NASDAQ: SION

We believe stabilizing NBD1 is central to unlocking dramatic improvements in clinical outcomes and quality of life for people with CF. The NBD1 domain of the CFTR protein, as illustrated in Figure 1 below, plays a key role in the folding, assembly, stability and trafficking of CFTR to a cell’s surface, where it normally functions as an ion channel to regulate chloride and water transport. Within the NBD1 domain, F508del severely destabilizes CFTR, disrupting its proper assembly, impairing half-life and decreasing chloride channel function. We have employed biophysical, cell-based and virtual screening campaigns and extensive use of structural biology to guide the optimization of our novel small molecule NBD1 stabilizers. We are also advancing a portfolio of complementary CFTR modulator candidates designed to work synergistically with our NBD1 stabilizers to improve CFTR function, as seen in preclinical models.

We believe our robust pipeline provides multiple potential pathways to achieve our mission, either through development of an NBD1 stabilizer and a complementary modulator in combination with each other to produce a proprietary dual combination, or an NBD1 stabilizer administered in combination with the standard of care for CF. While we have prioritized development of a proprietary dual combination, we believe both development pathways offer attractive commercial opportunities.

Figure 1

Our Pipeline

The following table summarizes our clinical stage pipeline:

Figure 2

Our proprietary portfolio is anchored by our NBD1 stabilizers and our complementary modulators. Our portfolio includes:

•SION-719, which is being evaluated as an add-on to the standard of care: SION-719, a highly potent NBD1 stabilizer, is currently in a Phase 2a proof-of-concept trial in CF patients, called PreciSION CF. The trial is evaluating SION-719 when administered with the standard of care for CF, Vertex Pharmaceuticals, Inc.’s (“Vertex”) Trikafta. Topline data from this trial is anticipated in mid-2026. In June 2025, we announced positive topline data from a Phase 1 trial of SION-719, which evaluated its pharmacokinetic (“PK”) profile, safety and tolerability in healthy volunteers.

•SION-451, which is being evaluated in combinations with SION-2222 and SION-109: SION-451, a highly potent NBD1 stabilizer, is currently being evaluated in dual combinations with each of galicaftor (SION-2222) and SION-109, two of our complementary modulators, in a Phase 1 trial in healthy

volunteers. Topline data from this trial is anticipated in mid-2026. In June 2025, we announced positive topline data from the single agent portion of the Phase 1 trial, which evaluated SION-451’s PK profile, safety and tolerability in healthy volunteers.

•SION-2222, a corrector that targets CFTR’s transmembrane domain 1 (“TMD 1”), was generally well tolerated in Phase 1 and Phase 2 trials previously conducted by AbbVie Global Enterprises Ltd. (“AbbVie”). Improvement in sweat chloride as a monotherapy and improvements in sweat chloride and lung function as a combination therapy with navocaftor (SION-3067), a potentiator, were observed.

•SION-109, a corrector that targets CFTR’s intracellular loop 4 (“ICL4”) region, has been evaluated in a Phase 1 clinical trial in healthy volunteers, which was completed in 2024.

•Additional complementary modulators: We have additional CFTR modulators in our portfolio. SION-2851, a TMD1-directed CFTR corrector, has completed a Phase 1 single-ascending dose (“SAD”) trial in healthy volunteers. SION-3067, a potentiator, has been evaluated in Phase 2 trials, where it demonstrated potential as a combination therapy.

Our pipeline of product candidates target distinct binding sites across the CFTR structure, as depicted in Figure 3 below:

Figure 3

Our Strategy

Our mission is to revolutionize the current treatment paradigm for CF by developing novel medicines that normalize the function of the CFTR protein to deliver clinically meaningful benefit to people with CF. The key pillars of our strategy are:

•Advance our novel NBD1 stabilizers leveraging a data-driven approach. Leveraging the differentiated profiles of SION-719 and SION-451, we have advanced both product candidates to the next phase of development. Figure 4 below presents our strategy for the advancement of SION-719 and SION-451, focusing on distinct development pathways.

•Develop and advance our pipeline of complementary modulators for proprietary combination product development. We are developing a proprietary pipeline of complementary CFTR modulators designed to work synergistically with our NBD1 stabilizers to improve CFTR function, as seen in preclinical models.

•Fortify our CF franchise through continued research efforts and utilization of the translational CFHBE model. Central to our development strategy is our use of the industry standard, clinically predictive preclinical cystic fibrosis human bronchial epithelial (“CFHBE”) model to measure CFTR function. The CFHBE model has been highly predictive of clinical outcomes for approved CFTR modulators, and our application of the model provides a key translational roadmap for us to prioritize compounds for further evaluation. We believe the model allows us to determine the target exposure needed to achieve a desired level of clinical activity, such as the level of improvement in a patient’s forced expiratory volume in one second (“FEV1”), a measure of lung function, and sweat chloride level, the clinical biomarker of CFTR function. We intend to invest in research activities and leverage insights from the model in our pursuit of delivering additional differentiated product candidates that meaningfully impact the lives of people with CF and facilitate our company’s long-term growth. We also intend to opportunistically consider strategic in-licensing opportunities to maximize the value of our pipeline.

•Expand and protect our intellectual property estate. We have developed a broad patent estate and expect to expand and protect our proprietary know-how and intellectual property.

Figure 4

Overview of Cystic Fibrosis, CFTR Function and the F508del Mutation

An estimated 106,000 people have been diagnosed with CF across 94 countries, which includes approximately 40,000 adults and children living with this disease in the U.S., according to the Cystic Fibrosis Foundation (“CFF”). About 1,000 new CF cases are diagnosed every year in the U.S. While life expectancy for people with CF has improved significantly over the years since the first CFTR modulator was approved, the median predicted survival age for individuals with CF born in the U.S. between 2020 and 2024 is still just 65 years, according to the 2024 CFF patient registry. The majority of people who have been diagnosed with CF live in the U.S., the United Kingdom and Europe. CF is the most common fatal inherited disease in the U.S., and it can affect people of every racial and ethnic group.

CF is caused by mutations to the CFTR gene that result in reduced or no function of the CFTR protein. The disease is autosomal recessive, meaning that two copies of a CFTR mutation are required to cause the disease: either two copies of the same mutation (“homozygous”) or two different mutations (“heterozygous”). The most common CFTR mutation is F508del, which is a deletion of the amino acid phenylalanine at position 508, which is in NBD1; approximately 90% of people with CF carry at least one copy of the F508del mutation, and approximately 44% of people with CF are homozygous for F508del. The F508del mutation is considered a severe CF mutation, and individuals with this mutation tend to fall at the worst end of the CF severity spectrum because they have little or no CFTR function in epithelial cells.

The CFTR protein is found on the apical membrane, or surface, of epithelial cells throughout the body, including in the lungs, pancreas, sweat glands, biliary tract and intestines. The CFTR protein is critical for proper salt and water balance in the cell, which drives production of freely flowing mucus for tissue hydration in the airways, digestive system and other organs. In people with CF, mutations in the CFTR gene cause the CFTR protein to become dysfunctional. When the CFTR protein is not working properly, chloride—a component of salt—gets trapped in cells, as illustrated in Figure 5. Without chloride to attract water to the cell surface, thick mucus accumulates in vital organs such as the lungs, pancreas and gastrointestinal tract and causes multisystem complications, including respiratory infections, chronic lung inflammation, poor nutrient absorption and often progressive respiratory failure, which is the primary cause of death in people with CF.

(Figure 5. Source: Favia, 2019)

As illustrated in Figure 6, the CFTR protein includes two nucleotide binding domains (NBD1 and NBD2) and two transmembrane domains (TMD1 and TMD2). The transmembrane domains form the ion channel across an epithelial cell’s membrane. The nucleotide binding domains facilitate the ion channel’s opening and closing by binding and hydrolyzing adenosine triphosphate. There are also four intracellular loops that link the nucleotide binding domains to the transmembrane domains and are important to regulating ion channel gating.

Figure 6

The F508del mutation occurs in the NBD1 domain near an interface with the fourth intracellular loop, ICL4, which is particularly critical to the folding of CFTR. When the ICL4 interface is disrupted, as it is by the F508del mutation, CFTR can neither fold nor function properly. The F508del mutation severely destabilizes CFTR’s NBD1 domain, preventing normal folding and trafficking of CFTR to a cell’s surface and impairing chloride channel function. Support for NBD1 as a key target is based in part on in vitro studies that introduced mutations at other sites on NBD1 that suppressed the effect of the F508del mutation.

Current Unmet Need and Market Opportunity

While advances in the treatment of CF have improved the lives of people with the disease and resulted in a large commercial market, we believe significant opportunity remains to provide clinically meaningful benefit to people with CF through the development of NBD1-anchored treatments. NBD1 has long been considered an important target to normalize CFTR function because it is the site where the F508del mutation—the most common mutation that causes CF—occurs. However, attempts by others to stabilize NBD1 have fallen short, leading to the view that NBD1 is “undruggable.” The current standard of care for CF, Trikafta, and Alyftrek, which

was approved in December 2024, are each made up of three components that target certain domains of CFTR, but not NBD1.

At least two-thirds of patients on Trikafta do not have normal CFTR function, defined as sweat chloride levels below 30 mmol/L. Even treated CF patients can continue to experience the ongoing effects of reduced CFTR function over time, including respiratory infections, pulmonary exacerbations, or “lung attacks,” and continued lung function decline. More than 6,000 patients have discontinued use of approved CFTR modulators, none of which target NBD1. Additionally, some patients on Trikafta reduce dosages due to tolerability issues, including elevated liver function tests and mental health effects such as mood disturbances, depression, and mental fogginess. In December 2024, the Trikafta label was updated to include a boxed warning for the risks of drug-induced liver injury and liver failure, and the Alyftrek label includes the same boxed warning. Seven to eight percent of patients on Trikafta have experienced significant mental health effects, and depression, including suicidal ideation and attempt, is listed in the warnings and precautions section of the summary of product characteristics for Kaftrio, the brand name for Trikafta in Europe. Patients who discontinue use of Trikafta or experience tolerability challenges have limited or no alternative treatments available to improve their clinical outcomes or quality of life.

Current treatment alternatives for these patients are limited to less efficacious combination products that include one or more components of Trikafta, or Alyftrek. In two Phase 3 clinical trials, Alyftrek demonstrated non-inferiority to Trikafta in the primary endpoint, providing participants with similar FEV1 to Trikafta and sweat chloride level improvements of approximately 3 to 8 mmol/L. In participants who were homozygous for the F508del mutation, the sweat chloride improvement observed was approximately 3 mmol/L. Across both trials, approximately 69% of Alyftrek patients did not achieve normal CFTR function. Our research with key opinion leaders has indicated the desire for more treatment options for people with CF, particularly in support of a new mechanism of action that could provide clinically meaningful benefit or an alternative for those patients who experience tolerability issues on Trikafta.

Worldwide revenue for approved CFTR modulators was approximately $12 billion in 2025, and it is expected to grow to over $15 billion by 2030. CF screening of newborn infants has served to identify CF patients as early as possible in their lives. For example, newborn screening for CF has been required in the U.S. since 2010, and in 2024, 55.8% of newly diagnosed people with CF in the U.S. were identified by newborn screening, based on CFF registry data. The availability of CFTR modulators has also increased the use of genetic testing to determine eligibility for treatment.

Current Standard of Care and its Limitations

The approved CFTR modulators are oral small molecule therapies that improve CFTR function either by potentiating channel gating or by improving cellular processing and trafficking of the CFTR protein. The current standard of care for people with the F508del mutation is a triple combination product marketed by Vertex as Trikafta (elexacaftor, tezacaftor, ivacaftor and ivacaftor). In addition, in December 2024, Vertex received approval from the U.S. Food and Drug Administration (“FDA”) for a second-generation, triple modulator combination, Alyftrek, for the treatment of CF in patients who have at least one F508del mutation or another responsive mutation in the CFTR gene. Vertex also markets three other approved CFTR modulators. None of the approved modulators directly stabilize NBD1.

Despite the clinical benefits Trikafta provides CF patients, including improved lung function and quality of life, at least two-thirds of people with CF being treated on Trikafta or another approved CFTR modulator do not have normal CFTR function. CF progression is most commonly assessed through a patient’s mean lung function, as measured by FEV1 improvement. In addition, sweat chloride level, the clinical biomarker of CFTR function, has been used for decades as a diagnostic test for CF and has served as a highly useful tool in the development of approved CFTR modulators. A sweat chloride level greater than or equal to 60mmol/L indicates that CF is likely, while a sweat chloride level under 30 mmol/L is normal and indicates that CF is unlikely. Sweat chloride levels between 30 mmol/L and 59 mmol/L are considered abnormal, indicating partial CFTR dysfunction or “residual function” in diagnostic settings. An observational study of 3,131 individuals with CF from the CFF Registry found that, while treatment with Trikafta resulted in improvements in sweat chloride level to below 60 mmol/L in most patients, two-thirds of patients still had sweat chloride levels above normal levels (Figure 7).

(Figure 7. Sweat chloride levels less than or equal to 29 mmol/L indicate that CF is unlikely; levels of 30 - 59 mmol/L indicate that CF is possible and additional testing is needed; and levels greater than or equal to 60 mmol/L indicate that CF is likely.)

Two-year interim data from a five-year post-marketing real-world observational trial of patients taking Trikafta showed that mean rates of pulmonary exacerbations and the presence of bacterial pathogens improved but were not normalized after initiating treatment on Trikafta. The three-year interim data, presented at the European CF Society meeting in Glasgow in 2024, showed numerical increases in mean rates of pulmonary exacerbations and decreases in mean lung function compared to the two-year interim data, supporting the opportunity for clinical improvements over the standard of care. In addition to continued pulmonary complications, patients also experienced negative mental health side effects, including numerical increases in rates of depression, anxiety disorder and hypertension after initiating treatment on Trikafta. Another side effect associated with ivacaftor (a component of Trikafta) is cataracts, which can complicate use and requires monitoring, especially in children. In addition, both the Trikafta and Alyftrek labels include a boxed warning for the risks of drug-induced liver injury and liver failure.

Alyftrek demonstrated non-inferiority to Trikafta in the primary endpoint of two Phase 3 clinical trials, providing patients with similar FEV1 as Trikafta and sweat chloride level improvements of approximately 3 to 8 mmol/L. In participants who were homozygous for the F508del mutation, the sweat chloride improvement observed was approximately 3 mmol/L. Across both trials, approximately 69% of Alyftrek patients did not achieve normal CFTR function. These results support our beliefs that NBD1 stabilization is required to meaningfully improve upon the standard of care and that a high unmet need remains for an alternative therapy that can provide clinically meaningful benefit to CF patients.

Research Findings Support NBD1 as a Key Target for Stabilizing F508del-CFTR

Multiple studies by third parties have concluded that NBD1 is a key drug target for correcting the F508del mutation, including in vitro studies that introduced mutations at other sites on NBD1 that suppressed the effect of the F508del mutation. For example, researchers at Utrecht University and University of Texas

Southwestern Medical Center identified a second site NBD1 mutation (“I539T”) that rescued the misfolding and instability of F508del-CFTR. They concluded the “co-translational rescue of F508del NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis.”

At University of Texas Southwestern Medical Center, University of Alabama Birmingham, and McGill University, a second group of researchers identified additional mutations that suppressed the effect of F508del and which, in in vitro studies, stabilized NBD1 and the NBD1-ICL4 interface and fully restored F508del-CFTR maturation and function to wild-type levels, as shown in the western blot in Figure 8. A western blot is an assay that uses gel electrophoresis to separate a mixture of proteins, which are then transferred to a solid membrane, and then an antibody is used to detect a specific protein in the sample. The mature apical CFTR band is seen with wild-type CFTR. Partial restoration is observed with NBD1 stabilization and ICL4 interface restoration individually; full restoration of CFTR function occurred in the presence of both NBD1 and ICL4 suppressor mutations. Without a suppressor mutation, no F508del-CFTR is produced (Ø).

(Figure 8. Source: Thibodeau, 2010)

Research Findings Link Further Improvements in CFTR Function to Improved Clinical Outcomes

Clinical evidence obtained by third parties has illustrated that further reductions in sweat chloride, the clinical biomarker of CFTR function, towards wild-type levels, are associated with improved clinical outcomes, even for patients who have already experienced some benefits from an approved modulator therapy. According to a trial published in the New England Journal of Medicine, when CF patients heterozygous for F508del and a “gating” mutation were switched from Kalydeco, which does not target F508del, to Trikafta, which targets F508del, they experienced significant improvements in CFTR function, as measured by improvements in the mean sweat chloride levels, and in mean lung function, as measured by FEV1. Patients with a gating mutation represent approximately 6% of the CF patient population. Their mean sweat chloride level at baseline was 50.9 mmol/L. After eight weeks of treatment with Trikafta, the patients’ mean sweat chloride level was 32.7 mmol/L, representing an improvement of approximately 20 mmol/L, and their mean lung function level, as measured by FEV1, improved by 5.8 percentage points.

Our Approach and Leveraging the CFHBE Model

Our programs leverage an industry standard, clinically predictive CFHBE model to measure CFTR protein function in vitro. The CFHBE model uses lung cells from people with CF and has been highly predictive of clinical outcomes for approved CFTR modulators. Activity in the CFHBE model has been shown to be correlated to chloride transport activity, which in turn, has been shown to be correlated to improved lung function in clinical trials designed to evaluate product candidates in CF patients. We have used, and plan to continue to use, insights from the CFHBE model to identify active compounds, predict potential clinical exposures, and inform critical pipeline prioritization and development decisions. For example, we selected SION-719 and SION-451 to advance based on their preclinical profiles, including potency in the CFHBE model. In preclinical studies using the CFHBE model, we evaluated our NBD1 stabilizers in several combinations (including SION-719 with the components of Trikafta (elexacaftor/tezacaftor/ivacaftor, or “ETI”), and SION-451 with each of SION-2222 and SION-109) in direct comparison to ETI alone, with all compounds at their respective highest effective dose (“Emax”), and observed a marked improvement in CFTR protein activity of more than 1.5-fold relative to ETI alone. We believe that we can leverage the reproducible correlation between chloride transport at different drug exposure levels in the CFHBE model and clinical outcomes to predict the target level of exposure to achieve clinically meaningful benefit in CF patients.

The CFHBE model uses electrophysiology to evaluate CFTR function by measuring CFTR protein activity in an Ussing Chamber, which is commonly used in CF drug discovery efforts. In this model, human bronchial cells derived from the lungs of CF patients are cultured in a manner to resemble the lung epithelium and to increase their numbers. These cultured cells are then placed in the Ussing Chamber, which uses electrodes to measure ion movement across the membranes of the cultured epithelial cells grown into a monolayer with tight junctions. Cultured CFHBE cells exhibit many of the structural and functional attributes believed to be associated with CF airway disease.

Vertex has successfully applied a variation of the CFHBE model with 20% human serum for multiple CFTR modulators advanced to clinical trials, including their five approved modulators, and has demonstrated that increased chloride transport in the CFHBE model is strongly correlated with improved CFTR function in CF patients. Importantly, the CFHBE model provided key preclinical data on CFTR function to support the clinical evaluation of elexacaftor as part of Trikafta. Based on publications detailing Vertex’s use of the CFHBE model, we believe we conducted our CFHBE model using similar methods and under similar experimental conditions to those Vertex employed. Similar to Vertex, in our model, cell culture media is supplemented with human serum to 20% by volume to estimate the amount of free drug available to engage CFTR in CFHBE cells. This adjustment is designed to simulate the in vivo environment, where much of a drug is bound to serum proteins and not available to enter epithelial cells.

We conduct detailed dose-response studies in our CFHBE model to estimate the level of clinical improvement we believe we can achieve with our modulators at specific levels of drug exposure in clinical trials. The addition of human serum helps correct for the high levels of protein binding that are characteristic of our modulators, similar to approved modulators, which we believe enables our model to more accurately predict the clinical exposure required for efficacy. Our CFHBE model accurately predicted the required total plasma concentration of lumacaftor (a component of Orkambi) at its efficacious clinical exposures, as shown in Figure 9 below. We compared lumacaftor’s CFTR-dependent chloride transport activity in two CFHBE model variants—with 20% human serum (like our model) and without 20% human serum—and benchmarked these against published Phase 2 clinical results regarding sweat chloride levels for lumacaftor. Figure 9 shows that the predicted lumacaftor dose response, as depicted by the red line, closely matched lumacaftor’s clinical dose response, as depicted by the black line. The CFHBE model without 20% human serum, depicted by the blue line, failed to accurately predict the clinical exposure of lumacaftor required for efficacy, even if adjusted for lumacaftor’s measured free fraction in human plasma, depicted by the dotted green line.

Figure 9

Using published data from the clinical trials of Vertex’s approved CFTR modulators, we have validated internally our CFHBE model by assessing the relationship between in vitro CFTR protein function, as measured by chloride transport in our CFHBE model, and the mean sweat chloride levels seen in Vertex’s clinical trials of these approved modulators.

As shown in Figure 10 below, improvements in CFTR function we observed in our CFHBE model for approved and investigational CFTR modulators have been highly correlated with improvements in sweat chloride measurements from clinical trials for these therapies. Notably, we have used the CFHBE model to predict negative clinical trial outcomes, too. For example, we modeled other third-party modulators previously in development and independently determined that these compounds had insufficient activity to demonstrate target clinical efficacy, which was supported by published clinical trial data.

Figure 10

Mean improvements in sweat chloride levels in clinical trials have been shown to be correlated with mean improvements in lung function as measured by FEV1, as shown in Figure 11 below.

Figure 11

We consider our CFHBE model a translational roadmap because of its ability to correlate with sweat chloride improvement in clinical trials, as seen in Figure 10 above, which in turn has been shown to correlate to improved lung function in clinical trials, as shown in Figure 11 above. We have observed this correlation with our CFHBE data and clinical lung function data for approved and investigational CFTR modulators that demonstrated activity in clinical trials, including SION-2222 and SION-3067, as shown in Figure 12 below.

Figure 12

We believe our CFHBE model allows us to predict the target exposure needed for our product candidates to achieve a desired level of clinical activity, such as the level of improvement in patients’ lung function, as measured by FEV1 improvement, and sweat chloride levels. We have tested our product candidates in the CFHBE model at Emax and generated a prediction of sweat chloride and FEV1 changes, based on the documented correlation, observed in clinical trials of approved and investigational modulators, between improvements in sweat chloride levels and improvements in lung function. We believe that the CFTR function improvement observed in our CFHBE model of our product candidates has the potential to translate clinically to deliver clinically meaningful benefit to CF patients.

Our CF Programs

We have a portfolio of NBD1 stabilizers and complementary modulators that target other regions of the CFTR protein, with the goal of advancing a combination therapy that has the potential to deliver clinically meaningful benefit to CF patients. We believe our robust pipeline provides multiple potential pathways to achieve our goal, either through development of an NBD1 stabilizer and a complementary modulator in combination with each other to produce a proprietary dual combination, or an NBD1 stabilizer administered in combination with the standard of care for CF. Leveraging the differentiated profiles of our two lead NBD1 stabilizer product candidates observed in their respective Phase 1 trials, we have advanced both SION-451 and SION-719 to the next phase of development.

NBD1 Stabilizer Program

NBD1 is recognized as a key target in treating CF patients with the F508del mutation, as the mutation drives NBD1 instability and defects in its interface assembly. However, NBD1 has presented significant challenges as a drug target due to the attributes of the region’s binding sites. Our NBD1 program builds on more than a decade of our cofounders’ research, which has combined biophysical, cell-based and virtual screening campaigns, along with extensive use of structural biology. We believe the technical challenge associated with NBD1-targeted drug discovery, along with our intellectual property rights, represent a substantial competitive barrier.

SION-719 — Clinical Data

Phase 2a PreciSION CF Trial

In October 2025, we announced the initiation of our ongoing Phase 2a proof-of-concept trial in CF patients, called PreciSION CF, which is evaluating SION-719 when added to the current standard of care. The

trial is designed to evaluate the safety, tolerability, and PK of SION-719 when administered with Trikafta, and to assess change in CFTR function as measured by sweat chloride levels. The trial is a two-way crossover trial anticipated to enroll approximately 16 participants with CF who are stable on physician-prescribed Trikafta. All participants will be randomly allocated to one of two trial arms and will continue taking Trikafta throughout the trial. Participants in “Arm A” will first receive Trikafta in combination with SION-719 for 14 days, and, after a 28-day washout period, will then receive Trikafta in combination with placebo for 14 days. Participants in “Arm B” receive the same treatments in reverse order, followed by a 28-day safety follow-up period. We expect topline data from the PreciSION CF trial in mid-2026.

Phase 1 Single Agent Trial of SION-719

In June 2025, we announced positive topline data from a randomized, double blind, placebo-controlled Phase 1 clinical trial of SION-719 in healthy participants. The trial was designed to evaluate the safety, tolerability and PK profile of single and multiple ascending doses (“MAD”) of SION-719, administered as an oral suspension. In a Part C of the Phase 1 trial, we evaluated the effect of food on PK and the bioequivalence of a tablet formation compared to the oral suspension used in the Phase 1 SAD and MAD trials.

A total of 100 healthy adult participants were dosed in this Phase 1 trial. The trial was designed to enroll eight participants, randomized 3:1 active:placebo, to each dosing cohort. SAD cohorts evaluated single doses ranging from 20 mg to 160 mg in a fasted state; 20 mg taken with food was also evaluated in a SAD cohort to provide a preliminary assessment of the effect of food on PK. Five MAD cohorts evaluated doses ranging from 20mg to 160mg dosed twice daily (“BID”) over ten dosing days. Twenty participants were dosed in the open-label food effect and tablet bioequivalence part evaluating 30 mg and 120 mg single doses each of suspension (fasted), tablet (fasted), and tablet (fed).

SION-719 was generally well tolerated at all dose levels administered in all parts of this Phase 1 trial. A summary table of reported treatment emergent adverse events (“TEAEs”) is shown in Figure 13 below. There were no serious adverse events (“SAEs”), and most TEAEs were mild to moderate (Grade 1 or Grade 2). No TEAEs led to the discontinuation of trial drug, and no dose-limiting TEAEs were observed. The most common TEAEs, occurring in >2 participants, were headache, diarrhea, and nausea. There were no TEAEs related to liver function tests in SION-719 treated patients. There were no clinically meaningful, treatment-emergent trends in other safety parameters, vital signs or electrocardiograms. The data from Part C support the use of a tablet formulation in future trials and indicate that SION-719 can be dosed in a fed or fasted state.

(Figure 13. Safety observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)

Increasing exposure was observed with increasing single and multiple doses. The concentration targets for SION-719 as an add-on to the standard of care and as part of a dual combination with SION-2222 or SION-109 were achieved with single and multiple doses.

The PK of SION-719 observed in the Phase 1 trial was consistent with BID dosing, and is summarized in Figure 14 below.

(Figure 14. Each solid line shows mean concentration data from a dosing cohort on Day 10. Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-719 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to the standard of care. PK observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)

Following completion of this Phase 1 trial, we evaluated the achieved clinical exposures of SION-719 in our CFHBE model with a fixed concentration of ETI, to assess SION-719's potential as an add-on to ETI. As shown in the CFHBE model, and depicted in Figure 15, at the clinical exposures achieved in the lower dose range of SION-719, SION-719 in combination with ETI has the potential to improve CFTR channel activity above our minimum target for clinically meaningful benefit, including up to wild-type levels. In Figure 15, CFTR activity in the model is expressed as a ratio relative to ETI at Emax, which is set at a reference value of 1.00. Based on these findings, we believe that SION-719, when added to standard of care, has the potential to provide clinically meaningful benefit to CF patients.

Figure 15

SION-451 — Clinical Data

Phase 1 Dual Combination Trial

In August 2025, we announced the initiation of a Phase 1 dual combination trial in healthy volunteers evaluating SION-451 in dual combinations with each of SION-2222 and SION-109, two of our complementary CFTR modulators. The trial is designed to evaluate the safety, tolerability, and PK of varying doses of the dual combinations and will inform selection of a dual combination for further development. We expect topline data from the trial in mid-2026.

Phase 1 Single Agent Trial

In June 2025, we announced positive topline data from the single-agent portion of a randomized, double blind, placebo-controlled Phase 1 clinical trial of SION-451 in healthy participants. The trial was designed to evaluate the safety, tolerability and PK profile of single and multiple ascending doses of SION-451, administered as an oral suspension. In Part C of the Phase 1 trial, we evaluated the effect of food on PK and the bioequivalence of a tablet formation compared to the oral suspension used in the Phase 1 SAD and MAD trials.

One hundred and ten total healthy adult participants were dosed in the single-agent portion of this Phase 1 trial. The trial was designed to enroll eight participants, randomized 3:1 active:placebo, to each dosing cohort. SAD cohorts evaluated single doses of 75 mg to 450 mg while fasted, as well as single doses of 25 mg and 75 mg with food to provide a preliminary assessment of the effect of food on PK. Five MAD cohorts evaluated doses between 75mg and 300mg BID over ten dosing days, and 25 mg taken with food to provide a preliminary assessment of the effect of food on PK. Twenty-four participants were dosed in the open-label food effect and tablet bioequivalence part, with separate cohorts evaluating 25 mg and 300 mg as single doses of suspension (fasted), tablet (fasted), and tablet (fed).

SION-451 was generally well tolerated at all dose levels administered. A summary table of reported TEAEs is shown in Figure 16 below. There were no SAEs, and most TEAEs were mild to moderate (Grade 1 or Grade 2). No TEAEs led to the discontinuation of trial drug, and no dose-limiting TEAEs were observed. Most TEAEs occurring in >2 participants were Grade 1 or Grade 2, and several were in an isolated dose cohort that was impacted by an outbreak of respiratory infection in the Phase 1 unit. One Grade 1 TEAE of increased transaminases was observed in a participant with influenza A infection; the same participant had transient Grade 3 neutropenia concurrent with influenza A infection. There were no other TEAEs related to liver function tests. There were no clinically meaningful, treatment-emergent trends in other safety parameters, vital signs or electrocardiograms. The data from Part C supported the use of a tablet formulation in future studies and indicate that SION-451 can be dosed in a fed or fasted state.

(Figure 16. Safety observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)

Increasing exposure was observed with increasing single and multiple doses. The concentration targets for SION-451 as both an add-on to the standard of care and as part of a dual combination with SION-2222 or SION-109 were achieved with single and multiple doses. A PK summary of SION-451 in the MAD portion of the trial is shown in Figure 17 below. The observed PK was consistent with BID dosing.

(Figure 17. Each solid line shows mean concentration data from a dosing cohort on Day 10. Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-451 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to the standard of care. PK observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)

Following completion of the single agent portion of this Phase 1 trial, we evaluated the achieved clinical exposures of SION-451 in our CFHBE model with a fixed concentration of SION-109 and SION-2222, to assess their potential in dual combinations. As shown in the CFHBE model, and depicted in Figure 18, at these clinical exposures achieved, SION-451 in combination with each of SION-2222 or SION-109 has the potential to improve CFTR channel activity above our minimum target for clinically meaningful benefit, including up to wild-type levels. In Figure 18, CFTR activity in the model is expressed as a ratio relative to ETI at Emax, which is set at a reference value of 1.00. Based on these findings, we believe that SION-451 in a dual combination with a complementary modulator has the potential to provide clinically meaningful benefit to CF patients, and we advanced SION-451 into our ongoing dual combination trial with each of SION-2222 and SION-109.

Figure 18

Preclinical Studies of SION-719 and SION-451

We have used numerous complementary methods to validate and characterize the activity of our compounds. In addition to the CFHBE model, we have utilized differential static light scattering (“DSLS”) experiments to measure the thermal stability of the NBD1 protein, surface plasmon resonance (“SPR”) studies to evaluate the interaction of SION-719 and SION-451 with the NBD1 domain, CFTR western blot analysis to assess the impact of NBD1 stabilizers on the folding, maturation and stability of F508del-CFTR, and metabolic pulse-chase analysis studies to assess the impact of SION-719 and SION-451 on F508del-CFTR half-life. Given the results of these preclinical studies, we believe that we have identified highly potent NBD1 stabilizers.

SION-719 and SION-451 Increased NBD1 Thermal Stability

In preclinical studies, SION-719 and SION-451 increased the stability of the NBD1 domain as measured using DSLS experiments. Light scattering provides a measure of the temperature at which a protein unfolds. As the temperature rises, the CFTR protein unfolds and creates aggregates that interfere with the passage of light. These preclinical studies evaluated the change in temperature that the protein aggregated as the ratio of the compound to CFTR protein increased, which is an indicator of stability. We also evaluated ETI in these preclinical studies, and we found that they had no effect on NBD1 thermal stability, as measured by light scattering techniques. Restoration of NBD1 thermal stability has been highlighted as being both necessary and sufficient to correct F508del CFTR folding and assembly. Both SION-719 (Figure 19, left) and SION-451 (Figure 19, right) increased F508del-NBD1 stability by approximately 16°C. These preclinical models show the ability of SION-719 and SION-451 to improve the stability of NBD1 as compared to ETI, as measured by light scattering techniques.

ΔTagg °C = Change in the temperature at which F508del-NBD1 protein unfolds and aggregates

N=4, error bars represent standard deviation

Figure 19

SION-719 and SION-451 Bound to NBD1 with High Affinity

To evaluate the binding ability of our stabilizer candidates, we employed SPR studies to evaluate the interaction of SION-719 and SION-451 with the NBD1 domain. SPR studies measure changes in the mass of biomolecules immobilized on a metal film. When a small molecule ligand binds to the immobilized target protein, the refractive index of the metal film changes, resulting in a changed reflection angle of light. In these studies, we found that the strength of the binding interaction was high; the binding affinity of SION-719 to F508del-NBD1 was approximately 4.3 nM and the binding affinity of SION-451 to F508del-NBD1 was approximately 2.4 nM, each expressed as a KD value.

SION-719 and SION-451 Restored F508del Folding and Maturation

In preclinical studies, we evaluated SION-719 and SION-451 in various combinations, including with ETI, SION-2222, and SION-109 to assess these combinations’ ability to improve CFTR folding, maturation and stability and thereby correct F508del-CFTR. Preclinical studies with both SION-719 and SION-451-based combinations resulted in F508del-CFTR maturation to levels that are similar to wild-type CFTR. We believe

these results demonstrated potential synergy between an NBD1 stabilizer and these complementary modulators.

The results of studies of CFTR maturation in human CF submucosal gland epithelial (“CFSMEo”) cells by western blot with SION-719 are shown in Figure 20 (top), and the results with SION-451 combinations are shown in Figure 20 (bottom). Together, the western blots illustrate F508del-CFTR protein in a submucosal-gland epithelial cell line that expresses CFTR, treated with various combinations of CFTR modulators. The top molecular weight bands, labeled C-band, indicate the presence of the active, mature apical glycoform of CFTR (dark bands), which is responsible for CFTR channel function. The compounds were evaluated at their Emax.

In Figure 20, the far-left column in the C-band is F508del in dimethylsulfoxide (“DMSO”) alone, showing no mature protein, and the far-right column is wild-type CFTR in DMSO with a dark band indicating the presence of mature CFTR protein. As seen in Figure 20 (top), dual combinations of SION-719 with SION-2222 or SION-109, or the addition of SION-719 to ETI, resulted in wild-type levels of corrected F508del-CFTR protein. Treatment with SION-719 as a single agent demonstrated a greater effect on F508del maturation than ETI at Emax. On the other hand, there was little improvement in the maturation of F508del-CFTR protein with SION-2222 alone, SION-109 alone or ETI at their respective Emax concentrations, as indicated by the light gray bands. The results with SION-451 presented in Figure 20 (bottom) are similar. The western blots below demonstrate the importance of NBD1 stabilization to the correction of F508del maturation.

Figure 20

SION-719 and SION-451 Improved the Half-life of F508del-CFTR

In preclinical studies, we used metabolic pulse-chase labeling analysis to evaluate the impact of NBD1 stabilizers SION-451 and SION-719 on F508del-CFTR half-life at the apical cell surface. In these studies, cells expressing F508del-CFTR were labeled to track newly synthesized CFTR protein, and the rate at which the labeled protein declined over time was measured to assess whether treatment with SION-719 or SION-451 increased the half-life of the mature CFTR protein relative to controls. We evaluated SION-451 in the presence or absence of SION-2222 or SION-109, and SION-719 in the presence or absence of ETI. As shown in Figure 21, treatment with either NBD1 stabilizer, as single agents or in combination with other complementary modulators, increased F508del-CFTR half-life to that of wild-type CFTR. In comparison, treatment with ETI alone had a minimal effect on F508del-CFTR half-life.

Figure 21

SION-719 and SION-451 Normalized CFTR Function in CFHBE Model at Emax

In our CFHBE model, SION-719 and SION-451 as single agents at Emax improved F508del-CFTR activity to levels observed near those with triple combination ETI at Emax. The results of the SION-719 and SION-451 studies are shown in Figure 22. In Figure 22, CFTR activity is expressed as a ratio relative to ETI at Emax. The vertical bars represent the mean CFTR channel activity (+/- standard error of eight replicates) from a representative study in homozygous F508del CFHBE cells in response to the treatments indicated. The dashed line represents the average response to ETI in each study.

Figure 22

In our CFHBE model, SION-719 when added to ETI and SION-451 in dual combinations with SION-2222 or SION-109, improved in vitro F508del-CFTR activity to wild-type levels, when administered at Emax. As noted above, improvements in CFTR function we observed in our CFHBE model have been highly correlated with mean improvements in sweat chloride levels and mean improvements in lung function.

Based on our findings in these preclinical studies and the strong correlation between chloride conductance and improved clinical activity, we believe that SION-719 in combination with ETI and SION-451 in combination with a complementary CFTR modulator, have the potential to achieve significant improvement in

CFTR function, as measured by sweat chloride levels and lung function, and thereby have the potential to lead to clinically meaningful benefit for CF patients.

Setting Initial Clinical Exposure Targets Based on CFHBE Model

To set total plasma concentration targets in our Phase 1 clinical trials with SION-719 and SION-451 in healthy volunteers, we conducted multiple dose response studies of both compounds in our CFHBE model that assessed F508del-CFTR activity as a function of each compound’s concentration in cell culture media supplemented with human serum to 20% by volume. We selected a target exposure for our Phase 1 trials based on an average of these preclinical dose response studies along with studies to define an adequate safety margin. Figure 23 below presents illustrative dose responses of SION-719, as a single agent and in combination with ETI, SION-109 or SION-2222, as a function of the fold efficacy (CFTR activity) of ETI at increasing dose concentrations, in CFHBE cells from single donors. The black dotted horizontal line indicates ETI’s improvement in F508del-CFTR activity at Emax, the teal horizontal line indicates our minimum target for clinically meaningful improvement in F508del-CFTR activity based on our CFHBE assay, and the green horizontal line represents the lower bound of the CFTR activity range observed across a panel of eight CFTR wild-type CFHBE donors. The X-axis shows increasing drug concentrations on a logarithmic scale. A roughly two-fold increase over ETI, as seen with SION-719 treatment at its Emax in each of the three combinations, is in the range of wild-type channel activity.

(Figure 23. ETI = 3 μM Elexacaftor + 45 μM Tezacaftor + 0.3 μM Ivacaftor. SION-109 and SION-2222 were used at 3 μM.)

Figure 24 below presents illustrative dose responses of SION-451, as a single agent and in combination with ETI, SION-109 or SION-2222, as a function of the fold efficacy (CFTR activity) of ETI at increasing dose concentrations, in CFHBE cells from single donors. A roughly two-fold increase over ETI, as seen with SION-451 treatment at its Emax in each of the three combinations, is in the range of wild-type channel activity.

(Figure 24. ETI = 3 μM Elexacaftor + 45 μM Tezacaftor + 0.3 μM Ivacaftor. SION-109 and SION-2222 were used at 3 μM.)

These dose response curves illustrate that our NBD1 stabilizers work synergistically with complementary modulators, and with the standard of care, to significantly improve CFTR function in preclinical models. Given the correlation seen in our preclinical studies between CFTR function and clinical activity, we believe that achieving target exposure levels for our product candidates in our ongoing and future clinical trials has the potential to translate to significant improvements in sweat chloride and lung function, as measured by FEV1, in CF patients.

Preclinical Safety/Pharmacology and Toxicology to Support Clinical Trials

For both SION-719 and SION-451, we conducted standard in vitro and in vivo toxicology and safety pharmacology studies necessary to support first in human studies. The preclinical study results supported early clinical testing above exposure levels that we have predicted can be effective.

Additional NBD1 Stabilizer Candidates

Our portfolio includes additional NBD1 stabilizer candidates with differentiated profiles from SION-719 and SION-451. We have nominated two additional NBD1 stabilizers as development candidates.

Complementary Modulator Programs

There are two types of complementary modulators: correctors, which partially improve CFTR protein folding to aid its trafficking to the cell surface, and potentiators, which increase CFTR channel function by enabling chloride flow through the cell membrane. We have established a pipeline of proprietary complementary modulators, representing three different mechanisms of action: TMD1-directed correctors, an ICL4-directed corrector, and a potentiator. Our two prioritized clinical-stage complementary modulators are SION-2222 and SION-109. We are currently evaluating each of SION-2222 and SION-109 in dual combinations with SION-451 in a Phase 1 trial in healthy volunteers.

Clinical Data — Complementary Modulators

TMD1 Programs—SION-2222 and SION-2851

SION-2222 is currently being evaluated in a dual combination with SION-451 in a Phase 1 healthy volunteer trial. In a Phase 2 clinical trial conducted by AbbVie prior to our in-licensing transaction, SION-2222 demonstrated clinical activity in improving sweat chloride and lung function as part of a combination trial with SION-3067. SION-2222 has been evaluated in Phase 1, Phase 1b and Phase 2 clinical trials involving healthy participants and CF patients. Across these studies, SION-2222 was generally well-tolerated at all doses administered. The majority of adverse events (“AEs”) were mild to moderate in severity. No SAEs were reported in healthy volunteers, and among CF patients, SAEs were reported infrequently and consisted of common manifestations of the underlying CF disease. The PK profile of SION-2222 in CF patients was similar to that observed in healthy volunteers. The activity of SION-2222 in patients with CF has been evaluated in three randomized, double-blind, placebo-controlled Phase 2 trials: trial M19-530, conducted by AbbVie, and trials GLPG-2222-CL-201 and GLPG-2222-CL-202, conducted by Galapagos NV (“Galapagos”).

Trial M19-530 was a Phase 2 dose-ranging trial that evaluated the safety, tolerability and efficacy of SION-3067 alone and in combination with SION-2222 in CF patients that were homozygous for F508del mutation. The primary efficacy endpoint of this trial was absolute change in lung function (ppFEV1), and the secondary efficacy endpoint was improvement in sweat chloride. In this trial, treatment with SION-2222 in combination with SION-3067 was associated with improvements from baseline ppFEV1 and sweat chloride, both compared to placebo, as shown in Figure 25. SION-2222 was generally well tolerated in combination with SION-3067. Most AEs were mild to moderate. Two SAEs were reported in two participants receiving SION-2222 in combination with SION-3067, which investigators considered unrelated to study drug.

Trial GLPG-2222-CL-202 was a Phase 2 dose-ranging trial that evaluated the safety and tolerability and the effect of SION-2222 on CFTR function (as assessed by sweat chloride), lung function (as assessed by ppFEV1) and the Cystic Fibrosis Questionnaire— Revised (“CFQ-R”), which measures health-related quality of life, in CF patients that were homozygous for F508del mutation. In this trial, mean sweat chloride concentrations decreased dose-dependently with increasing doses of SION-2222; the decrease was statistically significant in the 200 mg dose group. ppFEV1 and CFQ-R did not significantly improve in any group. SION-2222 was generally well-tolerated in this trial. The majority of reported TEAEs were mild or moderate in severity. SAEs reported were considered not related to study drug.

Trial GLPG-2222-CL-201 was a Phase 2 trial that evaluated the safety and tolerability and the effect of two dose levels of SION-2222 in CF patients that were heterozygous for the F508del mutation and a gating mutation, receiving ivacaftor, on CFTR function (as assessed by sweat chloride), lung function (as assessed by ppFEV1) and CFQ-R. In this trial, one SION-2222 treatment group (300 mg once daily) was associated with an improvement in sweat chloride compared to placebo, while other dose treatment groups did not show

statistically significant changes in sweat chloride. ppFEV1 and CFQ-R did not significantly improve in any group. SION-2222 was generally well-tolerated in this trial. Most TEAEs were mild in severity, and there were no SAEs.

These Phase 2 results demonstrated that SION-2222 as a single agent increased CFTR activity in patients with the F508del mutation. The activity of SION-2222 in combination with SION-3067 in Trial M19-530 was similar to the activity of approved dual combination modulators, as seen via indirect, cross-trial comparisons and as predicted based on our CFHBE model (Figure 25).

Figure 25

In addition to SION-2222, we licensed SION-2851 from AbbVie in July 2024. SION-2851 is a potent TMD1-directed corrector that has completed a Phase 1 SAD trial in healthy volunteers. The trial was conducted by AbbVie and Galapagos in Belgium in 2018. The primary endpoint was safety and tolerability, assessed by the number of participants with adverse events. Based on its mechanism of action and preclinical studies, we believe it may be potentially synergistic with NBD1 stabilizers.

ICL4 Program—SION-109

We are also advancing SION-109, which targets the ICL4 interface, for development in combination with an NBD1 stabilizer. SION-109 is currently being evaluated in combination with SION-451 in our ongoing Phase 1 dual combination trial.

In December 2024, we completed a randomized, double blind, placebo-controlled Phase 1 clinical trial of SION-109 in healthy participants, following clearance of its Investigational New Drug application ("IND") by the FDA in June 2023. The trial was designed to evaluate the safety, tolerability and PK profile of single and multiple ascending doses of SION-109, administered as an oral suspension. In a Part C of the Phase 1 trial, we evaluated the effect of food on PK and the bioequivalence of a tablet formation compared to the oral suspension used in the Phase 1 SAD and MAD cohorts.

Over 100 healthy adult participants received SION-109 in this Phase 1 trial. The trial was designed to enroll eight participants, randomized 3:1 active:placebo, to each dosing cohort. Six SAD cohorts evaluated single doses from 50 mg to 400 mg. Five MAD cohorts evaluated from 50 mg to 150 mg BID over ten dosing days. Fifteen participants enrolled in the open-label food effect and tablet bioequivalence part evaluating 100 mg single doses each of suspension fasted, tablet fasted, and tablet fed.

SION-109 was generally well tolerated at all dose levels administered in all parts of this Phase 1 trial. A summary table of reported TEAEs is shown in Figure 26 below. There were no SAEs, and most TEAEs were mild to moderate (Grade 1 or Grade 2). No TEAEs led to the discontinuation of trial drug, and no dose-limiting TEAEs were observed. Sporadic increases in potassium were observed that were determined to be related to sample collection and/or processing. A 150 mg MAD cohort was repeated with revised sampling guidance, and no increased potassium values were observed. Isolated and transient increases in transaminases were observed associated with four AEs in three participants in the MAD and Part C (one Grade 1 AE, two Grade 2 AEs and one Grade 3 AE) whose values returned to the normal range in follow-up. Other liver function tests,

including bilirubin, were unremarkable. There were no clinically meaningful, treatment-emergent trends in other safety parameters, vital signs or electrocardiograms.

(Figure 26. Safety observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)

Increasing exposure was observed with increasing single and multiple doses. The target exposure for SION-109 as part of a dual combination with SION-451 or SION-719 was achieved with multiple doses of 75 mg BID and higher doses.

A PK summary of SION-109 is shown in Figure 27 below. The PK observed was consistent with BID dosing.

(Figure 27. Each solid line shows mean concentration data for a dosing cohort over ten days of dosing. Data points for Day 2 through Day 9 are trough (pre-dose) concentrations. The dotted line represents the Cminimum (trough) PK exposure target for SION-109, with the aim to achieve targeted exposure to deliver clinically meaningful benefit when administered in a proprietary dual combination, based on CFHBE assay data. PK observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)

Potentiator Program—SION-3067

SION-3067 is a clinical-stage potentiator of CFTR gating activity that we have licensed from AbbVie. SION-3067 provides our pipeline with a third mechanism of action complementary to NBD1 stabilizers and future opportunities to develop additional combination products to potentially expand our CF franchise. SION-3067 has completed Phase 1, Phase 1b and Phase 2 trials and was generally well-tolerated in CF patients and healthy volunteers, with improvements observed in sweat chloride levels in combination with SION-2222. When SION-3067 was given as a monotherapy or in combination with SION-2222, all AEs were mild to moderate. The PK profile in CF patients was similar in healthy volunteers.

The activity of SION-3067 in patients with CF was evaluated in a randomized, double-blind, placebo-controlled Phase 2 trial in combination with SION-2222, as summarized above. Combination treatment of SION-3067 150 mg QD with SION-2222 resulted in improvements in FEV1 and sweat chloride levels in the homozygous F508del population. As expected, treatment with 50 mg QD or 150 mg QD SION-3067 monotherapy for 28 days did not result in improvements in FEV1 or sweat chloride levels.

Manufacturing

We have leveraged multiple third-party manufacturers to support the manufacturing of our product candidates for clinical trials and, if we receive regulatory approval, we intend to rely on third parties for commercial manufacture. We do not own or operate, and currently have no plans to establish, any manufacturing facilities. We expect this strategy will enable us to maintain a more efficient infrastructure, outsourcing instead of building manufacturing and supply chain capabilities, while simultaneously enabling us to focus our expertise on the clinical development of our product candidates. We expect to enter into commercial supply agreements with such manufacturers prior to any potential approval of our product candidates.

Commercialization

We have exclusive worldwide commercial rights to our product candidates. Given our stage of development, we have not yet established a commercial organization or distribution capabilities. The CF patient populations are well-characterized and clearly identified in the U.S., Canada, Europe, Australia, and several other regions around the world, with highly active and informed CF patient advocacy groups. Most CF patients are treated at a limited number of centralized CF patient care centers by teams of healthcare professionals who are experts in and dedicated to treating CF.

We plan to independently commercialize our products, if approved, in the U.S. and in other regions where we determine it makes commercial sense to do so. Given the established CF patient care centers and the concentrated group of prescribing healthcare professionals, we believe we could commercialize our product(s) for CF with a relatively small specialty sales force focused on CF treatment centers and prescribers. At the appropriate time, and subject to regulatory approval and the scope of any approved indication, we plan to recruit a sales force and expand our medical affairs team and take other steps to establish the necessary commercial infrastructure. As our product candidates advance through our pipeline, our plans may change with respect to the timing, scope and manner of commercialization.

Competition

The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. While we believe we have competitive advantages, we face substantial competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic research institutions and governmental agencies, and public and private research institutions. This may include other small-molecule drug discovery companies using similar approaches or other types of therapies, such as small molecule, gene therapy, gene editing and/or mRNA therapies.

In particular, we expect to compete with Vertex, which has multiple approved products, as well as additional product candidates in development, for the treatment of CF that would compete with our product candidates, if approved. Vertex is the manufacturer of the five approved CFTR modulators, including the standard of care, Trikafta, and the triple modulator combination, Alyftrek, approved in December 2024. Any product candidates that we successfully develop and commercialize will compete with these existing therapies, as well as any new therapies that may become available in the future that are approved to treat the same diseases for which we may obtain approval for our product candidates.

We may also face competition from other companies attempting to develop therapeutics targeting CF. For example, in October 2025, Fair Therapeutics, Inc. announced final results from a Phase 2b trial evaluating its CFTR modulators. Multiple companies are developing CF-utilizing nucleic acid therapies, which are compounds that allow expression of a functional CFTR protein and are relevant for the more than 5,000 people with CF who cannot make full-length CFTR protein and are not eligible for CFTR modulators. In addition, multiple companies are developing candidates for gene therapy approaches to treat CF.

Some of our competitors have significantly greater financial resources than we do and an established presence in the market. Our competitors may have greater expertise in research and development, manufacturing, obtaining regulatory approvals and marketing approved products and may obtain regulatory approvals for their products more rapidly than we can, if at all. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. We also compete with these companies in recruiting, hiring and retaining qualified scientific and management talent, establishing clinical trial sites and patient registration for clinical trials and obtaining manufacturing slots at contract manufacturing organizations.

If our product candidates do not offer advantages over available products, we may not be able to successfully compete against current and future competitors. The key factors affecting the success of our products, if approved, are likely to be their potential efficacy, safety, tolerability, convenience and availability of reimbursement.

Intellectual Property

We strive to protect and enhance the intellectual property and proprietary technology that we consider important to our business, including by pursuing patent applications that cover our product candidates and methods of using the same, as well as any other relevant inventions and improvements that we believe to be commercially important to the development of our business. We also rely on trade secrets relating to our proprietary know-how, continuing innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary and intellectual property position. We additionally may rely on regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions, where available.

Our commercial success may depend in part on our ability to: obtain, maintain, enforce and protect our intellectual property and other proprietary rights for commercially important technology, inventions and know-how related to our business; defend and enforce any patents we may own or in-license in the future; prevent others from infringing any patents we may own or in-license in the future; preserve the confidentiality of our trade secrets; and operate without infringing the valid enforceable patents and proprietary rights of third parties. Our ability to limit third parties from making, using, selling, offering to sell or importing our products may depend on the extent to which we have rights under valid and enforceable licenses, patents or trade secrets that cover these activities. In some cases, enforcement of these rights may depend on third party licensors. With respect to both licensed and company-owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same.

Patent expiration dates noted in the following paragraphs refer to statutory expiration dates and do not take into account any potential patent term adjustment or extension that may be available.

NBD1 Stabilizers

We co-own with Sanofi a patent family that discloses and covers each of SION-719 and SION-451 and methods of using SION-719 and SION-451 for the treatment of CF. The patent family has entered the national phase and is pending in the United States, Argentina, Australia, Brazil, Canada, Chile, China, Colombia, Ecuador, Egypt, Eurasian Patent Organization, European Patent Office, Hong Kong, India, Israel, Jordan, Japan, Mexico, New Zealand, Oman, Peru, Qatar, Saudi Arabia, Singapore, South Africa, South Korea, Taiwan, and the United Arab Emirates. The statutory expiration for this family is September 2043. We own a non-provisional patent application that discloses and claims the use of our NBD1 stabilizer product candidates in combination with other agents for the treatment of CF, which has a statutory expiration of March 2045.

Complementary Modulators

We exclusively license from Sanofi one patent family that discloses and covers SION-109 and methods of using SION-109 for the treatment of CF. The patent family has entered national phase and is pending in the U.S., the European Patent Office, African Regional Industrial Property Organization, African Intellectual Property Organization, Algeria, Australia, Bahrain, Brazil, Canada, Chile, China, Colombia, Eurasian Patent Office, Ecuador, Egypt, Guatemala, Hong Kong, Honduras, Israel, India, Jordan, Japan, Kuwait, Mexico, Malaysia, New Zealand, Nigeria, Oman, Panama, Peru, Philippines, Saudi Arabia, Singapore, South Africa, South Korea, Sri Lanka, Thailand and the United Arab Emirates. The statutory expiration for this family is November 2040.

We exclusively license from AbbVie one patent family that discloses and covers SION-2222 and methods of using SION-2222 for the treatment of CF. The patent family includes granted patents in the United States, Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Costa Rica, Croatia, Czech Republic, Denmark, Dominican Republic, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Mexico, Monaco, Netherlands, Norway, Panama, Peru, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, Uruguay, and Vietnam, and has a statutory expiration date of October 2035. We exclusively license from AbbVie one patent family that discloses and covers SION-2851 and methods of using SION-2851 for the treatment of CF. The patent family includes granted patents in the United States, Argentina, Australia, Brazil, Canada, Chile, China, Colombia, Costa Rica, Dominican Republic, France, Germany, India, Israel, Italy, Japan,

Malaysia, Mexico, New Zealand, Pakistan, Panama, Peru, Philippines, Russia, Singapore, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, Uruguay, and Vietnam, and has a statutory expiration date of July 2036.

We exclusively license from AbbVie one patent family that discloses and covers SION-3067 and methods of using SION-3067 for the treatment of CF. The patent family includes granted patents in the United States, Albania, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, China, Colombia, Costa Rica, Croatia, Cyprus, Czech Republic, Denmark, Dominican Republic, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Ireland, Israel, Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Macau, Malta, Mexico, Monaco, Netherlands, New Zealand, North Macedonia, Norway, Panama, Peru, Philippines, Poland, Portugal, Romania, Russia, San Marino, Serbia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Turkey, United Kingdom, and Vietnam, a pending application in Canada and Ecuador, and has a statutory expiration date of May 2037. Additionally, the patent family includes granted patents in Argentina and Taiwan, each of which has a statutory expiration date of June 2037.

We own two patent applications that each disclose and contain claims that recite the use of our NBD1 stabilizer product candidates in combination with SION-109, SION-2222, SION-3067, Trikafta and/or other modulators for the treatment of CF. The first is a Patent Cooperation Treaty international application and has a statutory expiration of October 2043, and the second is a non-provisional patent application (discussed above), which has a statutory expiration of March 2045.

Licensing and Collaboration Agreements

Sanofi License Agreement

On December 20, 2019, we entered into a license agreement, as amended by Amendment No. 1 dated May 14, 2020, Amendment No. 2 dated June 8, 2020, Amendment No. 3 dated December 14, 2021, Amendment No. 4 dated January 28, 2022, Amendment No. 5 dated February 21, 2023 and Amendment No. 6 dated October 28, 2024 (as amended, the “Sanofi License Agreement”), with Sanofi, pursuant to which we have been granted an exclusive, worldwide license to develop, commercialize, manufacture, use, hold, keep, register or dispose of certain compounds, patents and proprietary information and inventions, in each case for therapeutic, prophylactic, prognostic and diagnostic purposes in or for humans, subject to retained rights. The licensed and derived rights are directed, among other things, to CFTR modulator therapies which are being utilized in SION-719, SION-109 and SION-451.

Pursuant to the terms of the Sanofi License Agreement, we must use commercially reasonable efforts to develop, pursue regulatory approval for and commercialize a licensed product. Sanofi and its affiliates retain the right to practice under the licensed patents and use the licensed know-how solely to conduct non-clinical research for all therapeutic, prophylactic, prognostic and diagnostic uses in or for humans, other than for CF; provided, however, that Sanofi will not file any patents that claim a licensed compound.

As initial consideration for the license, we paid a non-refundable, upfront payment of $1.5 million, as well as a reimbursement of $0.3 million for Sanofi’s research and development expenses. In addition, we are required to pay Sanofi a total of up to $40.0 million upon achievement of certain late-stage developmental and commercial milestones. None of such milestones have been achieved to date. We are also required to pay royalties to Sanofi in the low single-digit percentage range based on net sales of licensed products, subject to customary reductions and offsets. Such royalty payments shall be reduced for products covered by derived patents. The royalty term will terminate on a product-by-product and country-by-country basis upon the later of (i) the expiration of the last-to-expire valid claim within the relevant licensed patent rights, (ii) the expiration of regulatory exclusivity in such country for such licensed product and (iii) the tenth anniversary of the first commercial sale of a licensed product in such country.

We are entitled to sublicense the rights granted to us under the Sanofi License Agreement under certain circumstances, provided that any such sublicense must be consistent with the terms of the Sanofi License Agreement. If we receive sublicense income from any such sublicense, we are required to pay Sanofi a low double digit percentage of such sublicense income.

We have also granted Sanofi an exclusive option to purchase, at a defined price, any priority review voucher (“PRV”) granted to us as a result of the development of the licensed compounds or products. In the event that Sanofi does not exercise its option with respect to any PRV, we may (x) use the PRV, in which case we must pay Sanofi a high seven-digit amount or (y) sell the PRV to a third party, in which case we must share a sub-teen double-digit percentage of the sale consideration with Sanofi.

We have the right, but not the obligation, to prepare, file, prosecute and maintain the licensed patents and product trademarks at our own cost. We have the first right to enforce and defend any licensed patents, with Sanofi having back-up enforcement and defense rights. We also have the sole right to enforce and defend any product trademarks at our sole cost and expense.

We have the right to terminate the Sanofi License Agreement for convenience, subject to a 90-day notice period. Sanofi has customary termination rights under the Sanofi License Agreement, including for our material breach, payment default, bankruptcy or challenge of the validity of any patent right, subject to specified notice and cure periods. Unless earlier terminated, the Sanofi License Agreement will expire in each country upon the expiration of the last-to-expire royalty term in such country and, with respect to the Sanofi License Agreement in its entirety, upon the expiration of the royalty term for the last licensed product for which there has been a first commercial sale. Upon expiration of the Sanofi License Agreement, the license granted to us will become non-exclusive, royalty-free, fully paid-up and perpetual.

CFF Payment Agreement

On December 20, 2019, we entered into a payment agreement (the “CFF Payment Agreement”) with CFF, pursuant to which we agreed to provide CFF with compensation in exchange for the grant of, and forbearance from exercising, certain of CFF’s rights existing under the Research, Development and Commercialization Agreement, dated October 1, 2011, by and between CFF (through an assignment by Cystic Fibrosis Foundation Therapeutics, Inc.) and Genzyme Corporation, an affiliate of Sanofi (the “CFFT-Genzyme Agreement”). As described above, we have been granted a license to certain compounds, patents and know-how pursuant to the Sanofi License Agreement, some of which were generated as a result of a research plan under the CFFT-Genzyme Agreement. Under the CFF Payment Agreement, we are obligated to compensate CFF in connection with our development and commercialization of licensed products under the Sanofi License Agreement. Concurrent with the execution of the CFF Payment Agreement, Sanofi and CFF terminated the CFFT-Genzyme Agreement.

As initial consideration for CFF’s grant of, and forbearance from exercising, its rights under the CFFT-Genzyme Agreement, we issued CFF 300,300 shares of our Series Seed preferred stock. In addition, we agreed to pay CFF a sub-teen double-digit percentage of any amounts paid by us to Sanofi under the Sanofi License Agreement, other than milestone, royalty or reimbursement payments. As of December 31, 2025, we have paid CFF a total of approximately $0.2 million in accordance with the terms of the CFF Payment Agreement. In addition, we are required to pay CFF a total of up to $40.0 million upon achievement of certain late-stage developmental and commercial milestones. None of such milestones have been achieved to date. We are also required to pay revenue-shares of royalty payments to CFF in the low single-digit percentage range based on net sales of licensed products, subject to customary reductions and offsets. Such milestone and royalty payments shall be reduced for products covered by derived patents. The royalty term will terminate on a product-by-product and country-by-country basis upon the later of (i) the expiration of the last-to-expire valid claim within the relevant patent rights that claims such product or its exploitation in such country, (ii) the tenth anniversary of the first commercial sale of a product in such country and (iii) expiration of regulatory exclusivity of a product in such country. Further, a side letter was executed between us and Sanofi, which clarifies the relationship between us, Sanofi and CFF, under which we are obligated to pay Sanofi 20% of the milestones it would have been obligated to pay CFF, net of the milestone amounts it is obligated to pay under the Sanofi License Agreement.

If at any time prior to the first commercial sale of a product developed as a result of the CFF Payment Agreement, we cease to use commercially reasonable efforts to develop, and obtain and maintain regulatory approvals for, at least one of our products for therapeutic, prophylactic, prognostic or diagnostic uses in or for humans in specified major markets for a continuous period of 365 days, CFF has the option to exercise rights to an exclusive, irrevocable, worldwide interruption license under our patents, the licensed patents and the

licensed know-how, to develop, manufacture, use, sell, offer to sell and import any of our products containing a licensed compound or any compound covered by a licensed patent or incorporating licensed know-how.

Either party may terminate the CFF Payment Agreement for a material breach by the other party, subject to a specified notice and cure period. Unless earlier terminated, the CFF Payment Agreement will expire (a) with respect to each product in each country, upon the expiration of the last-to-expire royalty term in such country, and (b) with respect to the CFF Payment Agreement in its entirety, upon the later of (i) the expiration of the royalty term for the last licensed product for which there has been a first commercial sale or (ii) the expiration or termination of our obligation to pay consideration to Sanofi under the Sanofi License Agreement.

AbbVie License Agreement

On July 11, 2024, we entered into a license agreement (the “AbbVie License Agreement”) with AbbVie, pursuant to which we have been granted an exclusive worldwide, royalty-bearing, sublicensable license to certain patent and other intellectual property rights to research, develop, commercialize, make, manufacture, use, import and sell products for prophylactic or therapeutic use in humans for all indications, subject to certain limitations and retained rights. The licensed rights are directed, among other things, to three clinical-stage CFTR modulator therapies: SION-2222, a TMD1-directed CFTR corrector, SION-3067, a CFTR potentiator, and SION-2851, a TMD1-directed corrector. Under the AbbVie License Agreement, we have assumed all global development and commercialization responsibilities for such therapies. Pursuant to the terms of the AbbVie License Agreement, we must use commercially reasonable efforts to develop, pursue regulatory approval for and commercialize a licensed product. We are also required to achieve certain development milestones within specified time periods for products incorporating intellectual property covered by the AbbVie License Agreement.

The license granted to us under the AbbVie License Agreement is subject to certain preexisting rights held by AbbVie and Galapagos. In particular, certain of the licensed patents and other intellectual property rights were developed by or on behalf of Galapagos and are sublicensed to us subject to the terms of the second amended and restated collaboration agreement between Galapagos and AbbVie dated as of October 24, 2018 (the “Galapagos License Agreement”), as amended by a side letter between Galapagos and AbbVie dated as of July 11, 2024. We are also entitled to sublicense the rights granted to us under the AbbVie License Agreement under certain circumstances, provided that any such sublicense must be consistent with the terms of the AbbVie License Agreement and the Galapagos License Agreement.

As initial consideration for the license, we paid a non-refundable, upfront payment of $5.0 million and issued 1,414,445 shares of our common stock to AbbVie. In addition, we are required to pay AbbVie a total of up to $360.0 million upon achievement of certain development and commercial milestones, consisting of up to $70.0 million in late-stage development milestones and up to $290.0 million in commercial milestones. None of such milestones have been achieved to date. We are also required to pay royalties to AbbVie in the low to mid single-digit percentage range based on net sales of licensed products, subject to customary reductions and offsets, with the percentage range depending in part on the compounds used. The royalty term will terminate on a product-by-product and country-by-country basis upon the later of (i) the expiration of the last-to-expire valid claim within the relevant patent rights that covers the manufacture, use, sale or other exploitation of a product in such country, (ii) the tenth anniversary of the first commercial sale of a product in such country and (iii) expiration of regulatory exclusivity of a product in such country. In addition, we are required to pay AbbVie up to $130.0 million in commercial and sales-based milestone payments, mid to high single-digit royalties on the licensed products or other payments due to Galapagos pursuant to the Galapagos License Agreement, to the extent such payments are triggered by our use of the licensed rights under the AbbVie License Agreement. To date, no payments have been triggered.

We have also granted AbbVie a right of first negotiation (the “ROFN”) if we decide to pursue a license or sublicense to commercialize a licensed product (a “Commercial License Transaction”) prior to initiating Phase 3 clinical trials. If AbbVie timely exercises the ROFN, then it will have an exclusive period to negotiate in good faith the terms of a Commercial License Transaction. In the event (x) AbbVie does not timely exercise the ROFN or notifies us that it does not intend to pursue a Commercial License Transaction (including after timely exercising the ROFN) or (y) the parties fail to reach agreement or enter into a definitive agreement for the Commercial License Transaction within the exclusive negotiation period, then the ROFN regarding all licensed products will terminate.

We are responsible for the prosecution and maintenance of the licensed patents at our own cost. We have the first right to enforce and defend any licensed patent at our own cost, with AbbVie having back-up enforcement and defense rights.

We have the right to terminate the AbbVie License Agreement for convenience, subject to a prescribed notice period. AbbVie has customary termination rights under the AbbVie License Agreement, including for our material breach, payment default, bankruptcy, challenge of the validity of any patent right or shelving of a product for a specified time period, subject to specified notice and cure periods. Unless earlier terminated, the AbbVie License Agreement will expire upon the expiration of the last-to-expire royalty term. Upon expiration of the AbbVie License Agreement, the license granted to us will become non-exclusive, royalty-free, fully paid-up and perpetual.

In the event the AbbVie License Agreement is terminated, we and AbbVie shall agree upon a transition plan to revert the licensed compounds or licensed products containing such licensed compounds to AbbVie. Within a prescribed time period of such termination, we are obligated to (i) assign and transfer all of our rights and interests in the documentation and data related to the reverting compounds or products to AbbVie, (ii) grant to AbbVie a non-exclusive, royalty-free license right of reference for AbbVie to develop or commercialize any of the reverting compounds or products, (iii) grant to AbbVie an exclusive, royalty-bearing worldwide license to exploit any of the reverting compounds or products and (iv) transfer to AbbVie control of all clinical studies being conducted for any of the reverting compounds or products.

Government Regulation

The FDA and comparable regulatory authorities in federal, state and local jurisdictions and in other foreign countries impose extensive requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs, such as those we are developing. These agencies and other federal, state and local entities extensively regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling, packaging, storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of drugs. The process of obtaining regulatory approvals in the U.S. and in foreign countries and jurisdictions, along with subsequent compliance with applicable federal, state, local and foreign statutes and regulations, requires the expenditure of substantial time and financial resources. Failure to comply with the applicable requirements at any time during the product development process, approval process or after approval, may subject an applicant and/or sponsor to a variety of sanctions. For example, failure to comply with the applicable U.S. requirements may result in administrative or judicial sanctions including refusal by FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.

Review and Approval of Drugs in the United States

In the U.S., the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (“FDCA”), and its implementing regulations. Drugs are also subject to other federal, state and local statutes and regulations.

The process required by the FDA before a drug may be marketed in the U.S. generally involves the following:

•completion of extensive nonclinical, or preclinical, laboratory tests, animal studies and formulation studies in compliance with the FDA’s Good Laboratory Practice (“GLP”) regulations;

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

•approval by an institutional review board (“IRB”) or independent ethics committee (“IEC”) at each clinical site before each trial may be initiated at that site;

•performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practices (“GCP”) requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational drug product for each proposed indication;

•preparation and submission to the FDA of an NDA after completion of all pivotal trials, together with the payment of application user fees, as applicable;

• a determination by the FDA within 60 days of its receipt of an NDA to accept the marketing application for review;

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

•satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMP requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

•satisfactory completion of FDA inspections of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; and

•FDA review and approval of the NDA.

Preclinical Studies

Before testing any drug product candidate, including our product candidates, in humans, the product candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluations of the product’s chemistry, purity, toxicity, formulation, and stability as well as in vitro and animal studies to assess potential safety and efficacy and in some cases to establish the rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety and toxicology studies.

The IND and IRB Process

Prior to beginning the first clinical trial with a product candidate in the U.S., we must submit an IND to the FDA. An IND sponsor must submit a protocol for each clinical trial, the results of the preclinical tests, manufacturing information, analytical data and any available clinical data or literature and plans for clinical studies, among other things, to the FDA as part of an IND. An IND is a request for authorization from the FDA to grant an exemption that allows an unapproved drug to be shipped in interstate commerce for use and administration in an investigational clinical trial for humans. The IND must become effective before human clinical trials may begin in the U.S. Some preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue even after the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the clinical trial on a clinical hold. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing clinical trial. Clinical holds may be imposed by the FDA when there is concern for patient safety, and may be a result of new data, findings or developments in clinical, nonclinical, and/or chemistry, manufacturing and controls or where there is non-compliance with regulatory requirements. A partial clinical hold is a delay or suspension of only part of the clinical work requested under the IND. Following issuance of a clinical hold or partial clinical hold, an investigation (or full investigation in the case of a partial clinical hold) may only resume after the FDA has notified the sponsor that the investigation may proceed. As a result, submission of an IND may not result in the FDA allowing clinical trials to initiate.

A separate submission to an existing IND must also be made for each successive clinical trial to be conducted, and the FDA must grant permission, either explicitly or implicitly by not objecting, before each clinical trial can begin.

A sponsor may choose, but is not required, to conduct a foreign clinical trial under an IND. When a foreign clinical trial is conducted under an IND, all FDA IND requirements must be met unless waived. When the foreign clinical trial is not conducted under an IND, the sponsor must ensure that the study is conducted in accordance with GCP, including review and approval by an IEC and informed consent from subjects. FDA must be able to validate the data from the study through an on-site inspection if necessary.

In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review of the study. The IRB is charged with protecting the welfare and rights of trial participants and considers whether the risks to individuals participating in the clinical trials are minimized

and are reasonable in relation to anticipated benefits. The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects and must monitor the clinical trial until completion. An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.

Clinical Trials in Support of an NDA

Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include the requirement that all research subjects, or their legal representative, provide their informed consent in writing for their participation in any clinical trial. Clinical trials are conducted under written study protocols detailing, among other things, the exclusion and inclusion criteria, the objectives of the trial, dosing procedures, subject selection, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. As part of an IND, a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA.

Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data monitoring committee ("DMC"), which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety or health risk for subjects or other grounds, such as no demonstration of efficacy.

Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health (“NIH”) for public dissemination on their www.clinicaltrials.gov website. Information related to the investigational product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial. Although sponsors are obligated to disclose the results of their clinical trials after completion, disclosure of the results can be delayed in some cases for some time. Failure to timely register a covered clinical study or to submit study results as provided for in the law can give rise to civil monetary penalties and also prevent the non-compliant party from receiving future grant funds from the federal government.

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

•Phase 1: The investigational drug is initially introduced into a limited population of healthy human subjects or, in certain indications such as cancer, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion, side effects, and, if possible, to gain an early indication of its effectiveness or determine optimal dosage.

• Phase 2: The investigational drug is administered to a limited patient population with a specified disease or condition to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage. Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning Phase 3 clinical trials.

•Phase 3: The investigational drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk/benefit profile of the product, and to provide adequate information for product approval and labeling of the product. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA, although in some cases a single trial may be considered sufficient.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval for an NDA.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur. In addition, within 15 calendar days after the sponsor determines that the information qualifies for reporting, written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human subjects and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor also 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 the information. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points. These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date and for the FDA to provide advice.

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

FDA Review of an NDA Submission and FDA Approval

Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. An NDA is a request for approval to market a new drug for one or more specified indications and must contain proof of the drug’s safety and efficacy for the requested indications. FDA must approve an NDA before a drug may be marketed in the U.S. For companies, the marketing application is required to include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings. 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 investigational drug product for the proposed indication to the satisfaction of the FDA. In most cases, the submission of an NDA is subject to a significant application user fee. Fee exceptions or fee waivers may be obtained under certain limited circumstances.

The FDA conducts a preliminary review of all NDAs within the first 60 days of its receipt, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

During its review of an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured. These pre-approval inspections may cover all facilities associated with an NDA, including drug component manufacturing (such as APIs), finished drug product manufacturing and control testing laboratories. The FDA will not approve an NDA 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.

In addition, as a condition of approval, or post-approval if it becomes aware of a serious risk associated with the use of the product, the FDA may require the submission of a Risk Evaluation and Mitigation Strategy

(“REMS”), if it determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks and to assure the safe use of the drug. 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 a REMS, if required. A REMS may include one or more elements, including medication guides, physician communication plans, patient package insert and/or elements to assure safe use, such as special training or certification for prescribing or dispensing, restricted distribution methods, special monitoring, patient registries or other risk minimization tools.

Under the Prescription Drug User Fee Act (“PDUFA”) guidelines that are currently in effect, the FDA has a 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, and six months from the filing date of a new molecular entity NDA with priority review. Accordingly, this review process typically takes 12 months and eight months, respectively, from the date the NDA is submitted to the FDA. The FDA does not always meet its PDUFA goal dates for standard or priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

In addition, under the Pediatric Research Equity Act of 2003, as amended (“PREA”), certain NDAs or supplements to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements. A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial Pediatric Study Plan (“PSP”), within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before initiation of the Phase 3 or Phase 2/3 study. The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information. The FDA and the sponsor must reach an agreement on the PSP. A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials and/or other clinical development programs.

The FDA may refer an application for a novel drug or a drug that presents difficult questions of safety or efficacy to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides 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.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a Complete Response Letter. 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 generally outlines the deficiencies in the submission and contains a statement of specific conditions that must be met in order to secure final approval of the NDA and it may require additional clinical or preclinical testing in order for FDA to reconsider the application. If a Complete Response Letter is issued, the applicant may resubmit the NDA, addressing all of the deficiencies identified in the letter, withdraw the application, or request a hearing. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

Even if the FDA approves a product, depending on the specific risk(s) to be addressed, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-marketing

studies or surveillance programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug product intended to treat a rare disease or condition, which is generally a disease or condition that affects either (i) fewer than 200,000 individuals in the U.S. or (ii) more than 200,000 individuals in the U.S. and for which there is no reasonable expectation that the cost of developing and making the product available in the U.S. for this type of disease or condition will be recovered from sales of the product. A company must request orphan drug designation before submitting an NDA. If the request is granted, the FDA will disclose the identity of the therapeutic agent and its potential use. Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product is entitled to orphan product exclusivity. Orphan product exclusivity means that the FDA may not approve any other applications to market the same product for the same indication for seven years, except in certain limited circumstances, including if a subsequent product with the same active ingredient for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand. Further, the FDA may approve more than one product for the same orphan indication or disease as long as the products contain different active ingredients. Moreover, competitors 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 drug has exclusivity. Orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages, and user-fee waivers.

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 U.S. 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.

Expedited Development and Review Programs for Drugs

The FDA maintains several programs intended to facilitate and expedite development and review of new drugs that were intended to address unmet medical needs in the treatment of serious or life-threatening diseases or conditions. Some of these programs are referred to as Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval, and the purpose of these programs is to either expedite the development or review of important new drugs to get them to patients earlier than under standard FDA development and review procedures.

The FDA has a Fast Track designation program that is intended to expedite or facilitate the process for reviewing new drugs that meet certain criteria. Specifically, new drugs are eligible for Fast Track designation if they are intended, whether alone or in combination with one or more other products, to treat a serious or life-threatening condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition. Fast Track designation applies to both the product and the specific indication for which it is being studied. The sponsor can request that the FDA grant the product Fast Track designation any time before receiving NDA approval but ideally no later than the pre-NDA meeting. Fast Track designation provides increased opportunities for sponsor interactions with the FDA review team to expedite development and review of the product. The FDA may also review sections of the NDA for a Fast Track designated product on a rolling basis before the completed application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application. The FDA’s goal for reviewing a Fast Track application does not begin until the last section of the

NDA is submitted. Fast Track designation may be rescinded if the designation is no longer supported by data emerging in the clinical trial process.

Additionally, a drug may be eligible for designation as a Breakthrough Therapy if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The benefits of Breakthrough Therapy designation include the same benefits as Fast Track designation, plus intensive guidance from the FDA to ensure an efficient drug development program. Breakthrough Therapy designation comes with all of the benefits of Fast Track designation, which means that the sponsor may file sections of the NDA for review on a rolling basis if certain conditions are satisfied, including an agreement with the FDA on the proposed schedule for submission of portions of the application and the payment of applicable user fees before the FDA may initiate a review. The FDA may take certain actions with respect to Breakthrough Therapies, including holding meetings with the sponsor throughout the development process; providing timely advice to the product sponsor regarding development and approval; involving more senior staff in the review process; assigning a cross-disciplinary project lead for the review team; or taking other steps to design the clinical trials in an efficient manner.

A product may also be eligible for priority review if it treats a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies. The FDA determines at the time that the marketing application is submitted, on a case-by-case basis, whether the proposed drug represents a significant improvement in treatment, prevention or diagnosis of disease when compared with other available therapies. Significant improvement may be demonstrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes and evidence of safety and effectiveness in a new subpopulation. A priority review designation is intended to direct overall attention and resources to the evaluation of such applications and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months for an NDA from the date of filing. If criteria are not met for priority review, the application is subject to the standard FDA review period of ten months after FDA accepts the application for filing. Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.

A product may also be eligible for accelerated approval if it treats a serious or life-threatening disease or condition, generally provides a meaningful advantage over available therapies and demonstrates 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 (“IMM”) that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments. Accelerated approval by the FDA is generally contingent on a sponsor’s agreement to conduct, in an adequate and diligent manner, additional post-approval confirmatory studies to verify and describe the product’s clinical benefit. These confirmatory trials must be completed with due diligence, and, under the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), the FDA is now permitted to require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval. Under FDORA, the FDA has increased authority for expedited procedures to withdraw the product from the market (and withdraw its approval). As a result, a product candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, could result in the FDA’s withdrawal of the approval and require the withdrawal of the product from the market on an expedited basis. All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA.

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

Hatch-Waxman Amendments

Section 505 of the FDCA describes three types of marketing applications that may be submitted to the FDA to request marketing authorization for a new drug. A Section 505(b)(1) NDA is an application that contains full reports of investigations of safety and efficacy. A 505(b)(2) NDA is an application that contains full reports of investigations of safety and efficacy but where at least some of the information required for approval comes from investigations that were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. This regulatory pathway enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy for an existing product, or published literature, in support of its application. Section 505(j) establishes an abbreviated approval process for a generic version of approved drug products through the submission of an Abbreviated New Drug Application (“ANDA”). An ANDA provides for marketing of a generic drug product that has the same active ingredients, dosage form, strength, route of administration, labeling, performance characteristics and intended use, among other things, to a previously approved product, known as a reference listed drug (“RLD”). ANDAs are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and efficacy. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent to, or performs in the same manner as, the innovator drug through in vitro, in vivo or other testing.

U.S. Non-Patent Exclusivity

Under the Hatch-Waxman Amendments, the FDA may not approve (or in some cases accept) an ANDA or 505(b)(2) application until any applicable period of non-patent exclusivity for the RLD has expired. Market exclusivity provisions under the FDCA can delay the submission or the approval of certain follow-on applications. The FDCA provides a five-year period of non-patent data exclusivity within the U.S. to the first applicant to gain approval of an NDA for a new chemical entity (“NCE”). A drug is an NCE 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 physiological or pharmacological action of the drug substance. In cases where such NCE exclusivity has been granted, the FDA may not accept for review an ANDA, for a generic version of the drug or a 505(b)(2) NDA for another version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval, until the expiration of five years unless the submission is accompanied by a paragraph IV certification, which states the proposed generic drug will not infringe one or more of the already approved product’s listed patents or that such patents are invalid or unenforceable, in which case the applicant may submit its application four years following the original product approval.

The FDCA also provides three years of market exclusivity for non-NCE NDAs, 505(b)(2) 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, for example, new indications, dosages or strengths of an existing drug. This three-year exclusivity period covers only the conditions of use associated with the new clinical investigations and often protects changes to a previously approved drug product, such as a new dosage form, route of administration, combination or indication, but it generally would not protect the original, unmodified product from generic competition. In other words, it does not prohibit the FDA from approving follow-on applications that do not reference the protected clinical data. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Pediatric exclusivity is another type of regulatory market exclusivity in the U.S. Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods for all formulations, dosage forms, indications of the active moiety, and listed 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, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining. The issuance of a Written Request does not require the sponsor to undertake the described clinical trials.

Hatch-Waxman Patent Certification and the 30-Month Stay

In seeking approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each patent with claims that cover the applicant’s product or an approved method of using the product. Upon approval, each of the patents listed by the NDA sponsor is published in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. Upon submission of an ANDA or 505(b)(2) NDA, an applicant is required to certify to the FDA concerning any patents listed for the RLD in the Orange Book that:

•no patent information on the drug product that is the subject of the application has been submitted to the FDA;

•such patent has expired;

•the date on which such patent expires; or

•such patent is invalid, unenforceable or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted.

Generally, the ANDA or 505(b)(2) NDA cannot be approved until all listed patents have expired, except where the ANDA or 505(b)(2) NDA applicant challenges a listed patent through the last type of certification, also known as a paragraph IV certification. If the applicant does not challenge the listed patents or indicates that it is not seeking approval of a patented method of use, the ANDA or 505(b)(2) NDA application will not be approved until all of the listed patents claiming the referenced product have expired. If the ANDA or 505(b)(2) NDA applicant has provided a paragraph IV certification the applicant must send notice of the paragraph IV certification to the NDA and patent holders once the application has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the paragraph IV certification. If the paragraph IV certification is challenged by an NDA holder or the patent owner(s) asserts a patent challenge to the paragraph IV certification, the FDA may not approve that application until the earlier of 30 months from the receipt of the notice of the paragraph IV certification, the expiration of the patent, when the infringement case concerning each such patent was favorably decided in the applicant’s favor or settled, or such shorter or longer period as may be ordered by a court. This prohibition is generally referred to as the 30-month stay. In instances where an ANDA or 505(b)(2) NDA applicant files a paragraph IV certification, the NDA holder or patent owner(s) regularly take action to trigger the 30-month stay, recognizing that the related patent litigation may take many months or years to resolve. Thus, approval of an ANDA or 505(b)(2) NDA could be delayed for a significant period of time depending on the patent certification the applicant makes and the reference drug sponsor’s decision to initiate patent litigation. If the drug has NCE exclusivity and the ANDA is submitted four years after approval, the 30-month stay is extended so that it expires seven and a half years after approval of the innovator drug, unless the patent expires or there is a decision in the infringement case that is favorable to the ANDA applicant before then.

Patent Term Restoration and Extension

A patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Amendments, which permits a patent term restoration of up to five years for patent term lost during product development and the FDA regulatory review. The restoration period granted is typically 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 ultimate approval date, provided the sponsor acted with diligence. Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date. Only one patent applicable to an approved drug product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question and within 60 days of drug approval. A patent that covers multiple drugs for which approval is sought can only be extended in connection with one of the approvals. The U.S. Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

Post-Approval Requirements

Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications or other labeling

claims are subject to prior FDA review and approval. There are also annual prescription drug product program fee requirements for marketed products.

The FDA may impose a number of post-approval requirements as a condition of approval of an NDA. For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

FDA regulations require that products be manufactured in specific facilities and in accordance with cGMP regulations which require, among other things, quality control and quality assurance, the maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs and those supplying products, ingredients and components of them are required to register their establishments with the FDA and state agencies and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements. Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and for notifying FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the U.S. Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP requirements and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

Once an approval of a drug is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in mandatory revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition of distribution or other restrictions under a REMS program. Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products. Other potential consequences include, among other things:

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

•fines, warning letters or clinical holds on post-approval clinical trials;

•refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or withdrawal of product 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;

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

•injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Drugs may be promoted by a manufacturer and any third parties acting on behalf of a manufacturer only for the approved indications and in a manner consistent with the approved label for the product. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“PDMA”), which regulates the distribution of drugs and drug samples at the federal level and sets

minimum standards for the registration and regulation of drug distributors by the states. Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution.

Failure to comply with any of 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 evaluated 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 on the subject of 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 agencies have also required that companies enter into consent decrees and/or imposed permanent injunctions under which specified promotional conduct is changed or curtailed.

Review and Approval of Drugs in the European Union

In the EU, the research, development and commercialization of medicinal products are also subject to extensive regulatory requirements. As in the U.S., medicinal products can only be marketed if a marketing authorization (“MA”) from the competent regulatory agencies has been obtained.

Clinical Trial Approval

In April 2014, the European Union adopted a Clinical Trials Regulation (EU) No 536/2014 (the “Clinical Trials Regulation”) which replaced the previous Clinical Trials Directive 2001/20/EC on January 31, 2022, subject to transitional provisions which meant that since January 31, 2025, all clinical trials in the EU have been subject to the Clinical Trials Regulation. The Clinical Trials Regulation is directly applicable in all European Union Member States, meaning no national implementing legislation in each European Union Member State is required. The legislation aims at simplifying and streamlining the approval of clinical trials in the European Union. For instance, the Clinical Trials Regulation provides for a streamlined application procedure via a single entry point and strictly defined deadlines for the assessment of clinical trial applications.

Drug Review and Approval

In the European Union, medicinal products can only be commercialized after obtaining an MA. There are two types of MA:

The centralized MA, which is issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use of the EMA. A centralized MA is valid throughout the entire territory of the European Union and in the additional Member States of the European Economic Area (“EEA”), which is comprised of the Member States of the European Union plus Norway, Iceland and Liechtenstein. The centralized procedure is mandatory for certain types of products, including medicines produced by certain biotechnological processes, advanced therapy medicinal products (gene-therapy, somatic cell-therapy or tissue-engineered medicines), products designated as orphan medicinal products and products containing a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases. The centralized procedure is optional for products containing a new active substance not yet authorized in the European Union, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the European Union.

National MAs, which are issued by the competent authorities of the Member States of the European Union and only cover their respective territory, are available for products not falling within the mandatory scope of the centralized procedure. Where a product has already been authorized for marketing in a Member State of the European Union, this national MA can be recognized in another Member State through the mutual recognition procedure. If the product has not received a national MA in any Member State at the time of application, it can be approved simultaneously in various Member States through the decentralized procedure.

Under the above described procedures, before granting the MA, the EMA or the competent authorities of the Member States of the European Union make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy. Following approval, MA holders are subject to ongoing obligations, including pharmacovigilance and safety reporting requirements.

Data and Market Exclusivity

In the European Union, innovative medicinal products approved on the basis of a complete and independent data package qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity. The data exclusivity, if granted, prevents generic applicants from referencing the innovator’s preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic (abbreviated) MA, for eight years from the date on which the reference product was first authorized in the European Union. During an additional two-year period of market exclusivity, a generic marketing authorization application can be submitted, and the innovator’s data may be referenced, but no generic or medicinal product can be placed on the European Union market until the expiration of the market exclusivity. The overall ten-year period may be extended to a maximum of 11 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 their authorization, are determined to bring a significant clinical benefit in comparison with existing therapies. There is no guarantee that a product will be considered by the EMA to be an innovative medicinal product, and products may not qualify for data exclusivity. Even if a product is considered to be an innovative medicinal product so that the innovator gains the prescribed period of data exclusivity, another company could nevertheless also market another version of the product if such company obtained an MA based on an application with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.

Orphan Drug Designation and Exclusivity

A product can be designated as an orphan medicinal product by the European Commission if its sponsor can establish that: (1) the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition; (2) either (a) such condition affects no more than five in 10,000 persons in the European Union when the application is made or (b) it is unlikely that the product, without the benefits derived from orphan status, would generate sufficient return in the European Union to justify the necessary investment in its development; and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the European Union or, if such method exists, the product will be of significant benefit to those affected by that condition. Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers. The application for orphan designation must be submitted before the application for marketing authorization. The applicant will receive a fee reduction for the MA application if the orphan designation has been granted, but not if the designation is still pending at the time the MA application is submitted. Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

Products receiving orphan designation in the European Union can receive ten years of market exclusivity, during which time no “similar medicinal product” may be placed on the market in the European Union. A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication. However, an MA may be granted to a similar medicinal product with the same indication as an authorized orphan product during the ten-year period with the consent of the MA holder for the original orphan medicinal product or if the manufacturer of the original orphan medicinal product is unable to supply sufficient quantities. Marketing authorization may also be granted to a similar medicinal product with the same indication as an authorizes orphan product if the applicant can establish that its similar product is safer, more effective or otherwise clinically superior to the original orphan medicinal product. The period of market exclusivity may, in addition, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

The aforementioned European Union rules are generally applicable in the EEA, which consists of the European Union Member States, plus Iceland, Liechtenstein and Norway.

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 European Union for all medicines (including those for rare diseases and for children). The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval and, in April 2024, the European Parliament proposed amendments to the legislative proposals. Once the European Commission's legislative proposals are approved (with or without amendment), they will be adopted into European Union law.

Other U.S. Healthcare Laws and Compliance Requirements

Healthcare providers, including physicians, and third-party payors play a significant role in determining what drug products are used by patients. Our current and future arrangements with healthcare providers, third party payors, patients and other parties within the healthcare industry as well as our business operations more generally may implicate broadly applicable fraud and abuse and other healthcare laws and regulations. Within the U.S., restrictions under applicable federal and state healthcare laws and regulations, including certain laws and regulations applicable only if we have marketed products, include the following:

•the federal healthcare anti-kickback statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made under federal and state healthcare programs such as Medicare and Medicaid. A person or entity does not need to have actual knowledge of the anti-kickback statute or specific intent to violate it in order to have committed a violation;

•the federal False Claims Act (“FCA”), which imposes criminal and civil penalties on individuals or entities for knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government and actions under the FCA may be brought by private whistleblowers as well as the government. In addition, the government may assert that a claim including items and services resulting from a violation of the federal anti-kickback statute constitutes a false or fraudulent claim for purposes of the FCA;

•the federal civil monetary penalties laws, which impose civil fines for, among other things, the offering or transfer of remuneration to a Medicare or state healthcare program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner or supplier of services reimbursable by Medicare or a state healthcare program;

• the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended, which imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program and also establishes requirements related to the privacy, security, and transmission of individually identifiable health information which apply to many healthcare providers, physicians and third-party payors with whom we interact;

•the federal false statements statute prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;

•the FDCA, which, among other things, strictly regulates drug product and medical device marketing, prohibits manufacturers from marketing such products for off-label use and regulates the distribution of samples;

•federal laws, such as the Medicaid Drug Rebate Program, that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under governmental healthcare programs;

•federal and state consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;

•the so-called federal “sunshine law” or Open Payments which requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Centers for Medicare & Medicaid Services information related to payments and other transfers of value to teaching hospitals, physicians, and other healthcare

practitioners, as well as ownership and investment interests held by physicians and their immediate family members; and

•analogous state laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers, and state laws which regulate interactions between pharmaceutical companies and healthcare providers, require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, require pharmaceutical companies to report information on transfers of value to other healthcare providers, marketing expenditures or pricing information and/or require licensing of sales representatives. State laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products. 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.

Given the breadth of the laws and regulations and narrowness of any exceptions, limited guidance for certain laws and regulations and evolving government interpretations of the laws and regulations, it is possible that some of our business activities could be subject to challenge under one or more of such laws. Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant penalties, including, without limitation, civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participating in federal and state funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, diminished profits and future earnings, reputational harm and the curtailment or restructuring of our operations, any of which could harm our business.

Payments made to physicians in certain European Union Member States must be publicly disclosed. Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization, and/or the regulatory authorities of the individual European Union Member States. These requirements are provided in the national laws, industry codes or professional codes of conduct applicable in the European Union Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, exclusion from participation in governmental healthcare programs, disgorgement, fines or imprisonment.

Healthcare Reform

In the U.S. and some foreign jurisdictions, there have been and continue to be ongoing efforts to implement legislative and regulatory changes regarding the healthcare system. Such changes could prevent or delay marketing approval of any product candidates that we may develop, restrict or regulate post-approval activities and affect our ability to profitably sell any product candidates for which we obtain marketing approval. Although we cannot predict what healthcare or other reform efforts will be successful, such efforts may result in more rigorous coverage criteria, in additional downward pressure on the price that we, or our future collaborators, may receive for any approved products or in other consequences that may adversely affect our ability to achieve or maintain profitability.

Within the U.S., the federal government and individual states have aggressively pursued healthcare reform. For example, the Affordable Care Act (“ACA”), implemented in 2010, substantially changed the way healthcare is financed by both governmental and private insurers and contains a number of provisions that

affect coverage and reimbursement of drug products and/or that could potentially reduce the demand for pharmaceutical products such as increasing drug rebates under state Medicaid programs for brand name prescription drugs and extending those rebates to Medicaid managed care and assessing a fee on manufacturers and importers of brand name prescription drugs reimbursed under certain government programs, including Medicare and Medicaid. Other aspects of healthcare reform, such as expanded government enforcement authority, could also affect our business.

Beyond the ACA, there have been ongoing health care reform efforts. Drug pricing and payment reform has been an ongoing focus of the Trump Administration and was a focus of the Biden Administration. For example, federal legislation enacted in 2021 eliminated the statutory cap on Medicaid drug rebate program rebates (currently set at 100% of a drug’s “average manufacturer price”) effective January 1, 2024. As another example, the Inflation Reduction Act of 2022 (“IRA”) includes a number of changes intended to address rising prescription drug prices in Medicare Parts B and D. These changes, which have varying implementation dates, include caps on Medicare Part D out-of-pocket costs for beneficiaries, Medicare Part B and Part D drug price inflation rebates, a new Medicare Part D manufacturer discount drug program (replacing the ACA Medicare Part D coverage gap discount program) and a drug price negotiation program for certain high spend Medicare Part B and D drugs (with the first set of negotiated prices having gone into effect January 1, 2026). The focus on health care reform, including reform of drug pricing and payment, has continued in the wake of the IRA.

The One Big Beautiful Bill Act of 2025 (“OBBBA”), for example, 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.

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 have also been 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 product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. In addition, regional health care 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 health care programs. We expect that additional state and federal healthcare reform measures will be adopted in the future, particularly in light of the new presidential administration, any of which could limit the amounts that federal and state governments will pay for healthcare products and services.

Healthcare reform efforts have been and may continue to be subject to scrutiny and legal challenge. For example, with respect to the ACA, tax reform legislation was enacted that eliminated the tax penalty established for individuals who do not maintain mandated health insurance coverage beginning in 2019 and, in 2021, the U.S. Supreme Court dismissed the latest judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA. As another example, revisions to regulations under the federal anti-kickback statute would remove protection for traditional Medicare Part D discounts offered by pharmaceutical manufacturers to pharmacy benefit managers and health plans. Pursuant to court order, the removal was delayed and subsequent legislation imposed a moratorium on implementation of the rule until January 2032. As another example, the IRA drug price negotiation program has been challenged in litigation filed by various pharmaceutical manufacturers and industry groups.

In the European Union, similar political, economic and regulatory developments may affect our ability to profitably commercialize our potential product candidates. Recently, many countries in the European Union have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the European Union. The downward pressure on healthcare costs in general, particularly prescription products, has become intense. 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 Member States, and parallel trade, i.e., arbitrage between low-priced and high-priced Member States, can further reduce prices. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products, if approved in those countries.

Coverage and Reimbursement

The regulations that govern marketing approvals, pricing, coverage and reimbursement for new drug products vary widely from country to country. Current and future legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price negotiations that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the product in that country. Adverse pricing limitations may hinder our ability to recoup our investment in one or more product candidates, even if our product candidates obtain marketing approval.

Our ability to commercialize any product candidates successfully also will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations. Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels. Coverage and reimbursement

by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is:

•a covered benefit under its health plan;

•safe, effective and medically necessary;

•appropriate for the specific patient;

•cost-effective; and

•neither experimental nor investigational.

In the U.S., there is no uniform policy of coverage and reimbursement for products among third-party payors. As a result, obtaining coverage and reimbursement approval of a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical and cost-effectiveness data for the use of our products on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained. The availability and adequacy of coverage and reimbursement by governmental healthcare programs such as Medicare and Medicaid, private health insurers and other third-party payors are essential for most patients to be able to afford our product candidates, if approved, and so will significantly affect our ability to successfully commercialize any such product candidates.

A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Coverage may not be available for any product that we commercialize or may be subject to controls imposed by third party payors to manage utilization (e.g., requiring specific approval for use of a product in a particular patient for coverage). Even if coverage is available, the resulting reimbursement payment rates may not be adequate or may require patient out-of-pocket costs that patients find unacceptably high. Reimbursement may affect the demand for, or the price of, any product candidate for which we obtain marketing approval. Obtaining and maintaining adequate reimbursement for our products may be difficult. We may be required to conduct expensive pharmacoeconomic studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies. If coverage and adequate reimbursement are not available or reimbursement is available only to limited levels, we may not be able to successfully commercialize any product candidate for which we obtain marketing approval. Additionally, we, or our collaborators, will be required to obtain coverage and reimbursement for any companion diagnostic tests developed separate and apart from the coverage and reimbursement we may seek for our product candidates, once approved.

There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the purposes for which the drug is approved by the FDA or similar regulatory authorities outside of the U.S. Moreover, eligibility for coverage and reimbursement does not imply that a drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution expenses. Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services. Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or requested by private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S. Our inability to promptly obtain coverage and adequate reimbursement rates from both government-funded and private payors for any approved products that we develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.

In some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. For example, the European Union provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. 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 product candidate to currently available therapies. A Member State may approve a specific price for the medicinal product or it may instead

adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. Historically, products launched in the European Union do not follow price structures of the U.S. and generally prices tend to be significantly lower.

There can be no assurance that our product candidates, even if they are approved for sale in the U.S. or in other countries, will be considered medically reasonable and necessary for a specific indication or cost-effective by third-party payors, or that coverage and an adequate level of reimbursement will be available or that third-party payors’ reimbursement policies will not adversely affect our ability to sell our product candidates profitably.

Data Privacy and Security Laws

Numerous state, federal and foreign laws, regulations, and standards govern the collection, use, access to, confidentiality and security of health-related and other personal information and could apply now or in the future to our operations or the operations of our partners. In the U.S., such laws and regulations include data breach notification laws, consumer privacy laws, health information privacy and security laws and consumer protection laws. Privacy and security laws, regulations and other obligations are constantly evolving and may conflict with each other to complicate compliance. The federal government and several states have also recently taken steps to restrict data transactions involving countries outside the U.S. For example, the Department of Justice’s January 8, 2025, Rule on Preventing Access to U.S. Sensitive Personal Data and Government-Related Data by Countries of Concern or Covered Persons, prohibits transfers of certain types of data, including health data, genetic data, and biospecimens, to countries of concern, including China. Actual or alleged violations of these laws and regulations may be punishable by criminal and/or civil sanctions.

Employees and Human Capital Resources

As of February 15, 2026, we had 59 full-time employees, of which 15 had M.D. or Ph.D. degrees. Within our workforce, 31 employees were engaged in research and development and 28 were engaged in general and administrative activities, including business development, finance, legal and corporate administration as of February 15, 2026. None of our employees are represented by labor unions or covered by collective bargaining agreements. We consider our relationship with our employees to be good.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and new employees, advisors and consultants. The principal purposes of our equity incentive plans are to attract, retain and reward personnel through the granting of equity-based compensation awards in order to increase shareholder value and support the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

We believe that our future success largely depends upon our continued ability to attract and retain highly skilled employees. We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, professional development programs that enable continued learning and growth and a robust employment package that promotes well-being across multiple aspects of employees' lives, including health care, retirement planning and paid time off.

Corporate Information

We were incorporated under the laws of the State of Delaware in August 2019 under the name Sling Therapeutics, Inc., and changed our name to Sionna Therapeutics, Inc. in November 2021. Our principal executive offices are located at 21 Hickory Drive, Suite 500, Waltham, MA 02451, and our telephone number is (617) 819-2020. We have one subsidiary, Sionna Therapeutics Securities Corporation (f/k/a Sling Therapeutics Securities Corporation), formed in 2020 under the laws of the Commonwealth of Massachusetts.

Available Information

Our website address is www.sionnatx.com. The information contained in or accessible from our website is not incorporated into this Annual Report, and you should not consider it part of this Annual Report. We have included our website address in this Annual Report solely as an inactive textual reference. Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and

15(d) of the Securities Exchange Act of 1934, as amended, are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (the "SEC"). Information on our website is not part of this Annual Report or any of our other securities filings unless specifically incorporated herein by 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.

Our code of business conduct and ethics, corporate governance guidelines and the charters of our Audit Committee, Compensation Committee and Nominating and Corporate Governance Committee are available through the “Investors” portion of our website. Additionally, we routinely post information to the “Investors” section of our website that may be important to investors. We encourage investors and potential investors to consult our website regularly for information about our Company.