints in the Phase 2b FASCINATE-2 clinical trial evaluating denifanstat in 168 biopsy-confirmed MASH patients with stage F2 or F3 fibrosis compared to placebo at week 52. In October 2024, the FDA granted Breakthrough Therapy designation to denifanstat for the treatment of non-cirrhotic MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). In October 2024, we completed successful end-of-Phase 2 interactions with the FDA.

Pediatric MASH. According to a study published in 2022, MASH is the most common form of liver disease in children; approximately 10% of children in the United States have MASLD, MASH was observed in 23% of children with MASLD, and 15% have F2-F3 fibrosis. We intend to submit plans to regulatory authorities for the development of denifanstat in pediatric MASH patients. We also plan to conduct toxicology studies in juvenile animals. The information provided could enable the design of a Phase 2 clinical trial in pediatric patients with MASH.

Acne: A highly prevalent skin condition

Acne is the most common skin condition in the United States, affecting up to 50 million Americans annually. Acne usually begins in puberty and affects many adolescents and young adults. Approximately 85% of people between the ages of 12 and 24 experience at least minor acne and the prevalence of severe acne may be as high as 20% of those affected by acne. FASN is responsible through lipid synthesis for the production of skin oils (sebum). More than 80% of key sebum lipids such as palmitate and sapienic acid are produced by DNL/FASN. In acne, excess sebum can lead to skin lesions and is a pro-inflammatory stimulus leading to exacerbation of those lesions, including development of nodules (nodular acne) and cysts (cystic acne). Studies in patients with acne vulgaris demonstrated that levels of sebum palmitate and sebum sapienate (a derivative of palmitate found in the skin) increased by 20% compared to healthy volunteers. Sebum reduction is one of the major mechanisms of isotretinoin (formerly branded as Accutane or Roaccutane), which is widely prescribed for cystic acne. However, isotretinoin has significant side effects including spontaneous abortion, birth defects and depression. Pfizer Inc. completed a Phase 1 clinical trial with a topical ACC inhibitor, which is another DNL inhibitor.

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Figure 29. FASN role in acne​

Acne clinical program

We have shown, in two separate Phase 1 clinical trials, that denifanstat can reduce the amount of sebum on patients’ skin. Sebum samples were collected from patients in the Phase 1 DNL trial described above and in the Phase 1 oncology solid tumor trial described below. Sebum changes were exploratory lipidomic assessments incorporated into these trials to provide a potential non-invasive assessment of pharmacodynamic activity, and not prospectively powered for statistical significance. In the Phase 1 DNL trial, denifanstat reduced total lipid secretion in sebum in a dose-dependent manner by an average of 7% (50mg, n=6), 29% (100 mg, n=4) and 64% (150 mg, n=2) on day 10 of once daily treatment. In the Phase 1 oncology trial that tested higher denifanstat dose levels (typically 150 mg or 200 mg once daily), sebum total triacylglycerol levels decreased from pretreatment levels by an average of 28% on day 8 or 16 (p≤0.05 vs baseline) and by 69% on day 28 (p≤0.05 vs baseline). This included significant reductions in total sapienic acid, a sebum fatty acid produced only by de novo lipogenesis, confirming FASN inhibition. We believe these results provide mechanistic proof of concept for denifanstat in acne.

Phase 3 clinical trial of denifanstat in acne

In June 2025, our license partner for China, Ascletis, announced that denifanstat met all primary and secondary endpoints in its Phase 3 trial in moderate to severe acne vulgaris in China. The Phase 3 clinical trial was a randomized, double-blind, placebo-controlled, multicenter clinical trial of 480 enrolled patients randomized 1:1 to receive denifanstat 50mg or placebo, once daily for 12 weeks.

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Figure 30. Ascletis acne Phase 3 clinical trial design

Ascletis reported the following efficacy data from the Phase 3 trial:

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●All primary endpoints were met, including:

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●the percentage of treatment success (defined as an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-point decrease from baseline) (denifanstat 33.2% vs. placebo 14.6%, p<0.0001).

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●the percentage change in total lesion count (denifanstat -57.4% vs. placebo -35.4%, p<0.0001).

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●the percentage change in inflammatory lesion count (denifanstat -63.5% vs. placebo -43.2%, p<0.0001).

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●The secondary endpoint of change in non-inflammatory lesion count was also met (denifanstat -51.9% vs. placebo -28.9%, p<0.0001).

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Ascletis reported that denifanstat was generally well-tolerated. Following 12 weeks of once-daily oral administration at 50 mg, the incidence rates of TEAE were comparable between denifanstat and placebo.

Figure 31. Ascletis acne Phase 3 clinical trial: All primary and key secondary endpoints met

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In January 2026, Ascletis reported positive topline results in the open-label Phase 3 trial evaluating the long-term safety of ASC40 (denifanstat) tablets in patients with moderate to severe acne in China. The Phase 3 multi-center open-label clinical trial ASC40-304 was designed to determine the long-term safety of denifanstat in patients with moderate to severe acne vulgaris who were previously enrolled in the double-blind, randomized, placebo-controlled 12-week Phase 3 ASC40-303 trial. All subjects in the open-label extension were administered oral denifanstat 50 mg once daily for up to 40 weeks. Subjects who were originally randomized to denifanstat in ASC40-303 study had a total of 52 weeks of denifanstat exposure.

Primary endpoints evaluated safety, and secondary endpoints evaluated efficacy, for up to 52 weeks of denifanstat treatment. Denifanstat was generally well tolerated, with the following:

●TEAEs: Only two categories of TEAEs had an incidence rate of 5% or more, with dry eye syndrome in 5.5% of denifanstat-treated subjects and dry skin reported in 5.2% of denifanstat-treated subjects.

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●AEs: All denifanstat-related AEs were mild or moderate; no denifanstat-related grade 3 or 4 AEs; no AE-related permanent discontinuations; Grade 1 hair thinning in the study was experienced by only one denifanstat-treated patient (which resolved within 8 weeks while remaining in study without a change in dose); no deaths were reported.

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●SAEs: No denifanstat-related SAEs; two non-denifanstat-related SAEs (one breast lump, one contusion), both resolved.

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In December 2025, Ascletis announced that the China NMPA has accepted its NDA for denifanstat for the treatment of moderate to severe acne.

Phase 2 clinical trial of denifanstat in acne

In May 2023, Ascletis Pharma announced positive topline results with the achievement of primary and key secondary endpoints in a Phase 2 clinical trial in 179 patients with moderate to severe acne vulgaris in China. These patients were randomized and dosed with 25mg, 50mg or 75mg of denifanstat (ASC40) or placebo daily for 12 weeks. Ascletis Pharma reported that denifanstat met the primary endpoint of percentage change from baseline in total lesion count at week 12 with median reductions of 53.1% in the 25mg group (p=0.006, n=45), 61.3% in the 50mg group (p=0.008, n=44), and 53.1% in the 75mg group (p=0.008, n=45) versus a reduction of 34.2% with placebo (n=45). The incidence rates of treatment-related AEs were comparable among 25mg (grade 1=28.9%; grade 2=20.0%), 50mg (grade 1=36.4%; grade 2=11.4%), 75mg (grade 1=44.4%; grade 2=17.8%) denifanstat groups and the placebo group (grade 1=35.6%; grade 2=13.3%). The majority of treatment-related AEs were dry eye, and all dose levels had a rate of dry eye similar to placebo (grade 1=28.9%; grade 2=6.6%). There were no denifanstat-related grade 3 or 4 AEs, no treatment-related SAEs and no deaths reported.

Phase 1 clinical trial of TVB-3567 in acne

In June 2025, we initiated a first-in-human Phase 1 clinical trial of our potent and selective small molecule FASN inhibitor, TVB-3567, for development of an acne indication. The Phase 1 clinical trial is a randomized double-blind placebo-controlled trial designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TVB-3567 in healthy participants with or without acne. The trial is comprised of several parts, including single ascending dose cohorts and multiple ascending dose cohorts in participants without acne, followed by testing in participants with acne including evaluation of pharmacodynamic biomarkers. Subject to consultation with regulatory authorities, and contingent on the results of the Phase 1 trial, we anticipate initiating the Phase 2 trial of TVB-3567 in 2026.

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Oncology

Dysregulation of lipid metabolism is a hallmark of cancer. Increased expression of FASN has been associated with poor prognosis and reduced survival in several tumor cell types. While most normal cells get their palmitate from dietary sources, cancer cells have a high requirement of lipids for membrane synthesis and cell signaling to meet the demands of high proliferation. Some cancer cells become dependent upon the FASN pathway for proliferation to provide a reliable and self-sufficient source of fatty acids, referred to as onco-metabolism. This is the case for specific cancers driven by driver oncogenes such as mutant KRAS (KRASM), tyrosine kinase receptors and hormone receptors, such as the androgen receptor. The fatty acids made by FASN are saturated or monounsaturated and therefore relatively resistant to oxidative stress caused by driver oncogenes, which allows the highly proliferating cancer cells to avoid cell death. We believe that this dependence on FASN provides a vulnerability that can be attacked with FASN inhibitors.

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FASN inhibition can also potentially address the enormous challenge of resistance to cancer therapies. Several cancer types have been shown to upregulate FASN to rewire lipid metabolism and change the nature of the tumor cell membrane making these cells resistant to traditional cancer drugs. Use of a FASN inhibitor to normalize metabolism and tumor cell membranes is an appealing strategy to confer susceptibility in combination with a second agent.

The following diagram depicts the role of FASN in the molecular mechanisms associated with cancer:

Figure 32. FASN role in molecular mechanisms associated with cancer.

FASN derived lipids play a structural role in membranes to avoid oxidative stress and create lipid rafts for oncogenic signaling (for example in KRASM or Androgen receptor signaling). This also contributes to resistance to targeted therapies. Palmitate itself (the immediate product of FASN) covalently modifies critical oncogenes to allow them to localize in membranes and function properly (for example KRAS4A). FASN derived lipids are important to create lipid rafts that anchor receptor tyrosine kinases appropriately in the plasma membrane for signaling, and the MET tyrosine kinase is one example of this class.​

FASN inhibitors for oncology program

We are developing FASN inhibitors to treat specific subsets of solid tumors that are FASN-dependent in combination with other classes of oncology drugs. Our first-in-human Phase 1 clinical trial for denifanstat was conducted in patients with advanced solid tumors. The results provided a foundation and path for future clinical trials. The data from our preclinical, translational and clinical studies have identified three FASN-dependent tumor subtypes with potential clinical application, as described below.

Identification of FASN-dependent tumor types

(i) Non-small cell lung cancer (NSCLC) with KRAS mutations: KRAS mutations are among the most common mutant driver genes in NSCLC tumors and these patients have a poor prognosis. KRASM signaling depends on FASN and also depends on reactive oxygen species to maintain its pathogenic nature and high proliferation. Introduction of the KRAS mutation into a NSCLC adenocarcinoma induces the cancer cell to be highly dependent on FASN for proliferation and survival. We have generated preclinical and clinical results that demonstrate the potential of FASN inhibitors for the treatment of NSCLC KRASM, as follows:

●In preclinical screening of a large panel of cancer lines for drug sensitivity, we observed that treatment of NSCLC KRASM cells with FASN inhibitor resulted in cell death, whereas KRAS wild type (KRASWT) are less sensitive. Similar findings were made in mouse models.

●The mechanism that underpins FASN-dependence has recently been demonstrated in published studies using models of human cancer; KRASM tumors hijack the FASN pathway to make membrane lipids that are enriched for saturated or mono-unsaturated triglycerides. These membranes are more robust and resistant to oxygen free radicals that KRASM creates. FASN

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inhibition disrupts this protective circuit meaning that cancer cells need to use poly unsaturated oxidation-prone fatty acids, which leads to stress induced cell death by ferroptosis.

●In our Phase 1 clinical trial in patients with solid tumors (described below), patients with NSCLC KRASM tumors treated with denifanstat exhibited stable disease significantly longer than NSCLC patients who did not have a KRAS mutation. The median time to disease progression was 22 weeks for KRASM versus five weeks for KRASWT (p<0.02, one sided ANOVA). We believe these clinical results with denifanstat validate the preclinical finding that KRASM is FASN-dependent.

●Preclinical combination studies of one of our FASN inhibitors plus a marketed KRASM G12C inhibitor, adagrasib, further decreased the growth of NSCLC KRASM tumors compared to either agent alone.

(ii) Hepatocellular carcinoma (HCC) FASN-dependent: We have generated preclinical results that demonstrate the potential of FASN inhibitors for the treatment of HCC, as follows:

●We have identified a subset of HCC tumors that are FASN-dependent, in a collaboration with Dr. Xin Chen at the University of California, San Francisco. This subset defined as MET-hi, PTEN-lo represents approximately 34% of human HCC, and is defined by high levels of the receptor tyrosine kinase MET and low levels of the tumor suppressor PTEN, which indicates high proliferation activity. Published clinical trials using mouse genetic HCC models support that these cancer pathways are FASN-dependent.

●Treatment of a mouse HCC MET-hi, PTEN-lo model with FASN inhibitor plus the standard of care kinase inhibitor cabozantinib triggered regression of HCC tumors. In addition, FASN inhibitor therapy combined with either cabozantinib or sorafenib, a second standard of care kinase inhibitor, improved the in vivo activity for c-MYC driven HCC.

●We have collaborated with Josep Llovet at Icahn School of Medicine at Mount Sinai, to profile FASN expression in samples from HCC patients. The results generated are consistent with the preclinical combination results with a kinase inhibitor.

●We have collaborated with Scott Friedman at Icahn School of Medicine at Mount Sinai on a preclinical mouse model of MASH with carbon tetrachloride induced fibrosis that develops HCC tumors. Treatment of mice with established liver fibrosis with FASN inhibitor significantly reduced the tumor burden compared to untreated mice. MASH-related HCC is an area that we will explore in bioinformatics analysis.

(iii) Metastatic castration resistant prostate cancer, FASN-dependent: Prostate cancer is a highly lipogenic tumor type. The androgen receptor (AR) is the main driver of disease progression in prostate cancer and upregulates levels of FASN to maintain membrane production and avoid oxidative stress. Several androgen receptor modulators are approved for treatment such as enzalutamide or abiraterone, but resistance emerges leading to relapse, often associated with new variants in AR such as Arv7.

●Preclinical results show that FASN inhibition can decrease the levels of resistance markers to androgen receptor modulators in prostate cancer preclinical models. Combination of FASN inhibitor with enzalutamide had a better anti-tumor effect than either agent alone. These results provided a strong mechanistic basis for conducting a clinical trial combining a FASN inhibitor with an AR inhibitor.

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●We have collaborated with Massimo Loda and David Nanus at Weill Medical College of Cornell University on FASN in prostate cancer. Our collaborators at Weill Medical College are conducting an Investigator Sponsored Study in men with metastatic castration resistant prostate cancer to explore this combination. The results of this Phase 1 study are expected in the first half of 2027.

Phase 1 results in multiple solid tumors

We conducted a first-in-human Phase 1 clinical trial (which included dose escalation) of denifanstat in patients with advanced, heavily pretreated and mostly metastatic solid tumors. We hypothesized that the dose of denifanstat for clinical activity would be higher in cancer patients than in MASH patients, because the objective is to completely shut down FASN activity and cause cell death in cancer, rather than normalize FASN activity. In the Phase 1 clinical trial, 136 patients were treated with denifanstat, 76 treated with denifanstat only (monotherapy), and 60 treated in combination with a taxane, a commonly used class of anti-cancer drugs. The trial identified the maximum tolerable dose as 100mg per square meter of body surface area (100mg/m2), or approximately 150mg to 200mg daily, whether denifanstat was used alone or in combination. Denifanstat monotherapy treatment resulted in a disease control rate (DCR) of 42%.

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Disease control was observed across multiple tumor types, including breast (100%), NSCLC (82%), and gynecological (ovarian and cervical) (53%). We believe these results are promising in these heavily pretreated, advanced stage patients.

In patients treated with denifanstat monotherapy, evaluation of time-to-progression (TTP) among patients with NSCLC revealed notably longer TTP for patients with a mutation in the KRAS gene (KRASM) (N=11) compared to those with a normal, or wild-type, KRAS gene (KRASWT) (N=6) (22 weeks versus five weeks; p<0·02).

Figure 33. Time to progression in Phase 1 oncology trial​

As anticipated, based on prior nonclinical toxicology clinical trial findings, the principal toxicities associated with denifanstat monotherapy were skin and ocular effects, with most being Grade 1 or 2. Common (i.e., incidence >10%) skin effects included alopecia (61%), PPE syndrome (46%), dry skin (22%), skin exfoliation (12%), and rash (11%). Ocular effects included dry eye (17%) and increased lacrimation (13%). Six episodes of serious pneumonitis were experienced by five patients receiving denifanstat and paclitaxel, one of which was fatal, all assessed by the investigator as at least possibly related to both denifanstat and paclitaxel. Pneumonitis was not observed in patients treated with denifanstat monotherapy. ECG and Holter monitoring data revealed no clinically relevant QTc prolongation with denifanstat.

This Phase 1 clinical trial successfully identified a recommended Phase 2 dose of 100mg/m2, which corresponds to 150mg or 200mg in most patients. It also identified several tumor types that may merit further development, including KRASM NSCLC, breast cancer, and ovarian cancer.

The next step would be to conduct additional clinical trials with a FASN inhibitor in tumor subtypes identified from preclinical, translational and the Phase 1 clinical study.

Glioblastoma

GBM is a disease of high unmet need. High FASN expression has been observed in glioblastoma tumors and may be associated with resistance to agents such as bevacizumab.

A Phase 2 investigator sponsored clinical trial was conducted in glioblastoma patients (Grade 4 astrocytoma) by Dr. Andrew Brenner from the University of Texas, San Antonio. In this trial, 25 bevacizumab naïve patients in their first relapse were treated with denifanstat (100mg/m2 once daily) plus bevacizumab (10mg/kg once every 2 weeks). The overall response rate was 56% (complete response 17%, partial response 39%) and six-month progression free survival was 31.4%. This represents a statistically significant improvement in six-month progression free survival over historical bevacizumab monotherapy such as the BELOB study 16% (p<0.01) and met the primary study endpoint. The observed six-month overall survival was 68%, with survival not reaching significance by log rank test (p=0.56). The most frequently reported AEs were PPE syndrome, hypertension, mucositis, dry eye, fatigue and skin infection. Most were Grade 1 or 2 in intensity. Based on these results, in early 2022, Ascletis Pharma initiated a Phase 3 registrational trial in China in patients with recurrent GBM. In September 2023, Ascletis Pharma announced the enrollment of 120 recurrent GBM patients. Ascletis announced cessation of its China GBM program in August 2025.

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Discovery-FASN inhibitors

FASN plays a pathogenic role in several diseases beyond MASH. The overall strategy of our decade long research program followed four core steps: a) identify diseases where FASN contributes to the underlying pathology, b) generate proof of concept data to demonstrate the mechanism of action, c) use precision medicine to identify patient populations enriched for clinical response where feasible and, d) move promising drug candidates into clinical development.

We recognized that the over-activity of FASN may be involved in a number of different human diseases and have discovered and developed specific inhibitors of this enzyme. The goal of our program was to develop small molecule inhibitors of the enzyme that could be delivered orally for ease of use, required no more than two doses daily, and were highly selective for the FASN enzyme in order to avoid unexpected side effects. Early generation FASN inhibitors developed by others suffered poor potency, off target activity, or suboptimal physiochemical or pharmacokinetic properties; none of these entered clinical development. While early FASN inhibitors functioned as substrate competitors, our inhibitors are designed to target co-factor binding sites and avoid these liabilities.

Hundreds of molecules were ultimately designed, synthesized, and tested through iterative cycles, with several emerging as leading candidates based on their laboratory properties. A few were selected for further characterization leading to the identification of denifanstat as the leading candidate for human clinical trials. Our library of FASN inhibitors provides us with the possibility of selecting other compounds for additional indications. For example, we can select a compound from our library with preferred physio-chemical properties for a topical formulation that may be attractive for certain dermatology indications. We selected denifanstat and TVB-3567 out of more than 1,200 compounds within our library of FASN inhibitors.

Competition

MASH

The biopharmaceutical industry is characterized by intense competition and rapid innovation. Accordingly, our competitors may be able to develop other compounds or drugs that are able to achieve similar or better results than our drug candidates. For example, Madrigal Pharmaceuticals, Inc. (Madrigal) announced the approval of resmetirom (commercially available as Rezdiffra) for the treatment of MASH in patients with moderate to advanced liver fibrosis by the FDA in March 2024 and by the European Commission in August 2025. In August 2025, Novo Nordisk A/S announced the FDA approval of Wegovy (semaglutide) for the treatment of MASH in adult patients with moderate to advanced liver fibrosis. Our competitors include multinational pharmaceutical companies, specialized biotechnology companies and universities and other research institutions, including Altimmune, Inc., AstraZeneca, Boehringer Ingelheim and Zealand Pharma, Eli Lilly and Company, Galmed Pharmaceuticals Ltd., Gilead Sciences, Inc., GSK plc (acquired Boston Pharmaceuticals in 2025), Inventiva S.A., Madrigal, Merck & Co., Inc., Novo Nordisk A/S (acquired Akero Therapeutics, Inc. in 2025), Pfizer Inc., Roche Holdings, Inc. (acquired 89bio, Inc. in 2025), Terns Pharmaceuticals, Inc., Viking Therapeutics, Inc., and Zydus Therapeutics Inc. Smaller or earlier-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large, established companies. We believe that the key competitive factors that will affect the development and commercial success of our drug candidates are efficacy, safety and tolerability profile, convenience of dosing, price, the level of generic competition and reimbursement.

Denifanstat could face competition from other classes individually or in combination, pursuing mechanisms including enzyme-specific inhibitors, gene expression activators, growth factor analogs, and anti-inflammation/anti-fibrotics. Given denifanstat’s potential mechanism of action, and its potential complementary mechanism to other therapies, we believe that denifanstat can be used alone or in combination with some of these potential MASH products in development.

Acne

The acne therapeutics market is highly competitive and characterized by a wide range of prescription and over-the-counter products marketed by large pharmaceutical companies, specialty dermatology companies, generic drug manufacturers and consumer healthcare companies.

Current acne treatments include topical therapies, oral systemic therapies, and procedural or device-based approaches, and are prescribed based on disease severity, patient characteristics, physician judgment, and treatment guidelines. Topical therapies are commonly used as first-line treatment for mild to moderate acne and include topical retinoids, antibiotics, benzoyl peroxide, hormonal agents, and fixed-dose combination products. Many topical acne treatments are available as low-cost generics, and branded products compete primarily on formulation characteristics, tolerability, dosing convenience, and physician familiarity. Oral systemic therapies

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are generally prescribed for moderate to severe acne or for patients who do not respond adequately to topical treatments. Oral therapies include antibiotics, hormonal agents, and oral isotretinoin. While oral isotretinoin is highly effective for cystic acne, its use is limited by significant safety considerations, monitoring requirements, and prescribing restrictions. Oral antibiotics are widely used but are generally recommended for limited duration due to concerns related to antibiotic resistance and adverse effects.

In addition, several companies are developing investigational acne therapies, including novel oral agents, new topical formulations, and reformulations or combinations of existing drugs. These product candidates are at varying stages of development and may compete with TVB-3567, if approved.

License agreement with Ascletis

In January 2019, we entered into a license agreement with Ascletis, a subsidiary of Ascletis Pharma, a biotechnology company incorporated in the Cayman Islands and headquartered in Hangzhou, China. The license agreement became effective in February 2019 in connection with the first closing of our Series E financing, which was led by Ascletis and its affiliates through a subsidiary. Under the license agreement, we granted Ascletis an exclusive, royalty-bearing, sub-licensable license under our know-how and patents to develop, manufacture, and commercialize denifanstat and products containing denifanstat-related compounds in the People’s Republic of China, Hong Kong, Macau and Taiwan (referred to herein as Greater China or the Territory). We retained certain manufacturing rights in Greater China and the right to practice our intellectual property in Greater China as necessary to perform our obligations under the license agreement. Ascletis granted us a non-exclusive, sublicensable, royalty-free license under certain intellectual property of Ascletis to develop, manufacture, and commercialize denifanstat and products containing denifanstat-related compounds outside Greater China.

Under the license agreement, we conducted all development activities in connection with the Phase 2 FASCINATE-1 clinical trial in the United States and Greater China at our sole expense, except for certain in-kind contributions by Ascletis in Greater China. Ascletis is solely responsible at its sole expense for conducting development activities in connection with obtaining and maintaining regulatory approvals for denifanstat in Greater China. Ascletis will solely own all regulatory filings and approvals in Greater China other than those regulatory filings jointly applied for in connection with the Phase 2 FASCINATE-1 clinical trial. Further, during the term of the license agreement, Ascletis agreed not to develop, manufacture or commercialize any FASN inhibitors outside the scope of the license agreement in Greater China.

We are eligible to receive development and commercial milestone payments from Ascletis in aggregate of up to $122.0 million. In July 2023, we recognized $2.0 million of revenue related to a development milestone triggered by the initial dosing of a Phase 3 trial for recurrent GBM, of which $1.7 million was received from Ascletis in August 2023, net of applicable taxes, which were recorded in general and administrative expense in the statement of operations and comprehensive loss.

We are also eligible to receive tiered royalty payments from Ascletis ranging from high single digit to mid-teen percentages on annual net sales of denifanstat and other products containing licensed compounds in the Territory, subject to customary reductions. Ascletis’ obligation to pay royalties expires on a product-by-product and region-by-region basis upon the earlier of the expiration of all valid claims covering a product in a region and 10 years following the first commercial sale of a product in a region.

Unless terminated earlier, the license agreement will continue until the expiration of the last to expire royalty payment obligation. Ascletis has the right to terminate the license agreement for any reason or no reason upon 90 days’ written notice. In addition, either party may terminate the license agreement upon the other party’s uncured material breach, insolvency, or bankruptcy. Termination of the license agreement does not terminate the non-exclusive license granted to us by Ascletis, however, in the event of early termination by Ascletis in the case of certain material breaches, we will pay Ascletis single digit royalties on net sales of products outside the territory covered by such non-exclusive license. In the event of early termination for any reason other than by Ascletis for our material breach, Ascletis will transfer all rights to us relating to the products, intellectual property, and regulatory approvals in Greater China, subject to our obligation to pay Ascletis royalties in the low single digit percentages on net sales of any reverted products in Greater China.

In October 2019, we entered into a Patent Assignment Agreement and Patent Re-Assignment Agreement with Gannex, an affiliate of Ascletis and subsidiary of Ascletis Pharma, whereby we assigned to Gannex all our rights, title, and interest in and to all patents and patent applications in China that we previously licensed to Ascletis pursuant to the license agreement. In July 2023, we amended and restated each of the Patent Assignment Agreement and Patent Re-Assignment Agreement to assign additional patents and patent applications to Gannex, effective as of October 2019, which additional patents and patent applications relate solely to licensed compounds under the license agreement, specifically, denifanstat and related compounds, and their use in the treatment of cancers, fatty liver diseases, inflammatory diseases, and diseases related thereto in Greater China. Also in July 2023, we entered into an Assignment

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and Assumption Agreement with Ascletis and Gannex under which Ascletis, while remaining responsible for performance under the License Agreement, assigned all of its rights and obligations under the License Agreement to Gannex and Gannex assumed such rights and obligations, effective as of October 2019. The assignment of patents did not alter the economic terms under the license agreement with respect to the assigned patents and patent applications, and we retained such rights under the assigned patents and patent applications that we had previously retained under the license agreement. Upon early termination of the license agreement for any reason other than by Ascletis for our material breach, Gannex will reassign all assigned patents and patent applications in China back to us. Additionally, we retain control of the prosecution of the pending patent applications assigned to Gannex.

Sales and marketing

We are focused on the discovery and development of our drug candidates. We currently have no sales, marketing or distribution capabilities to commercialize any approved drug candidates. If our drug candidates are approved, we intend either to establish a sales and marketing organization with technical expertise and supporting distribution capabilities to commercialize our products, or to outsource this function to a third party.

Manufacturing

We do not own or operate, and currently have no plans to establish, any manufacturing facilities. We currently rely, and expect to rely, upon third-party CMOs for the manufacture of any drug candidates that we may develop for larger-scale preclinical and clinical testing, as well as for commercial quantities of any drug candidates that are approved. We currently rely on several manufacturers for the production of raw materials, APIs, and the finished products of denifanstat, TVB-3567 and resmetirom, and we believe that there are multiple sources for all raw materials employed in the manufacturing of our drug substances and drug products, and we believe that several CMOs are able to manufacture lots as needed.

Our contracted CMOs have manufactured multiple lots of denifanstat, each one yielding multiple kilograms of drug, and have manufactured the clinical trial supply in both capsule and tablet forms. To date, we have relied on four CMOs based in Europe, the United States and China, as well as our license partner, Ascletis, to produce drug substances and two CMOs in the United States and China, as well as our license partner, Ascletis, to produce drug products, across our programs. We will need to manufacture additional materials to support completion of mid- and late-stage studies such as Phase 2 and Phase 3 trials.

In December 2025, we entered into a license agreement with Assia Chemical Industries Ltd., doing business as TAPI Technology & API Services (TAPI), a subsidiary of Teva Pharmaceutical Industries Ltd. (the TAPI Agreement). Under the TAPI Agreement, TAPI granted us a global, exclusive license to certain intellectual property rights covering innovative forms of TAPI’s resmetirom active pharmaceutical ingredient (API) for our technical evaluation and manufacture, and, if elected by us following an evaluation period, further development of a fixed-dose combination product containing denifanstat and resmetirom.

There are extensive regulations that govern the manufacturing of biopharmaceutical products, and the third-party manufacturing organizations we work with are required to adhere to these. Our CMOs are required to manufacture our drug candidates under cGMP requirements and applicable laws and regulations.

Intellectual property

We strive to protect the proprietary technologies that we believe are important to our business, including pursuing and maintaining patent protection intended to cover the composition of matter of our drug candidates, for example, denifanstat and TVB-3567, their methods of use, related technologies and other inventions that are important to our business. In addition to patent protection, we also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

Our commercial success depends in part upon our ability to obtain and maintain patent and other proprietary protection for our drug candidates and other commercially important technologies, inventions and know-how related to our business, defend and enforce our intellectual property rights, in particular, our patent rights, preserve the confidentiality of our trade secrets and operate without infringing valid and enforceable intellectual property rights of others.

The patent positions for biotechnology and pharmaceutical companies like us are generally uncertain and can involve complex legal, scientific and factual issues. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors.

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In addition, the coverage claimed in a patent application can be significantly reduced before a patent is issued, and its scope can be reinterpreted and even challenged after issuance. As a result, we cannot guarantee that any of our drug candidates will be protected or remain protectable by enforceable patents. Moreover, any patents that we hold may be challenged, circumvented or invalidated by third parties. For more information regarding the risks related to our intellectual property see “Risk Factors—Risks related to our intellectual property.”

As of December 31, 2025, we owned and/or had control of 12 U.S. patents, 151 issued foreign patents, which includes European patents that have been validated in various European countries, Hong Kong, and Macau, seven pending non-provisional U.S. patent applications, two pending U.S. provisional patent applications, three pending international PCT applications, and 40 pending foreign patent applications.

With regard to denifanstat, as of December 31, 2025, we owned one issued U.S. patent with composition of matter and pharmaceutical composition claims directed to denifanstat. The issued U.S. patent is expected to expire in 2032, without taking any potential patent term extension (PTE) into account. In addition, we owned and/or had control of patents that have been granted in various jurisdictions including Australia, Argentina, Brazil, countries across Europe, Canada, Eurasia, Hong Kong, Japan, China, South Korea, India, Israel, Macau, Mexico, New Zealand, Taiwan, and South Africa, which are expected to expire in 2032, without taking potential PTEs or other forms of extension into account. We also owned three issued U.S. patents with claims directed to methods of using denifanstat and combinations of denifanstat with additional agents. The issued U.S. patents are expected to expire in 2035 and 2036, without taking a potential PTE into account. Specifically, U.S. Patent No. 10,363,249, which is expected to expire in 2035, issued with claims directed to a method of treating a taxane-resistant tumor or cancer comprising administering a combination of denifanstat and a taxane. U.S. Patent No. 10,189,822, which is expected to expire in 2036, issued with claims directed to a method of treating various types of cancers (mantle cell lymphoma, chronic myelogenous leukemia, sarcoma; endometrial tumors, non-small cell lung carcinoma, gastric carcinomas, hepatocellular tumors, and head and neck cancer) comprising administering denifanstat, or a combination of denifanstat with additional agents. U.S. Patent No. 11,034,690, which is expected to expire in 2036, issued with claims directed to methods of treating MASH, formerly referred to as NASH, MASLD, formerly referred to as NAFLD, liver cirrhosis and liver fibrosis comprising administering denifanstat. In addition, we owned and/or had control of patents with claims directed to methods of using denifanstat, and/or methods of using combinations of denifanstat with additional agents, in Australia, China, Japan, various countries across Europe, South Korea, Israel, New Zealand, and Russia, which are expected to expire in 2035, 2036 and/or 2037. We also owned and/or had control of at least 12 pending applications in jurisdictions including the United States, Australia, China, Canada, Europe, Hong Kong, Japan, South Korea, Singapore, and South Africa, which, if issued, are expected to expire in 2036 and/or 2037, without taking potential PTEs into account. Additionally, we owned and/or had control of two pending U.S. applications and a pending international PCT application directed to a combination of denifanstat and THR-β agonists, including resmetirom, as well as methods of treating NASH/MASH using the same, which, if issued, are expected to expire in 2044, without taking potential PTEs into account. Further, the Company has a license from TAPI to certain innovative forms of resmetirom covered by pending patent applications in the United States, Canada and Europe; with respect to these patent applications, if issued, the patents are expected to expire in 2041, without taking potential PTEs into account.

We owned and/or had control of a pending international PCT application and a pending application in Tawain directed to a combination of denifanstat and GLP-1 agonists, including semaglutide for treating liver diseases, which, if issued, are expected to expire in 2044, without taking potential PTEs into account.

With regard to TVB-3567, as of December 31, 2025, we owned one issued U.S. patent with composition of matter claims, as well as claims directed to methods of using TVB-3567 to treat various types of cancer. The issued U.S. Patent No. 9,994,550 is expected to expire in 2035, without taking a potential PTE into account. In addition, we own and/or have control of patents that have been granted in Australia, Brazil, Canada, South Africa, Japan, South Korea, China, Hong Kong, Macau, Israel, India, Singapore, New Zealand, Russia, Mexico, and various countries across Europe, which are expected to expire in 2035, without taking potential term extensions into account. We also own and/or have control of granted patents in China, Israel, Japan, South Korea and New Zealand, which are expected to expire in 2037, without taking potential PTEs into account, and 12 pending patent applications in the United States, Australia, Canada, China, Europe, Hong Kong, Japan, South Korea, Singapore and South Africa with disclosures covering TVB-3567, which, if issued, are expected to expire in 2037 (2036 in the United States), without taking potential PTEs into account.

With respect to claims specifically directed to the treatment of MASH, formerly referred to as NASH, as of December 31, 2025, we owned U.S. Patent No. 11,034,690, which is expected to expire in 2036, without taking potential term extensions into account issued with claims directed to methods of treating MASH, formerly referred to as NASH, MASLD, formerly referred to as NAFLD, liver cirrhosis and liver fibrosis comprising administering denifanstat. In addition, we own and/or have control of patents that have been granted in Australia and South Korea (denifanstat), Israel, China, Japan and New Zealand (denifanstat and TVB-3567) which are

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expected to expire in 2037, without taking potential term extensions into account. We also own and/or have control of 12 applications pending in the U.S., Australia, Canada, Europe, China, Hong Kong, Japan, South Korea, Singapore, and South Africa, that disclose chemical genera encompassing denifanstat and TVB-3567 for the treatment of MASH, formerly referred to as NASH. Any patents issuing from these applications are expected to expire in 2037 (2036 in the United States), without taking potential PTEs into account. Additionally, we owned and/or had control of a pending international PCT application directed to methods of using denifanstat to treat MASH patients with F2 and F3 fibrosis, which, if issued, are expected to expire in 2045, without taking potential PTEs into account.

​

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the earliest date of filing a non-provisional patent application or international PCT application.

In the United States, the term of a patent covering an FDA-approved drug may, in certain cases, be eligible for a PTE under the Hatch-Waxman Act as compensation for the loss of patent term during the product development and the FDA regulatory review process. The period of extension may be up to five years, but cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval. Only one patent among those eligible for an extension and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. Similar provisions are available in Europe and in certain other jurisdictions to extend the term of a patent that covers an approved drug. It is possible that issued U.S. patents covering denifanstat and TVB-3567 may be entitled to PTE. If our drug candidates receive FDA approval, we intend to apply for PTE, if available, to extend the term of patents that cover the approved drug candidates. We also intend to seek PTE in any jurisdictions where they are available, however, there is no guarantee that the applicable authorities, including the FDA, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

In addition to patent protection, we also rely on trade secret protection for our proprietary information that is not amenable to, or that we do not consider appropriate for, patent protection. However, trade secrets can be difficult to protect. Although we take steps to protect our proprietary information, including restricting access to our premises and our confidential information, as well as entering into agreements with our employees, consultants, advisors and potential collaborators, such individuals may breach such agreements and disclose our proprietary information including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. In addition, third parties may independently develop the same or similar proprietary information or may otherwise gain access to our proprietary information. As a result, we may be unable to meaningfully protect our trade secrets and proprietary information. For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks related to our intellectual property.”

U.S. patent term restoration

Depending upon the timing, duration and specifics of the potential FDA approval of denifanstat and any future drug candidates, some of our U.S. patents may be eligible for limited PTE. The Hatch-Waxman Amendments permit a patent restoration term, often referred to as PTE, of up to five years as compensation for patent term lost during product development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent term restoration period is generally one half the time between the effective date of an IND and the submission date of an NDA plus the time between the submission date of an NDA and the approval of that application. Only one patent applicable to an approved drug or biologic is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves or denies the application for any PTE or restoration. In the future, we intend to apply for extension of patent term for one of our patents covering denifanstat to add patent life beyond its current expected expiration date.

Government regulation and product approval

As a pharmaceutical company that operates in the United States, and in foreign countries, we are subject to extensive regulation. Government authorities in the United States (at the federal, state, and local level) and in other countries extensively regulate, among other things, the research, development, testing, manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing, and export and import of drug products such as those we are developing. Any drug candidates that we develop must be approved by the FDA before they may be legally marketed in the United States, and by the appropriate foreign regulatory authority before they may be legally marketed in foreign countries. Generally, our activities in other countries will be subject to regulation that is similar in nature and scope as that imposed in the United States, although there can be important differences. Additionally, some significant aspects of regulation in the European Union (EU) are addressed in a centralized way, but country-specific regulation remains essential in many respects.

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U.S. drug development process

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (the FDCA) and implements regulations. Drugs are also subject to other federal, state, and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources. The process required by the FDA before a drug may be marketed in the United States generally involves the following:

●completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s Good Laboratory Practices (GLP) regulations, and other applicable regulations;

●submission to the FDA of an IND, which must become effective before human clinical trials may begin and must be updated annually or when significant changes are made;

●approval by an IRB or ethics committee at each clinical site before each clinical trial may be initiated;

●performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including GCP regulations and other clinical-trial related regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

●preparation and submission to the FDA of an NDA for a new drug after completion of all pivotal trials, which includes not only the results of the clinical trials, but also detailed information on the chemistry, manufacturing and controls for the drug candidate and proposed labeling;

●a determination by the FDA within 60 days of its receipt of an NDA to file the NDA for review;

●satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with the FDA’s cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality, and purity;

●potential FDA audit of the preclinical and/or clinical trial sites that generated the data in support of the NDA to assess compliance with GCP;

●satisfactory completion of an FDA advisory committee review, if applicable; and

●FDA review and approval of the NDA prior to any commercial marketing or sale of the drug in the United States.

Satisfaction of FDA pre-market approval requirements typically takes many years, and the actual time required may vary substantially based upon the type, complexity, and novelty of the proposed drug or disease. Even after obtaining initial marketing approval, a drug product and its manufacturer remain subject to extensive, continuing regulatory requirements, including with respect to manufacturing, quality control, adverse event reporting, advertising and promotion and periodic inspections by regulatory authorities.

U.S. preclinical and clinical development

Before testing any drug candidate in humans, the drug candidate enters the preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, toxicity, and formulation, as well as animal studies, to assess the potential safety and activity of the drug candidate. The conduct of the preclinical tests must comply with federal regulations and requirements, including GLPs. The sponsor must submit the results of the preclinical tests, together with chemistry, manufacturing and controls information, analytical data, any available clinical data or literature and a proposed clinical trial protocol to the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational drug product (i.e., the drug candidate) to humans.

An IND must become effective before human clinical trials may begin. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions or places the IND on clinical hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. The FDA may also impose clinical holds on a drug candidate at any time before or during clinical trials due to safety concerns, non-compliance or other

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issues affecting the integrity of the trial. Accordingly, submission of an IND may or may not result in the FDA allowing clinical trials to commence and, once begun, issues may arise that could cause the trial to be suspended or terminated.

Clinical trials involve the administration of the drug candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Further, each clinical trial must be reviewed and approved by an IRB or ethics committee at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of trial participants and considers factors such as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or data monitoring committee. This group provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial. There are also requirements governing the registration of ongoing clinical trials and posting of completed clinical trial results to public registries.

A sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor may submit data from the clinical trial to the FDA in support of an NDA. The FDA may accept a well-designed and well-conducted foreign clinical study not conducted under an IND if the study was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

●Phase 1. The drug candidate is initially introduced into a limited population of healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution, and excretion, and if possible, to gain early evidence of effectiveness. In the case of some drug candidates for severe or life-threatening diseases, especially when the candidate may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

●Phase 2. The drug candidate is evaluated in a limited patient population with the targeted disease or condition to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the drug candidate for the targeted disease or condition and to determine dosage tolerance, optimal dosage, and dosing schedule.

●Phase 3. The drug candidate is administered to an expanded patient population at geographically dispersed clinical trial sites, to provide substantial evidence of clinical efficacy and to further test for safety. These clinical trials are intended to establish the overall benefit/risk relationship of the drug candidate and provide adequate basis for the labeling of the drug candidate. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

In some cases, FDA may require, or sponsors may voluntarily pursue, post-approval studies, or Phase 4 clinical trials, that are conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, such as with drugs granted accelerated approval, FDA may mandate the performance of Phase 4 trials as a condition of approval of an NDA.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, must develop methods for testing the identity, strength, quality, and purity of the final drug. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

While the IND is active and before approval, progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators within fifteen days for serious and unexpected suspected AEs, findings from other studies suggesting a significant risk to humans exposed to the drug candidate and from animal or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a

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serious suspected adverse reaction over that listed in the protocol or investigator brochure. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of information. The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

U.S. NDA review and approval processes

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug candidate, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the drug candidate. Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the drug candidate to the satisfaction of the FDA. The submission of an NDA is subject to the payment of substantial application fees; a waiver of such fees may be obtained under certain limited circumstances. Sponsors of approved NDAs are also subject to an annual program fee. These fees are typically increased annually.

The FDA reviews all NDAs submitted before it accepts them for filing. As a result of such review, the FDA may refuse to file any NDA that it deems incomplete or not properly reviewable at the time of submission and may request additional information rather than accepting an NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt of the application. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA.

After the NDA submission is accepted for filing, the FDA reviews the NDA to determine, among other things, whether the proposed product is safe and effective for its intended use and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality, and purity. The FDA has a Prescription Drug User Fee Act (PDUFA) goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission, which means that review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted. The FDA does not always meet its PDUFA goal dates, and the review process is often significantly extended by FDA requests for additional information or clarification.

The FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation, and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions and typically follows the advisory committee’s recommendations.

Before approving an NDA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical sites to assure compliance with GCP requirements. If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information. Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

After the FDA evaluates the application, manufacturing process, and manufacturing facilities, it may issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA. The Complete Response Letter may require additional clinical data and/or (an) additional clinical trial(s), and/or other significant and time-consuming requirements related to clinical trials, preclinical studies, or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information is submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.

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If a product receives regulatory approval, the approval may be limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings, or precautions be included in the product labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct one or more post-market studies or clinical trials. For example, the FDA may require Phase 4 testing, which involves clinical trials designed to further assess a drug safety and effectiveness, and may require testing and surveillance programs to monitor the safety of approved products that have been commercialized, and the FDA may limit further marketing of the product based on the results of these post-approval studies. The FDA may also determine that a Risk Evaluation and Mitigation Strategy (REMS) is necessary to ensure that the benefits of the drug outweigh the potential risks. If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS; the FDA will not approve the NDA without an approved REMS, if required. REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use (ETASU). ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. The requirement for a REMS can materially affect the potential market and profitability of the product. Once granted, product approvals may be withdrawn if compliance with regulatory standards is not maintained or problems are identified following initial marketing.

Changes to some of the conditions established in an approved application, including changes in indications, labeling, or manufacturing processes or facilities, require submission to and FDA approval of a new NDA or NDA supplement before the change can be implemented. An NDA supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures and actions in reviewing NDA supplements as it does in reviewing NDAs. As with new NDAs, the review process is often significantly extended by the FDA requests for additional information or clarification.

In addition, the Pediatric Research Equity Act (PREA) requires a sponsor to conduct pediatric clinical trials for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The sponsor may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. The FDA may send a non-compliance letter to any sponsor that fails to submit the required assessment, keep a deferral current, or submit a request for approval of a pediatric formulation.

Expedited development and review programs

The FDA offers a number of expedited development and review programs for qualifying drug candidates. For example, the Fast Track designation program is intended to expedite or facilitate the process for reviewing new drug candidates that are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast Track designation applies to the combination of the drug candidate and the specific indication for which it is being studied. The sponsor of a Fast Track designated product has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA is submitted, the drug candidate may be eligible for priority review. A Fast Track designated drug candidate may also be eligible for rolling review, where the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

A drug candidate intended to treat a serious or life-threatening disease or condition may also be eligible for Breakthrough Therapy designation to expedite its development and review. A drug candidate can receive Breakthrough Therapy designation if preliminary clinical evidence indicates that the drug candidate, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the Fast Track designation program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the drug candidate, including involvement of senior managers.

Any marketing application for a drug candidate submitted to the FDA for approval, including a drug candidate with a Fast Track designation and/or Breakthrough Therapy designation, may be eligible for rolling review, as well as other types of FDA programs intended to expedite the FDA review and approval process, such as priority review and accelerated approval. A drug candidate is eligible

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for priority review if it is designed to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available alternatives for such disease or condition. For new molecular entity NDAs, priority review means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date.

Additionally, drug candidates studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the drug candidate has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing confirmatory clinical studies which must be conducted with due diligence to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit. Under the Food and Drug Omnibus Report Act of 2022 (FDORA), the FDA may require that such confirmatory studies be underway prior to approval or within a specific time period after the date accelerated approval is granted. Under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a drug or indication approved under accelerated approval if, for example, the sponsor fails to conduct the required confirmatory studies in a timely manner, or if such post-approval studies fail to verify the predicted clinical benefit. In addition, for products being considered for accelerated approval, the FDA generally requires, unless otherwise informed by the agency, pre-approval of all advertising and promotional materials, which could adversely impact the timing of the commercial launch of the product. Under FDORA, the FDA is empowered to take action, such as issuing fines, against companies that fail to conduct with due diligence any post-approval confirmatory study or submit timely reports to the agency on their progress.

Fast Track designation, Breakthrough Therapy designation, priority review, and accelerated approval do not change the standards for approval, but may expedite the development, review or approval process. Even if a drug candidate qualifies for one or more of these programs, the FDA may later decide that the drug candidate no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Orphan drug designation

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product. Orphan designation must be requested before submitting an NDA. After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug or biological product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities. The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers. Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity. Orphan exclusivity could also block the approval of a drug candidate for seven years if a competitor obtains approval of the same drug as defined by the FDA.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation. In addition, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if a second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

Post-approval requirements

Any drug products manufactured or distributed pursuant to FDA approvals are subject to continuing regulation by the FDA, including, among other things, requirements related to manufacturing, record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and complying with FDA promotion and advertising requirements, which include, among

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others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling (off-label use), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

The FDA closely regulates the marketing, labeling, advertising, and promotion of drug products. A company can make only those claims relating to safety and efficacy that are consistent with the FDA-approved labeling. The FDA and other agencies enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising, and potential civil and criminal penalties. Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications regarding off-label use of their products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion. The FDA and other regulatory authorities have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed. However, companies may share truthful and non-misleading information that is otherwise consistent with a product’s FDA-approved labelling.

In addition, quality control and manufacturing procedures must continue to conform to applicable manufacturing requirements after approval. We rely, and expect to continue to rely, on third parties for the production of clinical and, if approved, commercial quantities of our drug candidates in accordance with cGMP regulations. cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP requirements. Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws. Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented. Drug manufacturers using contract manufacturers, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms. These firms and, where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such facilities or the ability to distribute products manufactured, processed or tested by them. Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and notify the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

The FDA may withdraw product approvals or request product recalls if a company fails to maintain compliance with regulatory requirements and standards after the product reaches the market. Later discovery of previously unknown problems with a product, including AEs of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; requirements for post-market studies or clinical trials to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

●restrictions on the marketing or manufacturing of the product or complete withdrawal of the product from the market or product recalls;

●fines, FDA Form 483s warning letters, or untitled letters;

●clinical holds on clinical trials;

●refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals;

●product seizure or detention, or refusal to permit the import or export of products;

●consent decrees, corporate integrity agreements, debarment, or exclusion from federal healthcare programs;

●mandated modification of promotional materials and labeling and the issuance of corrective information;

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●the issuance of safety alerts, Dear Healthcare Provider letters, press releases, and other communications containing warnings or other safety information about the product; or

●injunctions or the imposition of civil or criminal penalties.

U.S. marketing exclusivity

Market exclusivity provisions under the FDCA can delay the submission or the approval of certain marketing applications. The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not approve or accept for review an abbreviated new drug application (ANDA) or a Section 505(b)(2) NDA submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

The FDCA also provides three years of marketing exclusivity for an NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from accepting ANDAs or Section 505(b)(2) NDAs for drugs referencing the approved application for review.

Orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances. Pediatric exclusivity is another type of non-patent market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods and, for drugs, patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

Regulation of companion diagnostics and complementary diagnostics

As a part of our later stage product development strategy, we may develop and commercialize one or more companion diagnostics or complementary diagnostics. Companion diagnostics and complementary diagnostics can identify patients who are most likely to benefit from a particular therapeutic product; identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product; or monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness. Companion diagnostics and complementary diagnostics are regulated as medical devices by the FDA. Such diagnostic tests generally require marketing clearance or approval from the FDA prior to commercialization. The two primary types of FDA marketing authorization applicable to a medical device are clearance of a premarket notification, or 510(k), and approval of a premarket approval application (PMA). Beginning in February 2026, the FDA will evaluate PMA submissions against the harmonized Quality Management System Regulation (QMSR). For a novel therapeutic product for which a companion diagnostic device is essential for the safe and effective use of the product, the companion diagnostic device should be developed and approved or 510(k)-cleared contemporaneously with the therapeutic. The use of the companion diagnostic device will be stipulated in the labeling of the therapeutic product. A complementary diagnostic is not considered essential for the safe and effective use of the therapeutic product and does not need to be approved or cleared contemporaneously with the therapeutic.

After a companion diagnostic device is cleared or approved, it is subject to applicable post-marketing requirements including the FDA’s QMSR, adverse event reporting, recalls and corrections, and product marketing requirements. Device manufacturers must register and list their devices with the FDA. Applicable portions of the QMSR may include the methods and documentation of the design, testing, production, processes, controls, quality assurance, labeling, packaging and shipping of medical devices. Companion and complementary diagnostic manufacturers are subject to unannounced FDA inspections at any time during which the FDA will conduct an audit of the product(s) and the facilities for compliance with regulatory requirements. In January 2024, FDA announced its intention to initiate the reclassification process for most in vitro diagnostics. Further, FDA indicated that it will continue taking a risk-based approach in the initial classification of individual in vitro diagnostics to determine whether a new test may be classified into class II through the de novo classification process. In so doing, FDA indicated that it may regulate most future companion diagnostics as class II devices.

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Disclosure of clinical trial information

Sponsors of applicable clinical trials of FDA regulated products are required to register their clinical trials within specific timeframes for publication on www.clinicaltrials.gov. Information related to the product, patient population, phase of investigation, trial sites and investigators, and other aspects of the clinical trial is made public as part of the registration. Sponsors are also obligated to disclose the results of their clinical trials after completion. Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved. Competitors and patients may use this publicly available information to gain knowledge regarding the progress of development programs. Failure to timely register a covered clinical study or to submit study results as provided for in the law could lead to consequences such as public notifications of noncompliance and civil monetary penalties.

Other U.S. healthcare laws and compliance requirements

Although we currently do not have any products on the market, we are and, upon approval and commercialization, will be subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which we conduct our business. In the United States, such laws include, without limitation, state and federal anti-kickback, fraud and abuse, false claims, price reporting, and healthcare provider sunshine laws and regulations.

The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting, or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, or arranging for the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs. The term remuneration has been interpreted broadly to include anything of value. The Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers, and formulary managers on the other. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution. The exceptions and safe harbors are drawn narrowly and practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing, or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances. Our practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor. Additionally, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

The federal False Claims Act prohibits, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government. A claim includes “any request or demand” for money or property presented to the U.S. government. Several pharmaceutical and other healthcare companies have been prosecuted under these laws for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product. Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of the product for unapproved, and thus non-covered, uses. In addition, a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act.

The Health Insurance Portability and Accountability Act (HIPAA) also created federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items, or services. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation. Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

Additionally, the U.S. Physician Payments Sunshine Act and its implementing regulations require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) annually report information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners) and teaching hospitals, certain ownership and investment interests held by such physicians and their immediate family members.

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In order to distribute products commercially, we must also comply with state laws that require the registration of manufacturers and wholesale distributors of pharmaceutical products in a state, including, in certain states, manufacturers, and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state. Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain. Several states have enacted legislation requiring pharmaceutical companies to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, track, and report gifts, compensation and other remuneration made to physicians and other healthcare providers, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical companies for use in sales and marketing, and to prohibit certain other sales and marketing practices. All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.

If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including without limitation, significant civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

Pharmaceutical coverage, pricing and reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any drug candidates for which we or our collaborators obtain regulatory approval. In the United States and markets in other countries, sales of any products for which we or our collaborators receive regulatory approval for commercial sale will depend, in part, on the extent to which third-party payors provide coverage, and establish adequate reimbursement levels for such drug products.

In the United States, third-party payors include federal and state healthcare programs, government authorities, private managed care providers, private health insurers, and other organizations. Third-party payors are increasingly challenging the price, examining the medical necessity and reviewing the cost-effectiveness of medical drug products and medical services, in addition to questioning their safety and efficacy. Such payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA-approved drugs for a particular indication. We or our collaborators may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain the FDA approvals. Nonetheless, our drug candidates may not be considered medically necessary or cost-effective. Moreover, the process for determining whether a third-party payor will provide coverage for a drug product may be separate from the process for setting the price of a drug product or for establishing the reimbursement rate that such a payor will pay for the drug product. A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

If we elect to participate in certain governmental programs, we may be required to participate in discount and rebate programs, which may result in prices for our future products that will likely be lower than the prices we might otherwise obtain. For example, drug manufacturers participating under the Medicaid Drug Rebate Program must pay rebates on prescription drugs to state Medicaid programs. Under the Veterans Health Care Act (VHCA) drug companies are required to offer certain drugs at a reduced price to a number of federal agencies, including the U.S. Department of Veterans Affairs and Department of Defense, the Public Health Service and certain private Public Health Service designated entities in order to participate in other federal funding programs, including Medicare and Medicaid. Discounted prices must also be offered for certain U.S. Department of Defense purchases for its TRICARE program via a rebate system. Participation under the VHCA also requires submission of pricing data and calculation of discounts and rebates pursuant to complex statutory formulas, as well as the entry into government procurement contracts governed by the Federal Acquisition Regulations. If our products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.

Additionally, we may develop complementary diagnostic tests for use with our drug candidates. We, or our collaborators, may be required to obtain coverage and reimbursement for these tests separate and apart from the coverage and reimbursement we seek for our drug candidates, once approved. While we have not yet developed any complementary diagnostic tests for our drug candidates, if we

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do, there is significant uncertainty regarding our ability to obtain coverage and adequate reimbursement for the same reasons applicable to our drug candidates.

Different pricing and reimbursement schemes exist in other countries. In the European Union, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers. Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular drug candidate to currently available therapies. Other Member States allow companies to fix their own prices for medicines, but monitor and control company profits. The downward pressure on health care costs in general, particularly prescription drugs, has become very intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from low-priced markets exert a commercial pressure on pricing within a country.

The marketability of any drug candidates for which we or our collaborators receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. In addition, emphasis on managed care in the United States has increased and we expect will continue to increase the pressure on pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we or our collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Healthcare reform

A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medical products and services, implementing reductions in Medicare and other healthcare funding and applying new payment methodologies. For example, in 2010, the Patient Protection and Affordable Care Act (the Affordable Care Act) was enacted, which affected existing government healthcare programs and resulted in the development of new programs.

Among the Affordable Care Act’s provisions of importance to the pharmaceutical industry, in addition to those otherwise described above, are the following:

●an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents apportioned among these entities according to their market share in some government healthcare programs;

●an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively, and a cap on the total rebate amount for innovator drugs at 100% of the Average Manufacturer Price (AMP), which, effective January 1, 2024, was eliminated as a result of the American Rescue Plan Act of 2021;

●a Medicare Part D coverage gap discount program, later supplanted by the Medicare manufacturer discount program under the Inflation Reduction Act, in which manufacturers were required to agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

●extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

●expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals, including individuals with income at or below 133% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability;

●expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program; and

●a Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

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Since its enactment, there have been executive, judicial and legislative challenges to certain aspects of the Affordable Care Act. It is unclear how any future litigation, and the healthcare reform measures of the current executive administration, will impact the Affordable Care Act.

Other legislative changes have also been proposed and adopted in the United States since the Affordable Care Act was enacted. For example, the Budget Control Act of 2011 and subsequent legislation, among other things, created measures for spending reductions by Congress that include aggregate reductions of Medicare payments to providers of on average 2% per fiscal year, which remain in effect through 2032. Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation. The U.S. American Taxpayer Relief Act of 2012 further reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our drug candidates for which we may obtain regulatory approval or the frequency with which any such drug candidate is prescribed or used.

Additionally, there has been increasing legislative and enforcement interest in the United States with respect to drug pricing practices. Specifically, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several U.S. Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs. The Inflation Reduction Act of 2022 (IRA), for example, includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 starting in 2025, thereby eliminating the so-called coverage gap; impose new manufacturer financial liability on certain drugs under Medicare Part D; allow the U.S. government to negotiate Medicare Part B and Part D price caps for certain high-cost drugs and biologics without generic or biosimilar competition; require companies to pay rebates to Medicare for certain drug prices that increase faster than inflation; and delay until January 2032 the implementation of the HHS rebate rule that would have limited the fees that pharmacy benefit managers can charge. Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have approved indication(s) for the rare disease or condition(s) described in its orphan designation(s). The implementation of the IRA is currently subject to ongoing litigation challenging the constitutionality of the IRA’s Medicare drug price negotiation program. The effects of the IRA on our business and the healthcare industry in general is not yet known.

In addition, the One Big Beautiful Bill Act of 2025 (OBBBA) imposed significant reductions in Medicaid funding, additional work requirements for Medicaid recipients, and more frequent reenrollment requirements. These changes are expected to place substantial pressure on state Medicaid budgets, reduce enrollment, and limit covered services, which could decrease utilization of, and reimbursement for, our products, if approved.

The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States. To date, there have been several recent U.S. congressional inquiries, as well as proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products. The Trump Administration has issued executive orders and supported proposed regulatory initiatives in 2025 that could have a significant impact on the prices that we, or any collaborators, may receive for any approved products.

On May 12, 2025, President Trump signed an executive order directing the Secretary of HHS to set and communicate most-favored-nation (MFN) price targets to manufacturers and propose a rulemaking plan to impose MFN pricing if “significant progress” is not made, and also directing the federal government to support regulatory paths to allow direct-to-patient sales for companies that meet these targets. The executive order further states that the Administration will take additional action (for example, examining whether marketing approvals should be modified or rescinded or considering individual drug importation waiver authorities) should manufacturers fail to offer American consumers the MFN lowest price. In July 2025, President Trump sent letters to certain pharmaceutical companies demanding that these companies extend MFN pricing to Medicaid and newly launched drugs as well as move to direct-to-consumer models priced at MFN pricing, and soliciting binding commitments by September 29, 2025. Since this time, multiple drug manufacturers have announced plans to, for certain of their drugs, lower prices to reflect similar pricing around the world, and to sell these reduced-price drugs on a direct-to-consumer purchasing platform developed by the federal government; however, it is not known what results will occur to the extent the recipients of these letters do not reduce their U.S. prices.

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On December 19, 2025, CMS released two proposed rules that would incorporate MFN pricing principles into federal reimbursement for prescription drugs. The first proposal, the Global Benchmark for Efficient Drug Pricing Model (GLOBE) for Medicare Part B, would require manufacturers of specified single source drugs and sole source biologics to pay incremental rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and eligibility criteria. The second proposal, the Guarding U.S. Medicare Against Rising Drug Costs (GUARD) model for Medicare Part D, would similarly mandate manufacturer rebates for qualifying sole source drugs where the Medicare net price exceeds an MFN benchmark derived from international reference pricing methodologies. As proposed, GLOBE would begin a five-year performance period on October 1, 2026 and GUARD would begin its performance period in 2027. These proposals will likely be subject to legal challenges that could delay their implementation or modify their impact on manufacturer pricing and revenue. Additionally, in November 2025, CMS introduced the GENErating cost Reductions for U.S. Medicaid (GENEROUS) Model, a voluntary MFN framework for manufacturers participating in the Medicaid Drug Rebate Program. Although it is voluntary, the GENEROUS Model could also impact the drug pricing landscape for manufacturers.

Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain drug access and marketing cost disclosure and transparency measures, and designed to encourage importation from other countries and bulk purchasing. Legally mandated price controls on payment amounts by third-party payors or other restrictions could harm our business, financial condition, results of operations and prospects. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. This could reduce the ultimate demand for our drugs or put pressure on our drug pricing, which could negatively affect our business, financial condition, results of operations and prospects.

We expect that additional U.S. federal and state healthcare reform measures will be adopted in the future, any of which could limit the amounts that third-party payors or customers will pay for healthcare drugs and services, which could result in reduced demand for our drug candidates or additional pricing pressures

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Data privacy and security laws

We may also be subject to federal, state, local, and foreign data privacy and security obligations such as various laws, regulations, guidance, industry standards, external and internal privacy and security policies, contractual requirements, and other obligations relating to data privacy and security. In the United States, numerous federal, state, and local laws and regulations, including state data breach notification laws, state health information privacy laws, and federal, consumer protection laws and regulations (e.g., Section 5 of the FTC Act), and similar laws (e.g., wiretapping laws) govern the collection, use, disclosure, protection, and other processing of health-related and other personal data and may apply to our operations or the operations of our partners upon which we rely. For example, HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and its implementing regulations, impose requirements relating to the privacy, security and transmission of individually identifiable health information on certain health care providers, health plans and health care clearinghouses, known as covered entities and their business associates that perform certain services that involve creating, receiving, maintaining or transmitting individually identifiable health information for or on behalf of such covered entities as well as their covered subcontractors. Entities that are found to be in violation of HIPAA as the result of, for example, a breach of unsecured protected health information, a complaint about privacy practices or an audit by HHS, may be subject to significant civil, criminal and administrative fines and penalties and/or additional reporting and oversight obligations if required to enter into a resolution agreement and corrective action plan with HHS to settle allegations of HIPAA non-compliance. Further, entities that knowingly obtain, use, or disclose individually identifiable health information maintained by a HIPAA covered entity in a manner that is not authorized or permitted by HIPAA may be subject to criminal penalties.

In addition, U.S. state laws govern the privacy and security of personal data, many of which differ from each other in significant ways and may be subject to different interpretations, thus complicating our compliance efforts. By way of example, the California Consumer Privacy Act (CCPA) applies to personal data of consumers, business representatives, and employees who are California residents, and requires businesses to provide specific disclosures in privacy notices and honor requests of such individuals. The CCPA provides for administrative fines of up to $7,500 per violation, as well as a private right of action for individuals affected by certain data breaches to recover significant statutory damages. In addition, the California Privacy Rights Act of 2020 (CPRA) expanded the CCPA’s requirements, including by adding a new right for individuals to correct their personal data and establishing a new regulatory agency to implement and enforce the law. Numerous other states have also passed or proposed similarly comprehensive privacy laws. These state laws and the CCPA provide individuals with certain rights concerning their personal data, including the right to access, correct, or delete certain personal data, and opt-out of certain data processing activities, such as targeted advertising, profiling, and automated decision-making. The exercise of these rights may impact our business and ability to provide our products and services. While these states, like

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the CCPA, also exempt some data processed in the context of clinical trials, these developments may further complicate compliance efforts, and increase legal risk and compliance costs for us and the third parties upon whom we rely. There are also states that are specifically regulating health information. For example, Washington’s My Health My Data Act, which became effective on March 31, 2024, regulates the collection and sharing of health information and has a private right of action, which further increases the relevant compliance risk. Connecticut and Nevada have also passed similar laws regulating consumer health data. In addition, other states have proposed and/or passed legislation that regulates the privacy and/or security of certain specific types of information. For example, a small number of states have passed laws that regulate biometric data specifically.

These various privacy and security laws may impact our business activities, including our identification of research subjects, relationships with business partners and ultimately the marketing and distribution of our products. New privacy legislation will add additional complexity, variation in requirements, restrictions and potential legal risk, require additional investment of resources in compliance programs, impact strategies and the availability of previously useful data and could result in increased compliance costs and/or changes in business practices and policies. In particular, the existence of comprehensive privacy laws in different states in the country will make our compliance obligations more complex and costly and may increase the likelihood that we may be subject to enforcement actions or otherwise incur liability for noncompliance. State laws are changing rapidly and there is discussion in the U.S. Congress of a new comprehensive federal data privacy law to which we may likely become subject, if enacted.

Outside the United States, an increasing number of laws, regulations, and industry standards govern data privacy and security, including the European Union’s General Data Protection Regulations (EU GDPR) and the United Kingdom’s GDPR (UK GDPR, and together with the EU GDPR, referred to as GDPR). The GDPR applies to any company established in the European Economic Area (EEA) or United Kingdom as well as to those outside the EEA or United Kingdom if they collect and use personal data in connection with the offering of goods or services to individuals in the EEA or United Kingdom or the monitoring of their behavior.

The GDPR creates significant and complex compliance burdens for covered companies, including strict requirements for processing personal data. Companies violating the GDPR may face temporary or definitive bans on data processing and other corrective actions; fines of up to €20 million (£17.5 million) or 4% of annual global revenue, whichever is greater; or private litigation related to processing of personal data brought by classes of data subjects or consumer protection organizations authorized at law to represent their interests. The processing of “special category personal data” ​(including health-related data) may also impose heightened compliance burdens under the GDPR and is a topic of active interest among relevant regulators.

Europe and other jurisdictions have enacted laws requiring data to be localized or limiting the transfer of personal data to other countries. In particular, the GDPR restricts the transfer of personal data from the EEA and United Kingdom to the United States and other countries whose privacy laws are believed to be inadequate. Although there are various mechanisms that may be used to transfer personal data from the EEA and the United Kingdom to the United States in compliance with law, such as the EEA and United Kingdom’s standard contractual clauses, the UK’s International Data Transfer Agreement / Addendum, and the EU-U.S. Data Privacy Framework and the UK extension thereto (which allows for transfers for relevant U.S.-based organizations who self-certify compliance and participate in the Framework), these mechanisms are subject to legal challenges and there is no assurance that we can satisfy or rely on these measures to lawfully transfer personal data to the United States. Other jurisdictions may adopt similarly stringent interpretations of their data localization and cross-border data transfer rules.

The EU GDPR also provides that EEA Member States may make their own laws and regulations to introduce specific requirements related to the processing of personal data and “special categories of personal data”, which may lead to greater divergence on the law that applies to the processing of such data across Europe. Country-specific regulations could also limit our ability to collect, use and share European data, and/or could cause our compliance costs to increase, ultimately having an adverse impact on our business and harming our business and financial condition.

Our employees and personnel may use generative AI technologies to perform their work, and the disclosure and use of personal data in generative AI technologies is subject to various privacy laws and other privacy obligations. Governments have passed and are likely to pass additional laws regulating generative AI. Our use of this technology could result in additional compliance costs, regulatory investigations and actions, and consumer lawsuits. If we are unable to use generative AI, it could make our business less efficient and result in competitive disadvantages.

In addition to data privacy and security laws, we are or may become contractually subject to industry standards adopted by industry groups and may become subject to such obligations in the future. We are also bound by other contractual obligations related to data privacy and security, and our efforts to comply with such obligations may not be successful. We publish privacy policies, marketing materials, and other statements, such as compliance with certain certifications or self-regulatory principles, regarding data privacy and

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security. If these policies, materials or statements are found to be deficient, lacking in transparency, deceptive, unfair, or misrepresentative of our practices, we may be subject to investigation, enforcement actions by regulators, or other adverse consequences.

Obligations related to data privacy and security are quickly changing, becoming increasingly stringent, and creating regulatory uncertainty. Additionally, these obligations may be subject to differing applications and interpretations, which may be inconsistent or conflict among jurisdictions. Preparing for and complying with these obligations requires us to devote significant resources and may necessitate changes to our services, information technologies, systems, and practices and to those of any third parties that process personal data on our behalf.

The U.S. Foreign Corrupt Practices Act (FCPA)

The FCPA prohibits any U.S. individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring us to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

Europe / rest of world government regulation

In addition to regulations in the United States, we will also be subject to a variety of comparable regulatory requirements in other jurisdictions governing, among other things, the research, development, testing, manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing, and export and import of drug products such as those we are developing. Whether or not we or our potential collaborators obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries.

Clinical trials in the EU

Similar to the United States, the various phases of preclinical and clinical research in the European Union (EU) are subject to significant regulatory controls.

In the EU, clinical trials are governed by the Clinical Trials Regulation (EU) No 536/2014 (CTR), which entered into application on January 31, 2022 repealing and replacing the former Clinical Trials Directive 2001/20/EC (CTD). As of January 31, 2025, all new clinical trial authorization applications in the EU must be made under the CTR.

The CTR is intended to harmonize and streamline clinical trial authorizations, simplify adverse-event reporting procedures, improve the supervision of clinical trials and increase their transparency. Specifically, the CTR, which is directly applicable in all EU Member States, introduces a streamlined application procedure through a single-entry point, the Clinical Trials Information System (CTIS); a single set of documents to be prepared and submitted for the application; as well as simplified reporting procedures for clinical trial sponsors. A harmonized procedure for the assessment of applications for clinical trials has been introduced and is divided into two parts. Part I assessment is coordinated by the competent authority of a reporting EU Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to be scientifically harmonized across EU Member States. This assessment is then submitted to the competent authorities of all concerned EU Member States in which the trial is to be conducted for their review. Part II is assessed separately by the competent authorities and ethics committees in each concerned EU Member State. Individual EU Member States retain the power to permit or refuse the conduct of clinical trials in their territory.

In all cases, the clinical trials are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

EU review and approval process

In the EU, medicinal products can only be commercialized after a marketing authorization (MA), has been granted. To obtain an MA for a medicinal product, an applicant must submit a marketing authorization application (MAA) either under a centralized procedure administered by the EMA or one of the procedures administered by the competent authorities of EU Member States (decentralized procedure, national procedure or mutual recognition procedure). An MA may be granted only to an applicant established in the EU.

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The centralized procedure provides for the grant of a single MA by the European Commission that is valid throughout the EEA (which is comprised of the 27 Member States of the European Union plus Norway, Iceland and Liechtenstein). Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for: (i) medicinal products derived from biotechnological processes, (ii) products designated as orphan medicinal products, (iii) advanced therapy medicinal products (ATMPs) (gene therapy, somatic-cell therapy and tissue engineered medicines), and (iv) products with a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases. For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of public health at the EU level, authorization through the centralized procedure is optional.

Under the centralized procedure, the EMA’s Committee for Medicinal Products for Human Use (CHMP), conducts the initial assessment of a product. The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing MA.

Under the centralized procedure, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops when additional information or written or oral explanations are to be provided by the applicant in response to questions of the CHMP. Accelerated assessment may be granted by the CHMP in exceptional cases, when a medicinal product targeting an unmet medical need is expected to be of major interest from a public health perspective and, in particular, from the viewpoint of therapeutic innovation. If the CHMP accepts a request for accelerated assessment, the time limit of 210 days will be reduced to 150 days (excluding clock stops). The CHMP can, however, revert to the standard time limit for the centralized procedure if it considers that it is no longer appropriate to conduct an accelerated assessment.

Unlike the centralized authorization procedure, the decentralized MA procedure requires a separate application to, and leads to separate approval by, the competent authorities of each EU Member State in which the product is to be marketed. This application is substantially similar to the application that would be submitted to the EMA for authorization through the centralized procedure. The reference EU Member State prepares a draft assessment report and drafts of the related materials within 120 days after receipt of a valid application. The resulting assessment report is submitted to the concerned EU Member States who, within 90 days of receipt, must decide whether to approve the assessment report and related materials. If a concerned EU Member State cannot approve the assessment report and related materials due to concerns relating to a potential serious risk to public health, disputed elements may be referred to the Heads of Medicines Agencies’ Coordination Group for Mutual Recognition and Decentralised Procedures—Human (CMDh), for review. If the CMDh cannot resolve the matter, the reference EU Member State may refer the matter to the CHMP for arbitration.

The mutual recognition procedure allows companies that have a medicinal product already authorized in one EU Member State to apply for this authorization to be recognized by the competent authorities in other EU Member States. Like the decentralized procedure, the mutual recognition procedure is based on the acceptance by the competent authorities of the EU Member States of the MA of a medicinal product by the competent authorities of other EU Member States. The holder of a national MA may submit an application to the competent authority of an EU Member State requesting that this authority recognize the MA delivered by the competent authority of another EU Member State.

An MA in the EU has, in principle, an initial validity of five years. The MA may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the EMA or the competent authority of the EU Member State in which the original MA was granted. To support the application, the MA holder must provide the EMA or the competent authority with a consolidated version of the eCTD (Common Technical Document) providing up-to-date data concerning the quality, safety and efficacy of the product, including all variations introduced since the MA was granted, at least nine months before the MA ceases to be valid. The European Commission or the competent authorities of the EU Member States may decide on justified grounds relating to pharmacovigilance to proceed with one further five-year renewal period for the MA. Once subsequently definitively renewed, the MA shall be valid for an unlimited period. Any authorization that is not followed by the actual placing of the medicinal product on the EU market (for a centralized MA) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).

Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the PRIority MEdicines (PRIME) scheme, which provides incentives broadly similar to the Breakthrough Therapy designation in the U.S. PRIME is a voluntary scheme aimed at enhancing the EMA’s support for the development of medicinal products that target unmet medical needs. Eligible products must target conditions for which there is an unmet medical need (there is no satisfactory method of diagnosis, prevention or treatment in the EU or, if there is, the new medicinal product will bring a major therapeutic advantage) and they must demonstrate the potential to address the unmet medical need by introducing new methods of therapy or improving existing ones. Benefits accrue to sponsors of drug candidates with PRIME

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designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted.

In the EU, a conditional MA may be granted in cases where all the required safety and efficacy data are not yet available. The European Commission may grant a conditional MA for a medicinal product if it is demonstrated that all of the following criteria are met: (i) the benefit-risk balance of the medicinal product is positive; (ii) it is likely that the applicant will be able to provide comprehensive data post-authorization; (iii) the medicinal product fulfils an unmet medical need; and (iv) the benefit of the immediate availability to patients of the medicinal product is greater than the risk inherent in the fact that additional data are still required. The conditional MA is subject to conditions to be fulfilled for generating the missing data or ensuring increased safety measures. It is valid for one year and must be renewed annually until all related conditions have been fulfilled. Once such conditions have been fulfilled, the conditional MA may be converted into a standard MA. However, if the conditions are not fulfilled within the timeframe set by the EMA and approved by the European Commission, the MA will cease to be renewed.

An MA may also be granted “under exceptional circumstances” where the applicant can show that it is unable to provide comprehensive data on efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced. These circumstances may arise in particular when the intended indications are very rare and, in the state of scientific knowledge at that time, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles. Like a conditional MA, an MA granted in exceptional circumstances is reserved for medicinal products intended for the treatment of rare diseases or unmet medical needs for which the applicant does not hold a complete data set that is required for the grant of a standard MA. However, unlike the conditional MA, an applicant for authorization in exceptional circumstances is not subsequently required to provide the missing data. Although the MA “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the MA will be withdrawn if the risk-benefit ratio is no longer favorable.

Manufacturing regulation in the EU

Various requirements apply to the manufacturing and placing on the EU market of medicinal products. The manufacturing of medicinal products in the EU requires a manufacturing authorization, and the import of medicinal products into the EU requires a manufacturing authorization that permits importation. The manufacturing authorization holder must comply with various requirements set out in the applicable EU laws, regulations and guidance, including EU good manufacturing practice (GMP) standards. Similarly, the distribution of medicinal products within the EU is subject to compliance with the applicable EU laws, regulations and guidelines, including the requirement to hold appropriate distribution authorizations granted by the competent authorities of EU Member States. MA holders, manufacturing and import authorization (MIA) holders and/or distribution authorization holders may be subject to civil, criminal or administrative sanctions, including suspension or revocation of any manufacturing authorization, in the event of non-compliance with the EU or EU Member States’ requirements applicable to the manufacturing of medicinal products.

Post-approval requirements

Where an MA is granted in relation to a medicinal product in the EU, the holder of the MA is required to comply with a range of regulatory requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products. Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the individual EU Member States. The holder of an MA must establish and maintain a pharmacovigilance system and appoint a qualified person responsible for pharmacovigilance who is responsible for oversight of that system. Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (PSURs).

All new MAAs must include a risk management plan (RMP), describing the risk management system that we will put in place and documenting measures to prevent or minimize the risks associated with the product. The regulatory authorities may also impose specific obligations as conditions of the MA. Such risk-minimization measures or post-authorization obligations may include additional safety monitoring requirements, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

In the EU, the advertising and promotion of medicinal products are subject to both EU and EU Member States’ laws governing promotion of medicinal products, interactions with physicians and other healthcare professionals, misleading and comparative advertising and unfair commercial practices. Although general requirements for advertising and promotion of medicinal products are established under EU legislation, the details are governed by regulations in individual EU Member States and can differ from one country

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to another. For example, applicable laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (SmPC), as approved by the competent authorities in connection with an MA. The SmPC is the document that provides information to physicians concerning the safe and effective use of the product. Promotional activity that does not comply with the SmPC is considered off-label and is prohibited in the EU. Direct-to-consumer advertising of prescription medicinal products is also prohibited in the EU.

Data and marketing exclusivity

The EU also provides opportunities for regulatory data and market exclusivity. Upon receiving an MA in the EU, innovative medicinal products generally receive eight years of data exclusivity followed by an additional two years of market exclusivity. If granted, data exclusivity prevents generic or biosimilar applicants from referencing the innovator’s preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA during a period of eight years from the date on which the reference product was first authorized in the EU. During the additional two-year period of market exclusivity, a generic or biosimilar MA can be submitted, and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed until the expiration of the market exclusivity period. The overall ten-year period may be extended to a maximum of eleven years if, during the first eight years of those ten years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to authorization, is considered to bring a significant clinical benefit in comparison with existing therapies.

In the EU, there is a special regime for biosimilars, or biological medicinal products that are similar to a reference medicinal product but that do not meet the definition of a generic medicinal product. For such products, the results of appropriate preclinical or clinical trials must be provided in support of an application for MA. Guidelines from the EMA detail the type and quantity of supplementary data to be provided for different types of biological products.

Pediatric development

In the EU, Regulation (EC) No 1901/2006 provides that all marketing authorization applications for new medicinal products must include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan (PIP), agreed with the EMA’s Pediatric Committee (PDCO). The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the medicinal product for which an MA is being sought. The PDCO may grant a deferral of the obligation to implement some or all of the measures provided in the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults. Furthermore, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data are not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients. Once an MA is obtained and study results are included in the product information, even when negative, the product is eligible for a six-month extension to the Supplementary Protection Certificate (SPC), provided an application for such extension is made at the time of filing the SPC application for the product, or at any point up to two years before the SPC expires. The incentive in the case of orphan medicinal products is that a two-year extension of orphan market exclusivity may be available (but no extension to an SPC is available in the case of orphan medicinal products).

Orphan designation

In the EU, Regulation (EC) No. 141/2000, as implemented by Regulation (EC) No. 847/2000 provides that a medicinal product can be designated as an orphan medicinal product by the European Commission if its sponsor can establish that: (i) the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition; (ii) either (a) such condition affects not more than 5 in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in developing the medicinal product; and (iii) there exists no satisfactory authorized method of diagnosis, prevention, or treatment of the condition that has been authorized in the EU, or even if such method exists, the product will be of significant benefit to those affected by that condition.

Regulation (EC) No 847/2000 sets out further provisions for the implementation of the criteria for designation of a medicinal product as an orphan medicinal product. An application for the designation of a medicinal product as an orphan medicinal product must be submitted at any stage of development of the medicinal product but before filing of an MAA. An MA for an orphan medicinal product may only include indications designated as orphan. For non-orphan indications treated with the same active pharmaceutical ingredient, a separate MA has to be sought.

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Orphan medicinal product designation entitles an applicant to incentives such as fee reductions or fee waivers, protocol assistance, and access to the centralized marketing authorization procedure. Upon grant of a MA, orphan medicinal products are entitled to a ten-year period of market exclusivity for the approved therapeutic indication, which means that the EMA and national competent authorities cannot accept another MAA or an application to extend an MA, and the European Commission cannot grant an MA, in each case for a similar medicinal product for the same indication for such ten-year period. The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed PIP. No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications. Orphan medicinal product designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The period of market exclusivity may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria on the basis of which it received orphan medicinal product designation, including where it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold. Additionally, an MA may be granted to a similar medicinal product with the same orphan indication during the ten-year exclusivity period if: (i) the MA holder for the authorized orphan product consents to a second medicinal product application, (ii) the manufacturer of the authorized orphan medicinal product is unable to supply sufficient quantities of the product; or (iii) the second applicant can establish that its product, although similar to an authorized orphan product, is safer, more effective or otherwise clinically superior to the authorized orphan medicinal product. A company may voluntarily remove a product from the register of orphan products.

Clinical trial data disclosure

Many jurisdictions have mandatory clinical trial information obligations incumbent on sponsors. In the EU, transparency requirements relating to clinical trial information are established in the CTR. The CTR establishes a general principle according to which information contained in CTIS shall be made publicly accessible unless confidentiality is justified on grounds of protecting personal data, or commercially confidential information, or is necessary to protect confidential communications between EU Member States in relation to the preparation of an assessment report, or to ensure effective supervision of the conduct of a clinical trial by EU Member States. This confidentiality exception may be overruled if there is an overriding public interest in disclosure. The publication of data and documents in relation to the conduct of a clinical trial will take place in accordance with specific timelines. The timelines are established by the EMA and are determined based on the documents and the categorization of the clinical trial.

In addition, Regulation (EC) No- 1049/2001 on access to documents, and the related EMA policy 0043 on access to documents, provide for a right for interested parties to submit an access to documents request to the EMA to access certain information held by the EMA. Certain limited categories of information are exempted from disclosure (i.e., commercially confidential information, which is construed increasingly narrowly and protected personal data). It is possible for competitors to access and use this data in their own research and development programs anywhere in the world, once these data are in the public domain.

Pricing, coverage and reimbursement

In the EU, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Other countries may require the completion of additional studies that compare the cost-effectiveness of a particular drug candidate to currently available therapies (so called health technology assessments) in order to obtain reimbursement or pricing approval. For example, some EU Member States may approve a specific price for a product, or they may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market. Other EU Member States allow companies to fix their own prices for products but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions. Recently, many EU Member States have increased the amount of discounts that pharmaceutical companies are required to offer. These efforts could continue as countries attempt to manage healthcare expenditures. The downward pressure on healthcare costs in general, particularly prescription products, has become intense. As a result, increasingly high barriers are being erected to the entry of new products onto national markets. Political, economic, and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various EU Member States, and parallel trade (arbitrage between low-priced and high-priced EU Member States), can further reduce prices.

In addition, some EU Member States may require the completion of additional studies that compare the cost-effectiveness of a particular medicinal drug candidate to currently available therapies. This Health Technology Assessment (HTA) process is the procedure according to which the assessment of the public health impact, therapeutic impact and the economic and societal impact of use of a given medicinal product in the national healthcare systems of the individual country is conducted. The outcome of HTA regarding

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specific medicinal products will often influence the pricing and reimbursement status granted to these medicinal products by the competent authorities of individual EU Member States. The Regulation No 2021/2282 on Health Technology Assessment (HTA Regulation) was adopted in December 2021 and became applicable on January 12, 2025, with phased implementation. The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including by introducing joint clinical assessments of new medicinal products. The new rules under the HTA Regulation will be introduced in stages, with joint clinical assessments initially applying to new cancer medicines or advanced therapy medicinal products, and ultimately being extended to all medicinal products authorized under the EU centralized procedure.

Regulation of Companion Diagnostics in the EU

In the EU, companion diagnostics are considered to be in vitro diagnostic medical devices (IVDs) and are governed by Regulation 2017/746 (IVDR), which entered into application in May 2022, repealing and replacing Directive 98/79/EC. The IVDR defines companion diagnostics as a device that is essential for the safe and effective use of a corresponding medicinal product to: (a) identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or (b) identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product.

The IVDR regulates the placing on the market, the general safety and performance requirements, the conformity assessment procedures, CE-marking and registration obligations for manufacturers and devices, as well as the vigilance and post-market surveillance requirements related to such products. IVDs, including companion diagnostics, must conform with the general safety and performance requirements (GSPR) of the IVDR. To demonstrate compliance with the GSPR laid down in Annex I to the IVDR, the manufacturer must conduct a conformity assessment procedure.

Companion diagnostics are specifically identified as falling within the scope of the IVDR. Prior to CE marking and marketing in the EU they must be the subject of a conformity assessment process that includes the intervention of a notified body. If the related medicinal product has been authorized, or is in the process of being authorized, through the centralized procedure for the authorization of medicinal products, the notified body will, before it can issue a CE Certificate of Conformity, be required to seek a scientific opinion from the EMA on the suitability of the companion diagnostic for use in relation to the medicinal product concerned. For medicinal products that have been or are in the process of authorization through any other route provided in EU legislation, the notified body must seek the opinion of the relevant national competent authority of an EU Member State.

All of the aforementioned EU rules are generally applicable in the EEA.

Reform of the Regulatory Framework in the European Union

The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children). In April 2024, European Parliament adopted its position on the legislative proposals and in June 2025, the Council of the European Union adopted its position. A common position on the text has been agreed upon December 11, 2025, in the context of subsequent inter-institutional trilogue negotiations. The proposed revisions remain to be adopted, and are not expected to become applicable before 2028.

Regulatory Framework in the United Kingdom

Following the end of the Brexit transition period on January 1, 2021 and the implementation of elements of the Windsor Framework from January 1, 2025, the United Kingdom, or UK, is not generally subject to EU laws in respect of medicines regulation. EU laws that have been transposed into UK law through secondary legislation remain applicable in the UK; however, new EU legislation such as the Clinical Trials Regulation (EU) No 536/2014 is not applicable in the UK. As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, is the UK's standalone medicines and medical devices regulator. As a result of the Northern Ireland Protocol, different rules applied in Northern Ireland than in England, Wales, and Scotland (together, "Great Britain," or GB) for a period following Brexit, with Northern Ireland continuing to follow certain aspects of the EU regulatory regime. However, on January 1, 2025 a new arrangement called the "Windsor Framework" came into effect and largely reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products placed on the UK market. The Windsor Framework removes EU licensing processes and certain EU labeling and serialization requirements in relation to medicinal products supplied to Northern Ireland under the UK-only scheme and introduces a UK-wide licensing process for medicines. In particular, the MHRA is responsible for approving medicinal products placed on the UK market (i.e., Great Britain and Northern Ireland), and the EMA no longer has a role in UK marketing authorizations. A single UK-wide MA may be granted by the MHRA for medicinal products to be sold in the UK, enabling

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products to be sold in a single pack and under a single authorization throughout the UK. In addition, the new arrangements require, for certain packs placed on the UK market on or after January 1, 2025, a "UK Only" label, indicating they are not for sale in the EU. However, although separate authorization is now required to market medicinal products in the UK, since January 1, 2024, the MHRA may apply the International Recognition Procedure, or IRP, when reviewing certain types of MAAs. Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (e.g. the medicines regulatory authorities in Australia, Canada, Switzerland, Singapore, Japan, the U.S.A. and the EMA in the EU) when assessing an application for a UK marketing authorization.

The MHRA has also been updating various aspects of the regulatory regime for medicinal products in the United Kingdom. These include: introducing the Innovative Licensing and Access Pathway to accelerate the time to market and facilitate patient access for innovative medicinal products; updates to the UK national approval procedure, introducing a 150-day target for assessing applications for MAs in the United Kingdom and a rolling review process for MA applications (rather than a consolidated full dossier submission).

Orphan designation in the United Kingdom is, unlike in the EU, not available prior to marketing authorization. Applications for orphan designation are made at the same time as an application for an MA. The criteria to be granted an orphan medicinal product designation are essentially identical to those in the EU but based on the prevalence of the condition in the United Kingdom.

The existing UK regulatory framework in relation to clinical trials is derived from the EU Clinical Trials Directive 2001/20/EC (as implemented into UK law, through secondary legislation). In April 2025, the UK government introduced the Medicines for Human Use (Clinical Trials) (Amendment) Regulations. Such legislation aims to provide a more flexible regime to make it easier to conduct clinical trials in the UK and increase the transparency of clinical trials conducted in the UK. This includes a notification scheme to enable lower-risk clinical trials to be automatically approved by the MHRA, where the risk is similar to that of standard medical care (although such trials would still require ethics committee approval). These changes will take full effect from April 2026 and aim to create a streamlined, risk-proportionate system that accelerates approvals while maintaining robust safety standards.

Ex-EU Regulatory Framework

For other countries outside of the EU, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all cases, clinical trials are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

If we or our potential collaborators fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Employees and human capital resources

As of December 31, 2025, we had a total of 16 full-time employees. Additionally, we utilize independent contractors and other third parties to assist with various aspects of our drug and product development as well as certain general and administrative functions. We are not a party to any collective bargaining agreements.

We recognize that our continued ability to attract, retain and motivate exceptional employees is vital to ensuring our long-term competitive advantage. Our employees are critical to our long-term success and are essential to helping us meet our goals. Among other things, we support and incentivize our employees in the following ways:

●Talent development, compensation and retention—We strive to provide our employees with a rewarding work environment, including the opportunity for success and a platform for personal and professional development. We provide a competitive benefits package designed to attract and retain a skilled and diverse workforce. We also offer employees a 401(k) plan.

●Health and safety—Employee health and safety in the workplace is one of our core values. One of the ways in which we support the health and safety of our employees includes a generous health insurance program.

●Inclusion and diversity—We are committed to efforts to increase diversity and foster an inclusive work environment that supports our workforce. We are an equal opportunity employer and strictly prohibit and do not tolerate discrimination against

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employees, including based on race, creed, color, religion, national origin, citizenship status, age, gender, military and veteran status and sexual orientation. We also prohibit any form of harassment or abuse in the workplace.

Corporate Information

We were incorporated in Delaware in December 2006 under the name 3-V Biosciences, Inc., and changed our name to Sagimet Biosciences Inc. in August 2019. Our principal executive offices are located at 155 Bovet Road, Suite 303, San Mateo, California 94402, and our telephone number is (650) 561-8600.

Our website address is www.sagimet.com. On our Investor Relations website, ir.sagimet.com/investor-relations, we make available free of charge a variety of information for investors, including our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to those reports, as soon as reasonably practicable after we electronically file that material with or furnish it to the Securities and Exchange Commission (the SEC). Information contained on, or that can be accessed through, our website is not incorporated by reference into this Annual Report or any other report we file with, or furnish to, the SEC, and the inclusion of our website address in this Annual Report is only an inactive textual reference. In addition, our filings with the SEC may be accessed through the SEC’s Interactive Data Electronic Applications system at www.sec.gov. All statements made in any of our securities filings, including all forward-looking statements or information, are made as of the date of the document in which the statement is included, and we do not assume or undertake any obligation to update any of those statements or documents unless we are required to do so by law.

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