NASDAQ: OKUR

OKI-219 is currently being investigated in a first-in-human Phase 1 open-label multi-arm clinical trial evaluating OKI-219 in patients with solid tumors, including breast cancer harboring a PI3KαH1047R mutation (“PIKture-01”). In the first arm, OKI-219 is being investigated as a monotherapy in patients with solid tumors, including breast cancer, harboring a PI3KaH1047R mutation. Data reported from this arm supported the initiation of the first combination arm investigating OKI-219 as part of a doublet therapy in combination with fulvestrant in patients with HR+/HER2- breast cancer harboring a PI3KαH1047R mutation (“Part B)”. In the second half of 2025, we expanded PIKture-01 to investigate OKI-219 as part of triplet regimens in two breast cancer subtypes, HR+HER2- (HR+) and HER2+. In September 2025, we initiated the first triplet expansion arm of PIKture-01 evaluating OKI-219 in combination with fulvestrant and ribociclib in patients with PI3KaH1047R mutated, HR+ metastatic breast cancer (“Part E”). In October 2025, we initiated a triplet expansion arm of PIKture-01 evaluating OKI-219 in combination with trastuzumab and tucatinib in patients with PI3KαH1047R mutated, HER2+ metastatic breast cancer (“Part C”).

In December 2024, we announced preliminary safety, tolerability, and pharmacokinetic (“PK”) data from Part A of PIKture-01 with a cut off date of October 28, 2024. These data showed that OKI-219 was well tolerated across all dose levels with no hyperglycemia, stomatitis, or rash observed at any dose, and all reported treatment-related adverse events (“TRAEs”) have been grade 1. No dose interruptions, delays, reductions, or discontinuations were reported for TRAEs. OKI-219 dosed at 900 mg twice daily showed steady-state exposure levels with near-continuous coverage of the in vivo EC80 for pAKT inhibition. These data supported the initiation of the first combination arm of PIKture-01, Part B, which began enrolling patients in the fourth quarter of 2024.

To date, we have completed the enrollment of patients in both Part A (monotherapy) and Part B (fulvestrant combination) of PIKture-01 and we are currently enrolling Part C (trastuzumab and tucatinib combination) and Part E (fulvestrant and ribociclib combination). We expect to report data from the monotherapy and fulvestrant combination arms of PIKTure-01 together with initial data from the triplet expansion arms (Parts C and E) in 2026.

7

Pharmacokinetic and Selectivity Profile

OKI-219 has shown favorable PK data in the PIKture-01 trial that support pharmacologically relevant exposures, potentially even at the lowest assessed dose levels, with a safety profile that is indicative of little or no inhibition of wild-type PI3Kα. At steady state, the exposures of OKI-219 exceed exposures associated with robust antitumor activity in preclinical models. The PK data are considered preliminary with a data cut-off of October 28, 2024.

As of the cutoff date, 13 of the 14 patients that received a ≥600 mg dose twice a day remained in the study. In addition, two patients with HR+/HER2- breast cancer who received the 300 mg dose showed prolonged stable disease, including one patient who sustained >95% reduction in PIK3CAH1047R ctDNA and was on treatment for more than seven months.

Preclinical Data

Results from preclinical in vivo models of OKI-219 used in combination with standard-of-care (“SOC”) therapies for HR+ breast cancers show strong combination activity of OKI-219 in doublet combinations with SERDs and in triplet combinations with SERD + CDK4/6 inhibitors. Additionally, OKI-219 was well tolerated at doses well above those required for tumor regressions, supporting the ability to combine OKI-219 with SOC therapies in breast cancer. Additional preclinical combination studies are ongoing.

Genetic analysis of tumors has become standard-of-care in oncology and has enabled oncologists to characterize tumors much more precisely than simple segmentation based on the tissue of origin. A more precise understanding of the genetic alterations driving the growth of specific tumors has also created an opportunity for the industry to develop drugs that are intended to target mutated or oncogenic forms of proteins that drive cancer growth and survival. In a number of notable cases, this approach has profoundly changed how these tumors are treated and has significantly improved outcomes for patients with cancers that depend on these oncogenes for survival. However, in many cases, it has been challenging to effectively target the mutated oncogenic form of a target protein. In particular, non-selective inhibition of the wild-type protein in normal tissues often leads to toxic effects that can limit effective target inhibition of the intended oncogenic protein in cancers and, therefore, offers suboptimal clinical benefit. One such challenging target is the oncogene PI3Kα.

PI3Kα is an attractive target for cancer drugs because it is one of the most commonly mutated oncogenes in cancers and is a key mediator of abnormal cell growth. Furthermore, PI3Kα kinase mutations are clinically correlated with drug resistance and poor clinical outcomes. Single amino acid mutations such as E542K, E545K, H1047R, H1047L, and H1047Y account for over 70% of PI3Kα mutations. Notably, the PI3KαH1047R mutation is very common in breast cancer, being identified in approximately 14% of breast cancer cases. The PI3Kα inhibitor alpelisib has been approved to treat patients with advanced breast cancers harboring PI3Kα mutations. Alpelisib is non-selective for the key mutations, and its inhibition of not only mutant but also wild-type PI3Kα leads to significant toxicities in patients, such as hyperglycemia, rash and diarrhea. These toxicities can present significant challenges to optimal dosing and use in this patient population. We are focused on addressing the shortcomings of alpelisib and other first-generation PI3Kα inhibitors (e.g., inavolisib) by developing product candidates that target these genetic alterations selectively while sparing the wild-type PI3Kα.

Our Development Pipeline

We are focused on the discovery and development of precision therapies that target

biologically validated drivers of diseases underserved by available therapies. Currently, we are focused on delivering highly selective drug candidates that preserve wild-type PI3Kα while effectively targeting the PI3Kα-mutations, initially in advanced breast cancer.

Our lead product candidate, OKI-219, is advancing in a Phase 1 clinical trial. We are also actively pursuing multiple additional discovery programs that target mutations of PI3Kα. We expect to announce a pan-mutant development candidate in the first quarter of 2026 targeting the most common PI3Kα mutations (i.e., H1047R, E545K, and E542K) in breast cancer. Additionally, we have initiated a discovery program in vascular malformations, where mutations in the PI3Kα pathway have been implicated.

8

Our Clinical Pipeline

Strategy

Our strategic objective is to conceive, develop and commercialize one or more mutation-specific PI3Kα inhibitors to address the needs of patients in cancer and beyond. With three PI3Ka inhibitor programs, we are committed to developing product candidates that address the needs of patients who suffer from diseases implicated by PI3Ka, a key disease creating gene. We rely on the experience of our team in precision kinase inhibitor drug design and development to carry out our strategy. In doing so, we intend to:

a)

Rapidly advance and expand the clinical development of our highly selective PI3KαH1047R inhibitor, OKI-219. The Phase 1 multi-arm clinical trial, OKI-219-101, known as PIKture-01, has completed enrollment of Parts A and B and is currently enrolling Parts C and E. Part C is a triplet combination of OKI-219 dosed in combination with trastuzumab and tucatinib in patients with PI3KαH1047R-mutated, HER2+ advanced breast cancer. Part E is a triplet combination of OKI-219 dosed in combination with ribociclib and fulvestrant, a selective estrogen receptor degrader (“SERD”) in patients with PI3KαH1047R-mutated, HR+/HER2- advanced breast cancer.

b)

Discover and develop a PI3Ka inhibitor development candidate that selectively targets all the most common PI3Ka mutations. We are actively pursuing a pan-mutant molecule to target all the most common PI3Kα mutations (i.e., H1047R, E545K, and E542K) that may have the potential to treat a broader patient population. Our research and development team has extensive expertise in discovering early development candidates with favorable drug properties, and we plan to announce a pan-mutant development candidate in the first quarter of 2026.

c)

Expand the development of PI3Ka inhibitors beyond breast cancer by harnessing the knowledge gained by our discovery team from understanding this key gene. We are applying our precision drug design approach and our team’s expertise to develop kinase inhibitors for PI3Kα mutations in patients with vascular malformations. PI3Kα mutations are the most common driver mutations for specific sub-types of vascular malformations. These mutations in the PIC3CA gene lead to over activation of the pathway, which controls cell growth, proliferation, and survival. We believe our portfolio of PI3Kα inhibitors have the potential to benefit patients in this underserved population. We plan to announce additional information on our vascular malformations program in 2026.

d)

Conduct clinical and regulatory programs to support our global regulatory and commercialization strategy. We retain worldwide rights to all our programs. We plan to expand our clinical development and seek regulatory approval for our current and future product candidates in the United States and abroad. Our long-term goal is to commercialize our products by establishing a commercial organization on our own and/or by leveraging the capabilities of potential commercial partners inside and outside of the United States. We plan to evaluate strategic opportunities that we believe can maximize the commercial potential of our product candidates with collaborators whose development and commercial capabilities could be complementary.

9

Genetic Tumor Profiling is Unlocking Novel Targets for Cancer Therapy

Over the past 20 years, drug developers have translated findings from tumor genetic analysis into greater insight into tumor biology, a development that has led to a major improvement in anti-cancer therapies. Tumors are no longer simply classified based on their tissue of origin; rather, they are segmented based on genetic alterations, which frequently predict the likely pathogenesis of a specific malignancy and/or its sensitivity to treatment with specific targeted therapies. As a key part of this genetic analysis, mutations in critical signaling pathways have been identified, many of which are potential targets for precision medicines. The signaling axis encompassing PI3K/AKT and mammalian target of rapamycin (“mTOR”) is believed to be a key growth driver of tumor cells and is often considered a master regulator of cancer. PI3K activity is upregulated by upstream oncogenes and growth factor receptors, or by activating mutations of PI3K itself, and aberrant PI3K activation is a common hallmark in tumor cell growth in both hematologic malignancies and solid tumors. PI3K activation is believed to contribute to cancer cell survival, angiogenesis, and tumor metastasis.

There are three subtypes of PI3K, known as Type I, Type II and Type III. Type I PI3K is believed to drive the proliferation of tumor cells and has been a key target for drug development. There are four biochemical variants, also known as isoforms or subtypes, of Type I PI3K: PI3Kα, PI3Kß, PI3Kg and PI3Kd. While they are differentiated from each other in sequence and structure, all these variants are based on the same fundamental kinase sequence, structure, and function.

PI3Kα is one of the most commonly mutated oncogenes in cancer. PI3Kα can be activated by oncogenic point mutations in the PI3Kα gene. The three most common mutations of PI3Kα are H1047R, E542K and E545K. Mutation of PI3KαH1047R in a mouse model has induced breast cancer tumorigenesis and is also associated with drug resistance to HER2-targeting agents in breast cancer. PI3Kα is mutated in up to 36% of breast cancer cases. Notably, the PI3KαH1047R mutation is also found in approximately 14% of breast cancer cases, making this an attractive target for novel therapeutics in metastatic breast cancer. In addition, targeting mutated PI3Kα is a clinically-validated approach following approvals of three drugs for patients with PI3Kα-mutated breast cancers: 1) the PI3Kα inhibitor alpelisib, marketed by Novartis as PIQRAY®, approved in combination with fulvestrant for the treatment of HR+, HER2-, locally advanced or metastatic breast cancer with PI3Kα mutations, 2) the AKT inhibitor capivasertib, marketed by AstraZeneca as TRUQAP®, also approved in combination with fulvestrant for the treatment of HR+, HER2-, locally advanced or metastatic breast cancer with PI3Kα mutations and 3) the PI3Kα-selective inhibitor inavolisib (ItovebiTM) which was approved in combination with the SERD fulvestrant and the CDK4/6 inhibitor palbociclib (IbranceTM) in endocrine-resistant HR+/HER2- locally advanced or metastatic breast cancer.

Both alpelisib and inavolisib are ATP-competitive PI3Kα kinase inhibitors that do not distinguish between mutant and wild-type PI3Kα. Likewise, capivasertib inhibits the pathway downstream of PI3Kα, and also does not differentiate between inhibition of wild-type and mutated PI3Kα signaling. Unlike these drugs, OKI-219 is a specific and selective allosteric inhibitor of H1047R-mutated PI3Kα. OKI-219 is designed to bind at an allosteric site located adjacent to the H1047R mutation which is distal from the active site. This has been shown in numerous x-ray images of OKI-219 bound to PI3KαH1047R.

Drug-related toxicities associated with non-selective PI3Kα pathway inhibitors such as alpelisib and capivasertib are caused by inhibiting the wild-type PI3Kα enzyme in normal tissues and limit the therapeutic dosing of these agents, resulting in sub-optimal dosing and limited efficacy. Adverse events commonly associated with PI3Kα inhibitors include hyperglycemia, rash, diarrhea, and stomatitis. Tumor sequencing analysis has led to the identification of specific mutations in the PI3Kα genes that offer novel drug targets for precision medicine with the potential to minimize the toxicities of non-selective PI3Kα inhibitors.

We are utilizing our precision medicine small molecule drug discovery platform to identify and develop therapeutic candidates that specifically bind to and inhibit the major PI3Kα mutations. We believe that by avoiding the targeting of wild-type PI3Kα, our product candidates have the potential to improve upon the safety, efficacy, or both, of other non-selective PI3Kα inhibitors.

10

Our Product Candidate

OKI-219, a Targeted Inhibitor of PI3KαH1047R

Our lead product candidate is OKI-219, an orally administered small molecule designed to selectively bind to and inhibit PI3KαH1047R, while avoiding inhibition of wild-type PI3Kα. It shows a differentiated safety profile and has demonstrated minimal on-target toxicity in both preclinical and clinical studies to date. In addition, in preclinical studies, OKI-219 showed best-in-class antitumor activity and combinability and tolerability with other SOC drugs, including ribociclib and fulvestrant combinations, a profile that we believe would position OKI-219 to be a preferred therapeutic option in early lines of PI3KαH1047Rmetastatic breast cancer.

OKI-219 is currently being investigated in a first-in-human Phase 1 trial. This is an open-label, international trial designed to evaluate OKI-219 for safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy with sites in the United States, European Union, and Asia. In December 2024, we reported preliminary safety, tolerability, and pharmacokinetic data from the PIKture-01 trial. OKI-219 was well tolerated across all dose levels tested with no hyperglycemia, and all treatment-related adverse events have been grade 1. No dose interruptions, delays, reductions, or discontinuations were reported for any adverse events. OKI-219 dosed at 900 mg twice daily showed steady-state exposure levels with near-continuous coverage of the in vivo EC80 for pAKT inhibition. These data supported the initiation of the first combination arm of PIKture-01 evaluating OKI-219 in combination with fulvestrant in the fourth quarter of 2024. Additionally, in the second half of 2025, we initiated two triplet dose escalation arms of PIKture-01. We expect to report data from the monotherapy and fulvestrant combination arms of PIKture-01 together with initial data from the triplet dose escalation arms (Parts C and E) in 2026. Additional clinical trials will be required demonstrating that OKI-219 is safe and effective prior to regulatory approvals for the commercial sale of OKI-219.

Commercial Opportunity in Breast Cancer

Breast cancer is the most diagnosed cancer worldwide and is the leading cause of cancer death in women. In the United States, there were an estimated 300,590 new cases of breast cancer in 2023, resulting in 43,700 deaths. According to the National Cancer Institute, approximately 70% of breast cancer patients are HR+/HER2-, approximately 14% are HER2+ and approximately 11% are classified as triple negative, with the remaining 6% of patients being unclassified.

PI3Kα is the most commonly mutated oncogene in breast cancer. Mutations in the PI3K pathway are associated with increased failure of clinical treatments in advanced breast cancer, such HER2 therapy, endocrine therapy, and CDK inhibitor therapy. Notably, the activity of fulvestrant with or without CDK inhibitors in advanced or metastatic breast cancer is worse in PI3KαH1047R mutated tumors, suggesting that adding PI3Kα inhibitors to standard of care therapies in HR+ and HER2+ breast cancer may have strong clinical benefit in patients with PI3Kα-mutated cancers. Some currently approved drugs, such as inavolisib and alpelisib show strong clinical benefit in combination with fulvestrant +/- CDK inhibitors in PI3Kα-mutated breast cancers; however these agents are still associated with significant toxicity from targeting the WT form of the enzyme, which is thought to limit the clinical benefit and quality of life for patients. While a number of molecules with modest selectivity for mutations versus WT PIK3CA are being developed, we believe that highly-selective inhibition of mutated PI3Ka is necessary to enable optimal target coverage and clinical benefit without eroding safety and quality of life due to inducing PI3Ka-related toxicity.

We believe the potential market opportunity for PI3Kα inhibitors is large. Total new HR+/HER2- advanced breast cancer patients each year with the most common PI3Ka mutations (H1047, E542 and E545) is approximately 29,000 in the U.S. and >60,000 in the U.S.+ EU5+Japan (see Figure 1). The single most common PI3Kα mutation, PI3KαH1047R, is found in approximately 14% of all breast cancers. For comparison, the HER2+ population in breast cancer also accounts for approximately 14% of all patients.

The other common PI3Ka mutations, PI3KαE542K and PI3KαE545K, are less prevalent, and combined are found in approximately 10% of breast cancers.

We believe that there is a significant market opportunity for a highly-selective PI3KαH1047R inhibitor, with the ability to target an annual population of ~17,000 patients in the United States and >35,000 patients in the United States +EU5 (UK, Spain, Italy, Germany and France) + Japan with PI3KαH1047R-mutated tumors across all lines of metastatic breast cancer (see Figure 1).

11

Based on the data from the PIKture-01 trial, as of the October 28, 2024 cutoff date, and the selectivity of OKI-219 (approximately 80-fold selectivity for PI3KαH1047R over PI3KαWT), we believe we have the opportunity with OKI-219 to optimize efficacy and safety in patients with PI3KαH1047R-mutated tumors, thus being well positioned to be an important therapeutic in this sizeable patient population.

Assumption

U.S.

EU 5

JAPAN

CHINA

Incidence

Annual Breast Cancer Incidence

305,000

290,000

100,000

380,000

Total New HR+/HER2- Advanced Breast Cancer Patients Each Year

65,000

53,000

16,000

70,000

Biomarker Prevalence

% Patients with Kinase domain (H1047R or Helical Domain (E542K/E545K) Mutations

PI3Ka

Kinase

PI3Ka

Helical

PI3Ka

Kinase

PI3Ka

Helical

PI3Ka

Kinase

PI3Ka

Helical

PI3Ka

Kinase

PI3Ka

Helical

~14%

~10%

~14%

~10%

~14%

~10%

~14%

~10%

Line of Therapy Progression

1L aBC Annual New Patient Starts

~9,000

~6,500

~7,300

~5,300

~2,300

~1,600

~9,700

~7,000

2L aBC Annual New Patient Starts

~5,500

~3,600

~4,200

~3,200

~1,700

~1,200

~6,100

~4,500

3L aBC Annual New Patient Starts

~2,500

~1,800

~2,000

~1,400

~1,100

~800

~3,200

~2,300

Figure 1. Estimated breast cancer incidence metrics across certain regions of the world. Source: OnKure third party research

Limitations of Currently Approved PI3K Inhibitors

Mutations in the PI3K/AKT/mTOR signaling axis occur frequently in many cancer types. PI3Kα is frequently mutated and activated in cancer, and aberrant PI3Kα activation is believed to be involved in tumor growth and metastasis. PI3Kα is composed of two components, a regulatory subunit, p85α, and catalytic subunit, p110α. An activating gain-of-function mutation in the catalytic p110α region of PI3Kα is one of the most common drivers of mutations in solid tumors.

Due to its role in mediating signaling in multiple cell types in humans, inhibition of the normal wild-type PI3Kα enzyme is associated with a diverse range of toxicities, including hyperglycemia, rash, diarrhea, nausea, and stomatitis, which present a challenge to maintenance of patients on therapy. Hyperglycemia is one of the readily monitorable key toxicities in both patients and animal models that limits the efficacy of currently approved PI3Kα inhibitors and is often used as a sentinel indicator of on-target activity vs wild-type PI3Kα, however other effects, such as rash and GI toxicities can also be severe and debilitating for patients.

Alpelisib (PiqrayTM) was the first PI3Kα inhibitor approved, in combination with fulvestrant for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer. At the approved dose in the SOLAR-1 trial for alpelisib, toxicities expected for inhibition of wild-type PI3Kα for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer were common. Other adverse events may be associated with the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PI3Kα-mutated, advanced or metastatic breast cancer. Increases in glucose were observed in 79% of patients treated with alpelisib (39% Grade 3 or 4) in this study. Other adverse events commonly associated with PI3K inhibition were also frequently observed: diarrhea (58%, 7% Gr3/4); nausea (45%, 2.5% Gr3/4); rash (52%, 20% Gr3/4); fatigue (42%, 5% Gr3/4) and stomatitis (30%, 2.5% Gr3/4).

Capivasertib (TruqapTM) is an AKT inhibitor developed by AstraZeneca, indicated in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations. Capivasertib adverse events associated with PI3K pathway inhibition have also been commonly observed, highlighting the safety challenges of broadly inhibiting this pathway. Specifically, in the CAPItello-291

12

study that supported approval of capivasertib, while the rate of hyperglycemia (37% overall, 3.1% Gr3/4) was lower than observed with alpelisib, other PI3K-related AEs were more notable, including: diarrhea (77% overall, 12% Gr3/4); cutaneous (56%, 15% Gr3/4); fatigue (38%, 1.9% Gr3/4); stomatitis (25%, 1.9% Gr3/4) and nausea (35%, 1.3% Gr3/4).

Inavolisib (ItovebiTM, Genentech) is a PI3Kα-selective inhibitor that was approved in 2024, in combination with fulvestrant and palbociclib in endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer. While the tolerability profile of inavolisib is considered to be manageable, this molecule still shows frequent adverse events associated with inhibition of the wild-type form of PI3Kα. These include increases in fasting glucose (85% overall, 22% Gr2 and 12.6% with Gr3/4); stomatitis (51% overall, 6% Gr3/4); diarrhea (48% overall, 3.7% Gr3/4); rash (26% overall, 0% Gr3/4), fatigue (38% overall, 1.9% Gr3/4) and nausea (28% overall, 0.6% Gr3/4).

While initial PI3Kα pathway inhibitors are active clinically, the frequent rate of adverse events due to inhibition of the wild-type PI3Kα pathway impact their use and are a challenge for patients, highlighting the need for more-selective inhibitors of mutated PI3Kα that can limit on-target toxicity. By minimizing the targeting of PI3KαWT (approximately 80-fold selectivity for PI3KαH1047R over PI3KαWT), we believe OKI-219 can achieve exposures required for activity in PI3Kα-mutated cancers with minimal effect on wild-type PI3Kα signaling, thus limiting the on-target toxicities, such as hyperglycemia, GI effects, fatigue, and rash. We believe that this is a key differentiator for OKI-219 compared to first-generation non-selective PI3Kα inhibitors.

In December 2024, we announced preliminary safety, tolerability, and PK data from PIKture-01 as of a data cut off on October 28, 2024. OKI-219 was well tolerated across all dose levels with no hyperglycemia, stomatitis, or rash observed with other PI3Kα inhibitors. Additionally, all TRAEs have been grade 1, with no dose interruptions, delays, reductions, or discontinuations reported for any TRAEs.

Figure 2. Initial TRAEs observed across dose levels in PIKture-01 Part A.

Data cutoff October 28, 2024. Source: OnKure data.

Blood-Brain Barrier Penetration

Brain metastases are estimated to occur in 98,000 to 170,000 cancer patients in the United States each year and in 10% to 26% of patients who die from their cancers. The observed growth in the incidence of brain metastasis over the last decade is believed to be partially attributed to the challenges of chemotherapeutic agents gaining access to the brain. While clinical outcomes for systemic malignancies have improved, the survival prognosis for brain metastasis has remained poor and for many patients remains at less than one year.

The blood-brain barrier (the “BBB”) is a semi-permeable membrane that regulates the transfer of substances from the circulatory system into the brain and provides protection for the brain from potentially harmful

13

substances present in the rest of the body. The BBB is composed of cells that line blood vessels, known as endothelial cells, which are joined to each other with tight junctions and are surrounded by a layer of cells known as pericytes found in the capillary basement membrane. The tight junctions limit the entry of most molecules greater than approximately four hundred Daltons in molecular weight. While it is protective of the brain and contributes to overall health, the BBB nonetheless presents a challenge to physicians seeking to deliver anti-cancer agents to the brain and to treat brain metastasis. Preclinical data for OKI-219 in a rat model suggest that OKI-219 is highly brain-penetrant, reaching free drug concentrations in the brain similar to those observed in plasma, indicating potential utility in central nervous system disease.

Distribution of OKI-219 through the BBB and into the brain has also been confirmed in both dogs and monkeys. We believe that the ability of OKI-219 to penetrate the BBB may enable it to effectively treat patients with brain metastasis in addition to those with systemic malignancies.

Current Treatment Landscape in PI3K-mutated Breast Cancer

The treatment landscape for metastatic breast cancer is changing rapidly, with the introduction of multiple novel and next-generation drugs with potential for improved safety and efficacy and that target specific molecularly defined patient populations. Combinations of multiple drugs and mechanisms based on patients’ mutational status are now routine, particularly in early lines of treatment, reflecting this increased molecular understanding of disease. Although metastatic breast cancer is still considered incurable, with the introduction of novel targeted therapies, patients now experience prolonged survival: patients with HR+/HER2- distant (Stage IV) breast cancer show a 36.5% 5-year survival rate, which is expected to rise as additional novel therapies gain acceptance. Given this changing treatment environment, in which patients expect to receive multiple years of targeted therapy, typically in combinations, new therapies will need to not only demonstrate efficacy but increasingly must show both a clear safety advantage and a lack of drug interactions that facilitate targeted combination regimens that enable patients to remain on and tolerate optimal therapy for extended periods of time, particularly in early lines of therapy.

Many cancers are treated with combinations of two or more anti-cancer drugs. Specifically, in breast cancer, the choice of therapy is dependent on the type and stage of disease. Breast cancers are segmented diagnostically based on growth drivers, including hormonal receptors such as estrogen and progesterone receptors and the HER2/neu receptor. In general, treatment options for patients are divided into three groups based on: (1) the status of either hormone receptors (over-express the estrogen receptor (ER) and/or or progesterone receptor (PR) (classified as HR+)); (2) the HER2/neu receptor (classified as HER2+); or (3) the lack of expression of either HR or HER2 (classified as triple negative (TNBC)). Mutations in PI3Ka occur in approximately 36% of breast cancers and are generally considered to be truncal (occur early in disease and typically present from initial tumor development through metastasis).

Approximately 70% of breast cancers are HR+ (most being HR+/HER2-), however with a minority of these being HR+/HER2-). Patients with HR+/HER2-/PI3KMT breast cancer are often treated with unique therapies,

14

reflecting the advent of drugs to target both the estrogen receptor and the PI3K pathway (see figure above). In general, in the adjuvant setting, these patients are treated similarly to PI3KWT patients, typically treated with anti-estrogen therapy, such as an aromatase inhibitor (e.g., letrozole) or a selective estrogen receptor modulator (SERM) such as tamoxifen in the adjuvant setting. Some patients with intermediate or high-risk disease may also receive chemotherapy prior to anti-estrogen therapy. Typically, adjuvant drugs are administered for up to five years. For patients who experience a recurrence of disease (locally advanced or metastatic) treatment options for the specific group of patients who have HR+/HER2-/PI3KaMT mBC first-line therapy now includes the use of targeted PI3K inhibitors in some settings. Specifically, the portion of these patients who develop advanced or metastatic disease while still on, or rapidly after completion (<12 months) of, adjuvant therapy are considered to be higher risk and are recommended to be treated with a triplet therapy combining the SERD fulvestrant, the CDK4/6 inhibitor palbociclib, and the PI3K-inhibitor inavolisib (ITOVEBITM, Genentech). HR+/HWE2-/PI3KMT patients who develop metastatic disease more than 12 months from completion of adjuvant therapy are considered still to be sensitive to anti-estrogen therapy, and are recommended to get a combination of an aromatase inhibitor (letrozole, anastrozole or exemestane) with a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib). In the second-line setting, treatment can vary depending on identified mutations in various genes. Patients with PI3Kα mutations are eligible to receive fulvestrant plus a PI3Kα- or AKT-targeting agent such as alpelisib or capivasertib. ESR1 mutations commonly develop in patients who have disease that progresses on aromatase inhibitors (approximately 40% of patients). For HR+/HER2-/PI3KMT patients with ESR1 mutations, physicians may prescribe an oral SERD such as elacestrant (marketed by Stemline Therapeutics, a subsidiary of Menarini Group, as Orserdu®), or imlunestrant (Inluriyo™ marketed by Eli Lilly) and often, these patients may receive oral SERDs before combinations with fulvestrant and a PI3K pathway inhibitor. For other patients, fulvestrant with or without the mTOR inhibitor everolimus would be indicated; however, this combination is not specifically approved for patients with a PI3K mutation). Following disease progression on both AI and SERDs, mBC is typically considered to be estrogen insensitive, and patients may be treated with an ADC or chemotherapy.

Approximately 14% of breast cancer patients over-express the HER2/neu receptor and are classified as HER2+. These patients are treated with HER2-targeting agents such as trastuzumab, marketed by Roche as Herceptin®; generic biosimilars to trastuzumab; pertuzumab, marketed by Roche as Perjeta®; ado-trastuzumab emtansine or T-DM1, marketed by Roche as Kadcyla®; fam-trastuzumab deruxtecan-nxki or T-DXd, marketed by Daiichi Sankyo and AstraZeneca as Enhertu®; and tucatinib, marketed by Pfizer as Tukysa®. Typically, in early-stage or metastatic disease, the standard-of-care is trastuzumab plus chemotherapy, with or without pertuzumab. Ado-trastuzumab emtansine was the standard-of-care in second-line metastatic disease until the approval of trastuzumab deruxtecan in 2019. Trastuzumab deruxtecan is frequently prescribed in second-line HER2+ disease, whereas ado-trastuzumab emtansine is now typically used in the third-line setting. In patients with disease that progresses on all these therapy regimens, a triple combination of tucatinib, trastuzumab and capecitabine is often used in the fourth-line or salvage setting.

Approximately 10% of breast cancer patients do not over-express HR or HER2 receptors. These tumors are classified as triple negative breast cancer (“TNBC”). Patients with TNBC are treated with chemotherapy, sacituzumab govitecan, marketed by Gilead as Trodelvy®, immunotherapy such as pembrolizumab, marketed by Merck as Keytruda®, or atezolizumab, marketed by Genentech as Tecentriq®.

Beyond HR and HER2 receptors, breast cancer patients are also screened for PD-L1 positivity, which encompasses approximately 40% of patients, as well as for mutations in the germline BRCA1 or BRCA2 genes. The prevalence of a BRCA1 or BRCA2 mutation is only 3%–4% in HR+/HER2- patients but is approximately 15% in patients with TNBC. In PD-L1 positive, triple negative breast cancer, patients are treated with atezolizumab or pembrolizumab, while two Poly ADP Polymerase inhibitors (“PARP inhibitors”) are approved for BRCA1/2 mutants: Olaparib, marketed by AstraZeneca as Lynparza®, and talazoparib, marketed by Pfizer as Talzenna®.

The PI3Kα-targeting agent alpelisib and the AKT-targeting agent capivasertib are currently approved in combination with fulvestrant in advanced HR+/HER2- breast cancer, providing a proof of concept for targeting mutated PI3Kα in this disease. These therapies have significant toxicity, however, which presents a challenge for their use. We believe that the ability to safely combine with fulvestrant or other SERDs. As well as with any of the approved CDK4/6 inhibitors (ribociclib, abemaciclib or palbociclib) is a critical advantage for any new therapy targeting PI3Kα-mutated HR+ breast cancer. OKI-219 was tested in combination with fulvestrant + either palbociclib or ribociclib or with a next-generation SERD known as camizestrant in a preclinical breast cancer model utilizing the T47D cell line. T47D is an estrogen receptor-positive luminal A subtype breast cancer cell line that harbors the PI3KαH1047R mutation and is frequently utilized in research of hormonal signaling in breast cancer. In

15

mouse xenograft models implanted with T47D cells, a combination of OKI-219 (25 mg/kg, QD) + fulvestrant (5 mg/mouse, QW) + ribociclib (75 mg/kg, QD) or palbociclib (10 mg/kg, BID) showed increased antitumor activity and regressions compared to either OKI-219 alone or the fulvestrant + CDK4/6 inhibitor combination. Likewise, monotherapy treatment with camizestrant at 10mg/kg QD resulted in slower tumor growth than the control but did not result in significant tumor volume reduction from baseline. Similarly, monotherapy dosing with OKI-219 at 25mg/kg QID resulted in delay of tumor growth as well. The combination of OKI-219 and camizestrant resulted in significant and dose-dependent tumor shrinkage, supporting the potential for combination therapy of OKI-219 and SERDs in metastatic breast cancer.

We tested the combination of OKI-219 with tucatinib, an anti-HER2 small molecule tyrosine kinase inhibitor, in the HER2+ PI3KαH1047R HCC1954 breast cancer cell line. This cell line is resistant to tucatinib treatment, and in mouse xenograft models implanted with HCC1954 cells this was demonstrated by the continued tumor growth with 50mg/kg BID tucatinib dosing. OKI-219 monotherapy at 200mg/kg QD appears to limit the tumor’s ability to grow but is not effective enough by itself to drive tumor shrinkage. The combination of tucatinib and OKI-291 resulted in tumor shrinkage, suggesting that inhibiting mutant PI3Kα in combination with targeting HER2 can overcome poor responses to HER2-targeting agents used alone.

We believe that breast cancer is an ideal tumor type for the initial development of mutant-selective PI3Kα inhibitors due to several factors:

•

the fact that PI3Kα inhibitors have been approved in PI3Kα-mutated HR+ metastatic breast cancer;

•

the high prevalence of the PI3KαH1047R mutation in breast cancer;

•

the poor prognosis of patients with metastatic breast cancer who have PI3Kα mutations; and

•

the fact that PI3Kα mutations appear to be truncal, meaning that they originate early in cancer development and, when mutated, are found in most cancer cells in a patient.

We believe that initially focusing on PI3KαH1047R in advanced breast cancer patients may enable the eventual development of OKI-219 in earlier lines of therapy as well as in patients with tumors with different tissues of origin besides breast and expanding the patient population that may benefit from treatment with OKI-219.

Phase 1 PIKture-01 Trial

OKI-219 is currently being investigated in the PIKture-01 trial, a Phase 1 trial. This is an open-label, multi-arm international trial with sites in the United States, European Union, and Asia designed to evaluate the safety, tolerability, PK, PD, and preliminary antitumor activity of OKI-219 in patients with solid tumors, including breast cancer harboring a PI3KαH1047R mutation.

The PIKture-01 trial has four active parts:

•

Part A is a dose-ranging basket trial of solid tumors testing OKI-219 as a monotherapy. This part of the trial enrolled patients with solid tumors with the PI3KαH1047R mutation for whom there is no effective available therapy. The starting dose is 300mg BID, and this trial uses a Bayesian Optimal Interval design. We have dosed up to 1500mg BID. We completed and closed enrollment in Part A as of August 2025. We expect to provide an update from this arm of the trial in the first quarter of 2026.

•

Part B is investigating OKI-219 in combination with fulvestrant in HR+/HER2- advanced breast cancer. These patients must have locally advanced, unresectable or metastatic cancer with the PI3KαH1047R mutation and have received at least one prior line of hormonal therapy and at least one prior line of CDK 4/6 inhibitor therapy in the advanced or metastatic setting unless contraindicated. Part B was initiated in the fourth quarter of 2024. We completed and closed enrollment of the dose-escalation portion of Part B as of August 2025. We expect to announce initial data from this arm of the trial in the first quarter of 2026.

•

Part C is investigating OKI-219 in combination with trastuzumab and tucatinib in patients with HER2+ advanced breast cancer with the PI3KαH1047R mutation. These patients must have HER2+, locally advanced unresectable or metastatic breast cancer and also have received prior taxane, trastuzumab, pertuzumab, tucatinib or trastuzumab deruxtecan unless unavailable or contraindicated. Part C was initiated in October 2025. We expect to announce initial data from this arm of the trial in 2026.

16

•

Part E is investigating OKI-219 in combination with ribociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer with the PI3KαH1047R mutation. Part E was initiated in September 2025. We expect to announce initial data from this arm of the trial in the first quarter of 2026.

Part B has enrolled patients in a single-arm dose escalation plus back-fill cohorts, and the clinical protocol currently includes an option to investigate high and low doses to comply with FDA’s project OPTIMUS dose optimization requirement. The objective of a dose-finding trial is to find the optimum dose instead of utilizing the maximum tolerated dose, which historically has been the dose chosen for pivotal trials of cancer drugs.

The primary endpoint of Part A is to assess the safety of OKI-219 and to identify the maximum tolerated dose and pharmacologically active dose(s) (“PAD”). Secondary endpoints include additional measures of safety and tolerability in addition to:

•

assess plasma PK of OKI-219;

•

assess the effect of food on the PK of OKI-219;

•

estimate preliminary antitumor activity;

•

assess the dose-response impact of circulating tumor DNA (“ctDNA”); and

•

assess the PD activity of OKI-219 and its association with PK, safety, and efficacy.

For Part B, the primary endpoints during dose-ranging are to assess the safety of OKI-219 when taken in combination with fulvestrant and to identify two PAD levels that will be utilized during the dose optimization portion, if necessary, for which the primary endpoint is to compare two PAD levels of OKI-219 plus a fixed dose of fulvestrant in order to identify the recommended Phase 2 dose. Secondary endpoints include additional measures of safety and tolerability of OKI-219 when taken in combination with fulvestrant in addition to:

•

assess the plasma PK of OKI-219 when in combination with fulvestrant;

•

estimate preliminary antitumor activity of OKI-219 when taken in combination with fulvestrant;

•

assess the dose-response impact of OKI-219 when taken in combination with fulvestrant; and

•

assess the PD activity of OKI-219 and determine the impact of OKI-219 dosing in combination with fulvestrant on blood glucose and insulin.

Additionally, exploratory endpoints for all parts include an exploration of predictive biomarkers of response to OKI-219 in blood and tumor tissue as monotherapy and while in combination with fulvestrant. For dose optimization only, we also seek to determine the impact of OKI-219 on quality of life.

During dose optimization, we anticipate that 20 participants will be randomized between two PAD levels in Part B. A sample size of 20 participants in each arm will provide 79% power to detect an increase in objective response rate from 5% to 20% within each PAD arm using a one-sided exact binomial test at the 10% level of significance. Monotherapy is not powered to assess efficacy.

For Parts C and E, the primary endpoints during dose-ranging are to assess the safety of OKI-219 when taken in combination with tucatinib plus trastuzumab and fulvestrant plus ribociclib, respectively. Secondary endpoints include measures of safety and tolerability of OKI-219 when taken in combination with tucatinib plus trastuzumab (Part C) and fulvestrant plus ribociclib (Part E) in addition to:

•

assess the plasma PK of OKI-219 when taken in combination with tucatinib plus trastuzumab (Part C) and fulvestrant plus ribociclib (Part E);

•

estimate preliminary antitumor activity of OKI-219 when taken in combination with tucatinib plus trastuzumab (Part C) and fulvestrant plus ribociclib (Part E);

•

assess the dose-response impact of OKI-219 when taken in combination with tucatinib plus trastuzumab (Part C) and fulvestrant plus ribociclib (Part E); and

17

•

assess the PD activity of OKI-219 and determine the impact of OKI-219 dosing when taken in combination with tucatinib plus trastuzumab (Part C) and fulvestrant plus ribociclib (Part E) on blood glucose and insulin.

Figure 3. PIKture-01 trial design, key eligibility criteria and key endpoints as of December 2025.

OKI-219 Potential Future Trials

OKI-219 was designed to target the PI3KαH1047R mutation to maintain or improve upon the efficacy and simultaneously to minimize the toxicities associated with first-generation PI3KαWT inhibitors. We anticipate that this precision targeting of the H1047R mutation and minimal inhibition of wildtype PI3Kα should enable OKI-219 to safely combine with one or two other cancer drugs and potentially result in synergistic clinical efficacy. We plan to explore OKI-219 in combination with other drugs in multiple lines of treatment in breast cancer. Based on initial data from these combination studies, a number of possible development strategies will be considered, including developing OKI-219 in combination with a SERD in second-line breast cancer patients; developing OKI-219 in patients who have disease that has progressed on prior inavolisib or alpelisib treatment; and development of OKI-219 in front-line metastatic breast cancer, in combination with CDK inhibitors, plus either an aromatase inhibitor or a SERD. With positive data in the metastatic setting, we would consider developing OKI-219 in combination with an AI+ a CDK inhibitor in the adjuvant setting.

Pan-mutant PI3Ka Precision Kinase Inhibitor Program

A key goal of cancer therapy is to improve efficacy, while maintaining a very well tolerated side effect profile, thus improving patient benefit and quality of life for patients. Our focus is on discovering and developing highly mutant-selective PI3Kα inhibitors that can improve target coverage and efficacy in PI3Kα-mutated cancers compared to existing agents, while also improving safety by sparing inhibition of wild type PI3Kα. OKI-219 has approximately 80-fold selectivity for PI3KαH1047R over the wild type form of the enzyme, a profile that may optimize the potential for efficacy and safety for treatment of tumors with a PI3KαH1047R mutation, the most common PI3Kα mutation in breast cancer.

We believe that to fully target all the most common PI3Kα mutations in SOC combinations in HR+ mBC, a PI3Kα “Pan-mutant” inhibitor will need to demonstrate approximately 10-fold selectivity against each of the most common mutations (PI3KαH1047X, PI3KαE542K and PI3KαE545K). Currently, we are aware of no compounds in clinical development that can achieve this level of selectivity across all the most common mutations, leaving an opportunity for development and approval of a pan-mutant PI3Kα inhibitor for patients regardless of their PI3Kα mutation.

18

We are actively developing pan-mutant candidates with activity and selectivity (>10X) across the most common PI3Kα mutations (i.e., H1047R, E545K, and E542K). We believe a highly selective and potent pan-mutant inhibitor has the potential to achieve a maximal efficacy and safety profile in combinations in metastatic breast cancer, and may further enable sufficient activity as a single agent to target PI3Kα-mutated advanced cancer populations beyond breast cancer. This represents a significant patient population for which there are no current targeted therapies: Approximately 11% of all cancers harbor mutations in PI3Kα, and no PI3Kα-targeted therapies have shown sufficient efficacy to gain approval as a single-agent, potentially due to poor selectivity limiting the ability to get sufficient target inhibition without dose-limiting toxicities. We propose that a highly selective pan-mutant inhibitor may have the efficacy to enable use in this underserved patient population beyond breast cancer. We expect to announce a pan-mutant development candidate in the first quarter of 2026.

Competition

The pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. While we believe that our technology, the expertise of our team, and our development experience and scientific knowledge provide us with competitive advantages, we face increasing competition from many different sources, including pharmaceutical and biotechnology companies, academic institutions, governmental agencies, and public and private research institutions. Product candidates that we successfully develop and commercialize (whether alone or in partnership with others) may compete with existing therapies and new therapies that may become available in the future.

Many of our competitors, either alone or with their collaborators, have significantly greater financial resources, established presence in the market, and expertise in research and development, manufacturing, preclinical and clinical testing, obtaining regulatory approvals and reimbursement, and marketing approved products than we do. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel, in establishing clinical trial sites and patient registration for clinical trials, and in-licensing or acquiring technologies complementary to, or necessary for, our programs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with larger companies. Additional mergers and acquisitions may result in even more resources being concentrated in our competitors. Our commercial potential could be reduced or eliminated if our competitors develop and commercialize products that are safer or more effective, have fewer or less-severe side effects, or are more convenient or less expensive than products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we can, which could result in those competitors establishing a strong market position before we are able to enter the market or could otherwise make the development or commercialization of our products more complicated. The key competitive factors affecting the success of all of our programs are likely to be efficacy, safety and patient convenience.

There are multiple PI3Kα-pathway targeted agents either approved or under clinical development that may compete with OKI-219 and our PI3Kα-targeted portfolio. These include the marketed medicines alpelisib (Piqray®, a PI3Kα-selective inhibitor marketed by Novartis) and capivasertib (Truqap®, an AKT1 inhibitor marketed by Astra Zeneca), both of which are approved for the treatment of PI3Kα-mutated breast cancer patients in combination with the SERD fulvestrant in ER+ mBC. The PI3Kα-selective inhibitor inavolisib (ItovebiTM) is also approved in combination with the SERD fulvestrant and the CDK4/6 inhibitor palbociclib (Ibrance®) in endocrine resistant HR+/Her2- locally advanced or metastatic breast cancer. We are also aware of several novel PI3K-targeted therapies that are in clinical development. These include both multiple non-mutation-selective PI3K inhibitors such as gedatolisib (Celcuity Inc.), MEN1611 (Menarini), and TOS-358 (Totus Medicines), and inhibitors designed to have greater selectivity for mutated PI3Kα, including RLY-2608 (Relay Therapeutics), STX-473 (Scorpion Therapeutics) and SNV4818 (Synnovation Therapeutics). Multiple other companies have disclosed or published research efforts in PI3K inhibitors that are at an early stage but could potentially advance to the clinic.

Finally, there are numerous other investigational therapies, spanning many modalities that are being evaluated preclinically and in clinical trials for breast cancer.

Manufacturing

We do not own or operate, and currently have no plans to establish any manufacturing facilities. We rely, and expect to continue to rely, on third parties for the manufacture of our product candidates for preclinical and clinical testing, and expect to rely on third parties for commercial manufacturing should any of our product candidates obtain marketing approval. We believe that this strategy allows us to maintain a more efficient

19

infrastructure by eliminating the need to invest in our own manufacturing facilities, equipment and personnel while also enabling us to focus our expertise and resources on the discovery and development of our product candidates. In addition, we generally expect to rely on third parties for the manufacture of any companion diagnostics we may develop.

To date, we have obtained the starting materials and cGMP-compliant active pharmaceutical ingredients from certain suppliers, but could contract with other CMOs for these materials as the raw materials we use are common and available from multiple sources. We also currently rely on CMOs, for the drug product for OKI-219, but may contract with other CMOs for the manufacture of drug product in the future. We are in the process of developing our supply chain for our product candidates and intend to put in place framework agreements under which third-party CMOs will generally provide us with necessary quantities of API and drug product on a project-by-project basis based on our development requirements.

As we advance our product candidates through development, we plan to explore adding backup suppliers for intermediates, the API, and drug product for OKI-219 and future product candidates in order to protect against any potential supply disruptions.

Intellectual Property

We strive to protect and enhance the proprietary technologies, inventions and improvements that are commercially important to our business by, among other methods, pursuing and obtaining patent protection in the United States and in jurisdictions outside of the United States directed to these technologies, inventions, improvements and to our drug candidates. We also rely on trade secrets, know-how, trademarks, continuing technological innovation and licensing opportunities to develop and maintain our proprietary and intellectual property position.

As of March 6, 2026, our patent portfolio included 63 owned patent applications and one owned U.S. issued patent, covering various aspects of our proprietary technology, product candidates, and related inventions and improvements. The patent portfolio also included 49 patent applications pending in jurisdictions outside of the United States.

PI3K Platform

We currently own 13 patent families directed to our PI3K platform technology as summarized below. The patent families are differentiated based on the chemical structures of the PI3K inhibitor compounds. All of the family members are currently at the application stage and exist as one or more U.S. provisional (“USP”) applications, a Patent Cooperation Treaty (“PCT”) application, or as U.S. and non-U.S. national phase applications. Several of our current patent applications relate to and include composition of matter claims for OKI-219. All six of the patent families which are at the PCT application stage also have a Taiwanese (“TW”) patent application. The U.S. provisional applications secure an early filing date and provide an additional twelve months of patent protection beyond the normal 20-year lifetime of any patent granted thereon. The PCT applications are single-application placeholders for filings in a majority of the countries and geographic regions of the world. The types of claims for each application are listed, and an expiration year for each family based on the actual or projected PCT filing dates is also provided.

Family 1: 15 national applications w/product and method of treatment claims/2043 expiration

Family 2: 15 national applications w/product and method of treatment claims/2043 expiration

Family 3: 12 national applications w/product and method of treatment claims/2044 expiration

Family 4: PCT and TW applications w/product and method of treatment claims/2045 expiration

Family 5: PCT and TW applications w/product and method of treatment claims/2045 expiration

Family 6: PCT and TW applications w/product and method of treatment claims/2044 expiration

Family 7: PCT and TW applications w/product and method of treatment claims/2045 expiration

20

Family 8: PCT and TW applications w/product and method of treatment claims/2045 expiration

Family 9: PCT and TW and AR applications w/product and method of treatment claims/2046 expiration

Family 10: USP application w/product and method of treatment claims/2046 expiration

Family 11: USP application w/product and method of treatment claims/2046 expiration

Family 12: USP application w/product and method of treatment claims/2046 expiration

Family 13: USP application w/product and method of treatment claims/2046 expiration

We cannot guarantee that our owned pending patent applications, or any patent applications that we may in the future file or license from third parties, will result in the issuance of patents. We also cannot predict the scope of claims that may be allowed or enforced in our patents. In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance. Consequently, we may not obtain or maintain adequate patent protection for any of our programs and product candidates.

The terms of individual patents depend upon the legal terms of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the earliest date of filing a non-provisional patent application. In the United States, the patent term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process. The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent. Similar provisions are available in Europe and other non-U.S. jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when our products receive FDA approval, we expect to apply for patent term extensions on patents covering those products. We also plan to seek patent term extensions on any of our issued patents in any jurisdiction where available, but there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.

In addition to patent protection, we also rely on trademark registration, trade secrets, know how, other proprietary information, and continuing technological innovation to develop and maintain our competitive position. We protect and maintain the confidentiality of proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection. Although we take steps to protect our proprietary information and trade secrets, including through contractual means, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Therefore, we may not be able to meaningfully protect our trade secrets. It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. Our agreements with employees also provide that all inventions conceived by the employee in the course of employment or from the employee’s use of our confidential information are our exclusive property. However, such confidentiality agreements and invention assignment agreements can be breached and we may not have adequate remedies for any such breach.

The patent positions of biotechnology companies like us are generally uncertain and involve complex legal, scientific and factual questions. Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, alter our products or processes, obtain licenses, or cease certain activities. Our breach of any license agreements or our failure to obtain a license to proprietary rights required to develop or commercialize our future products may have a material adverse impact on us. If third parties prepare and file patent applications in the United States that also claim technology to which we have rights, we may have to participate in derivation proceedings in the USPTO to determine priority of invention. For more information, see the section entitled “Risk Factors—Risks Related to our Intellectual Property.”

Government Regulation

21

Our product candidates and our operations are subject to extensive regulation by the FDA and other federal and state authorities in the United States, as well as comparable authorities in other countries.

The FDA and other federal, state, local and foreign authorities regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing, and export and import of drug and combination products. Generally, before a new drug can be marketed, considerable data demonstrating its quality, safety, and efficacy must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

U.S. Drug Development

In the United States, the FDA regulates drugs under the Food, Drug, and Cosmetic Act (“FDCA”) and its implementing regulations. Drug products and substances are subject to other federal, state and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process, or post-market may subject an applicant to administrative or judicial sanctions. These sanctions could include, among other actions, the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement, and civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.

Our current product candidates and any future small molecule product candidates must be approved by the FDA through the new drug application (“NDA”) process before they may be legally marketed in the United States. The process generally involves the following:

•

completion of extensive preclinical studies in accordance with applicable regulations, including the FDA’s good laboratory practice requirements;

•

submission to the FDA of an IND, which must become effective before clinical trials may begin;

•

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

•

performance of adequate and well controlled clinical trials in accordance with applicable Investigational New Drug Application (“IND”) regulations, good clinical practice (“GCP”) requirements and other clinical trial-related regulations to establish the safety and efficacy of an investigational product for each proposed indication;

•

preparation and submission to the FDA of an NDA;

•

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

•

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

•

potential FDA audit of the preclinical study and/or clinical trial sites that generated the data in support of the NDA;

•

FDA review and approval of the NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the United States; and

•

compliance with any post-approval requirements, including the potential requirement to implement a risk evaluation and mitigation strategy (“REMS”), and the potential requirement to conduct post-approval studies.

Preclinical and Clinical Studies

22

The preclinical and clinical testing and approval process requires substantial time, effort, and financial resources, and we cannot be certain that any approvals for any future product candidates will be granted on a timely basis or at all. Preclinical tests generally involve laboratory evaluations of drug chemistry, formulation, and stability, as well as studies to evaluate toxicity in animals, including pharmacology, pharmacokinetics, toxicokinetic, and metabolism studies that support subsequent clinical testing in humans. The results of the preclinical studies, together with manufacturing information, analytical data, any available clinical data or literature, and a proposed clinical protocol, are submitted to the FDA as part of the IND. An IND is a request for authorization from the FDA to administer an investigational product to humans.

Long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.

The central focus of an IND submission is the general investigation plan and the protocol(s) for human studies. An IND must become effective before clinical trials may begin. 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 trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.

For each successive clinical trial conducted with the investigational drug, a separate, new protocol submission to an existing IND must be made, along with any subsequent changes to the investigational plan. Sponsors are also subject to ongoing reporting requirements, including submission of IND safety reports for any serious adverse experiences associated with use of the investigational drug or findings from preclinical studies suggesting a significant risk for human subjects, as well as IND annual reports on the progress of the investigations conducted under the IND.

Clinical studies involve the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative, and must monitor the clinical trial until completed. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries, including the website maintained by the U.S. National Institutes of Health, ClinicalTrials.gov.

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

Clinical trials in the United States generally are conducted in three phases, known as Phase 1, Phase 2, and Phase 3. Although the phases are often conducted sequentially, they may overlap or be combined.

•

Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the product candidate. The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, tolerability and safety of the drug.

•

Phase 2 clinical trials typically involve studies in a limited population of disease-affected patients to determine possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal dosage, and dosing schedule.

23

•

Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to evaluate the effectiveness of the product for its intended use, its safety in use, and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval. These trials may include comparisons with placebo and/or other comparator treatments.

Post-approval clinical 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. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and clinical study investigators. Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from 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 must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. 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.

Phase 1, Phase 2, and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group provides authorization for whether a trial may move forward at designated check-points based on access to certain data from the trial. Concurrent with clinical trials, companies usually complete additional animal safety studies and also must develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of our product candidates. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that our product candidates do not undergo unacceptable deterioration over their labeled shelf life.

NDA Review

Following completion of clinical trials, data are analyzed to assess whether the investigational product is safe and effective for the proposed indicated use or uses. The results of preclinical studies and clinical trials are then submitted to the FDA as part of an NDA, along with proposed labeling, chemistry, and manufacturing information in a request for approval to market the drug for one or more specified indications. The application must 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 efficacy of a product’s use 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 efficacy of the investigational product to the satisfaction of the FDA. FDA approval of an NDA must be obtained before a drug may be marketed in the United States.

Under the Prescription Drug User Fee Act, as amended (the “PDUFA”), each NDA must be accompanied by an application user fee. The FDA adjusts the PDUFA user fees on an annual basis. The PDUFA also imposes an annual program fee for each marketed human drug. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a qualifying small business.

The FDA reviews all submitted NDAs before it accepts them for filing to determine if they are sufficiently complete to permit a substantive review, and the FDA may request additional information rather than accepting the NDA for filing. In this event, the application must be resubmitted with the additional information and is subject to payment of additional user fees. The FDA must make a decision on accepting an NDA for filing within 60 days of

24

receipt. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the NDA. Under the PDUFA, the FDA has agreed to certain performance goals in the review of NDAs through a two-tiered classification system: standard review and priority review. According to the PDUFA performance goals, the FDA endeavors to review applications subject to standard review within ten months, whereas the FDA’s goal is to review priority review applications within six months. The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

The FDA may refer applications for novel drug products or products which present difficult questions of safety or efficacy to an advisory committee for review, evaluation, and recommendation as to whether the application should be approved and under what conditions.

Before approving an NDA, the FDA will typically conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. The FDA also may audit data from clinical trials to ensure compliance with GCP requirements. The FDA also closely analyzes the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process. Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

After the FDA evaluates an NDA and conducts inspections of manufacturing facilities, it will issue an Approval Letter or a Complete Response Letter. An Approval Letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA. The Complete Response Letter may require additional clinical data, including the potential requirement to conduct additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, or to conduct additional preclinical studies or manufacturing changes. If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive, and the FDA may interpret data differently than we interpret the same data. Further, FDA’s “real time” release of newly issued Complete Response Letters associated with withdrawn or abandoned applications, if applicable to any of our product candidates, can materially impact our business and competitive advantage.

Expedited Development and Review Programs

The FDA has a fast-track program that is intended to expedite or facilitate the process of reviewing new drugs that meet certain criteria. Specifically, new drugs are eligible for fast-track designation if they are intended 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 designate the product for fast-track status at any time before receiving NDA approval, but ideally no later than the pre-NDA meeting with the FDA. Any product submitted to the FDA for marketing, including under a fast-track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval. Any product is 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.

A product may also be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies. In addition, such product must demonstrate 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”), which endpoint is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well controlled post-marketing clinical trials. The FDA may withdraw drug approval or require changes to the labeled indication of the drug if confirmatory post-market trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug. If the FDA concludes that a drug shown to be effective can be safely used only if distribution or use is

25

restricted, it may require such post-marketing restrictions as it deems necessary to assure safe use of the drug. The Food and Drug Omnibus Reform Act made several changes to the FDA’s authority and its regulatory framework, including, among other changes, reforms to the accelerated approval pathway, such as requiring the FDA to specify conditions for post-approval study requirements and setting forth procedures for the FDA to withdraw a drug on an expedited basis for non-compliance with post-approval requirements.

Additionally, a drug may be eligible for designation as a breakthrough therapy if (a) it is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and (b) preliminary clinical evidence indicates that it may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints. 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. Fast-track designation, priority review, accelerated approval and breakthrough therapy designation do not change the standards for approval, but may expedite the development or approval process.

Post-Approval Requirements

Following approval of a new product, the product is subject to continuing regulation by the FDA, including, among other things, requirements relating to facility registration and drug listing monitoring and record-keeping adverse event and other periodic reporting, product sampling and distribution, and product promotion and advertising. The FDA strictly regulates marketing, labeling, advertising, and promotion of products that are placed on the market. Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label. 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.

Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such uses. Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use or first publication.

After approval, if there are any changes to the approved product, including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical trials. There also are continuing user fee requirements, under which FDA assesses an annual program fee for each product identified in an approved NDA. In addition, quality control, drug manufacture, packaging, and labeling products must continue to conform to cGMP requirements after approval. We rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of our products in accordance with cGMP regulations. Manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. The discovery of violative conditions, including failure to conform to cGMP regulations, could result in enforcement actions, and the discovery of problems with a product after approval may result in restrictions on a product, its manufacturer, or the NDA holder, including recalls.

The FDA may also place other conditions on approvals including the requirement for a REMS, to assure the safe use of the product. If the FDA concludes that a REMS is needed, the NDA sponsor must submit a proposed REMS. The FDA will not approve the product without an approved REMS, if required. A REMS could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription, or dispensing of products. Product approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.

The FDA may withdraw approval of a product if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Corrective action could delay drug distribution and require significant time and financial expenditures. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, problems with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, imposition of post-market studies or clinical studies to assess new safety

26

risks or imposition of distribution restrictions, or other restrictions under a REMS program. Other potential consequences include, among other things:

•

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

•

fines, warning letters, or holds on clinical trials;

•

refusal of the FDA to approve pending applications or supplements to approved applications;

•

suspension or revocation of product approvals;

•

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

•

mandated modifications of promotional materials and labeling and the issuance of corrective information;

•

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

•

injunctions or the imposition of civil or criminal penalties.

We also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling, known as “off-label use,” industry-sponsored scientific and educational activities, and promotional activities involving the internet and social media.

The FDA may also require post-approval studies and clinical trials if it finds that scientific data, including information regarding related drugs, make this appropriate. The purpose of such studies would be to assess a known serious risk or signals of serious risk related to the drug or to identify an unexpected serious risk when available data indicate the potential for a serious risk. The FDA may also require a labeling change if it becomes aware of new safety information that it believes should be included in the labeling of a drug.

Failure to comply with the applicable regulatory requirements at any time during the product development process, the approval process, or after approval may subject an applicant or manufacturer to, among other things, adverse publicity, warning letters, corrective advertising, and potential civil and criminal penalties. FDA sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical hold, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits, or civil or criminal penalties.

U.S. Patent-Term Restoration and Marketing Exclusivity

Depending upon the timing, duration, and specifics of FDA approval of any future product candidates, some of our U.S. patents may be eligible for limited patent term extension under the Hatch-Waxman Act. The Hatch-Waxman Act permits restoration of the patent term of up to five years as compensation for patent term lost during product development and FDA regulatory review process. Patent-term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. An application for patent extension must be filed with the USPTO within 60 days of FDA approval of the drug product even if the product cannot be commercially marketed at that time.

The patent term restoration period is generally one-half the time between the effective date of an IND or the issue date of the patent, whichever is later, and the submission date of an NDA plus the time between the submission date of an NDA or the issue date of the patent, whichever is later, and the approval of the NDA application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved drug is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond our current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

27

Market exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications. The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not approve an abbreviated new drug application (“ANDA”), or a 505(b)(2) NDA, submitted by another company 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. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement. The FDCA also provides three years of marketing exclusivity for an NDA, 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 covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent. Such three-year and five-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.

Other U.S. Regulatory Matters

Our current and future arrangements with healthcare providers, third-party payors, customers, and others may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations, which may constrain the business or financial arrangements and relationships through which we research, as well as, sell, market, and distribute any products for which we obtain marketing approval. The applicable federal, state, and foreign healthcare laws and regulations that may affect our ability to operate include, but are not limited to the following:

•

The Anti-Kickback Statute (“AKS”), which makes it illegal for any person, including a prescription drug or medical device manufacturer (or a party acting on its behalf), to knowingly and willfully solicit, receive, offer or pay any remuneration that is intended to induce or reward referrals, including the purchase, recommendation, order or prescription of a particular drug, for which payment may be made under a federal healthcare program, such as Medicare or Medicaid. Moreover, the Patient Protection and Affordable Care Act of 2010 (“ACA”) provides that the government may assert that a claim including items or services resulting from a violation of the federal AKS constitutes a false or fraudulent claim for purposes of the federal False Claims Act (“FCA”).

•

The FCA, including the civil FCA that can be enforced by private citizens through civil whistleblower or qui tam actions, and civil monetary penalties prohibit individuals or entities from, among other things, 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/or impose exclusions from federal health care programs and/or penalties for parties who engage in such prohibited conduct.

•

The Health Insurance Portability and Accountability Act (“HIPAA”) prohibits, among other things, executing or attempting to execute a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters.

•

HIPAA also imposes obligations on covered entities such as health insurance plans, healthcare clearinghouses, and certain health care providers and their respective business associates and their covered subcontractors, including mandatory contractual terms, with respect to safeguarding the privacy, security, and transmission of individually identifiable health information.

•

The federal Physician Payments Sunshine Act requires applicable manufacturers of covered drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to annually report to the CMS information regarding certain payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), certain non-physician healthcare professionals (such as physician assistants and nurse practitioners, among others), and teaching hospitals,

28

as well as information regarding ownership and investment interests held by physicians and their immediate family members.

•

The federal Foreign Corrupt Practice Act (“FCPA”) prohibits any U.S. individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with: accounting provisions requiring them to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations; analogous state and foreign 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; state laws that require biotechnology companies to comply with the biotechnology industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government; state and local laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures and require the registration of their sales representatives; state laws that require biotechnology companies to report information on the pricing of certain drug products; and state and foreign laws that govern the privacy and security of health information in some circumstances (such as Washington’s My Health, My Data Act, which, among other things, provides for a private right of action), many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Pricing and rebate programs must also comply with the Medicaid rebate requirements of the U.S. Omnibus Budget Reconciliation Act of 1990 and more recent requirements in the ACA. If products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply. Manufacturing, sales, promotion, and other activities also are potentially subject to federal and state consumer protection and unfair competition laws. In addition, the distribution of pharmaceutical and/or medical device 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 and/or medical device products. Products must meet applicable child-resistant packaging requirements under the U.S. Poison Prevention Packaging Act of 1970 as well as other applicable consumer safety requirements.

The failure to comply with any of these laws or regulatory requirements could subject companies to possible legal or regulatory action. Depending on the circumstances, failure to meet applicable regulatory requirements can result in significant civil, criminal, and administrative penalties, including damages, fines, disgorgement, imprisonment, exclusion from participation in government funded healthcare programs such as Medicare and Medicaid, integrity oversight and reporting obligations, contractual damages, reputational harm, diminished profits and future earnings, injunctions, requests for recall, seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, or refusal to allow a firm to enter into supply contracts, including government contracts.

Coverage and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any product candidate for which we may seek regulatory approval. Sales in the United States will depend, in part, on the availability of sufficient coverage and adequate reimbursement from third-party payors, which include government health programs such as Medicare, Medicaid, TRICARE, and the Veterans Administration, as well as managed care organizations and private health insurers. Prices at which our customers may seek reimbursement for our product candidates can be subject to challenge, reduction, or denial by third-party payors.

The process for determining whether a third-party payor will provide coverage for a product is typically separate from the process for setting the reimbursement rate that the payor will pay for the product. A third-party payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be available. Additionally, in the United States there is no uniform policy among payors for coverage or reimbursement. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies, but also have their own methods and approval processes. Therefore,

29

coverage and reimbursement for products can differ significantly from payor to payor. If coverage and adequate reimbursement are not available, or are available only at limited levels, successful commercialization of, and/or a satisfactory financial return on, any product we develop may not be possible.

Third-party payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. In order to obtain coverage and reimbursement for any product that might be approved for marketing, we may need to conduct expensive studies in order to demonstrate the medical necessity and cost-effectiveness of any products, which would be in addition to the costs expended to obtain regulatory approvals. Third-party payors may not consider our product candidates to be medically necessary or cost-effective compared to other available therapies, or the rebate percentages required to secure favorable coverage may not yield an adequate margin over cost or may not enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development.

In most foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing and reimbursement 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. 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. 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. Historically, products launched in the European Union do not follow price structures of the United States and generally prices tend to be significantly lower. For more information, see the section entitled “Risk Factors—We may face difficulties from changes to current regulations and future legislation. Healthcare legislative measures aimed at reducing healthcare costs may have a material adverse effect on our business and results of operations.”

Healthcare Reform

In the United States, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities and affect the profitable sale of product candidates. Among policy makers and payors in the United States, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives. In March 2010, the ACA was passed, which substantially changed the way healthcare is financed by both the government and private insurers, and significantly impacts the U.S. pharmaceutical industry.

The ACA, among other things: (1) increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations; (2) created a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for certain drugs and biologics that are inhaled, infused, instilled, implanted, or injected; (3) established an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents apportioned among these entities according to their market share in certain government healthcare programs; (4) expanded the availability of lower pricing under the 340B drug pricing program by adding new entities to the program; (5) expanded the eligibility criteria for Medicaid programs; (6) created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research; (7) created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (and 70% commencing January 1, 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; and (8) established a Center for Medicare Innovation at the CMS, to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drugs.

Since its enactment, there have been executive, judicial, and congressional challenges to certain aspects of the ACA. For example, in June 2021 the U.S. Supreme Court held that Texas and other challengers had no legal standing to challenge the ACA, dismissing the case on procedural grounds without specifically ruling on the constitutionality of the ACA. Further, prior to the U.S. Supreme Court ruling, on January 28, 2021, President Biden

30

issued an executive order that initiated a special enrollment period in 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

This executive order also instructs certain governmental agencies to review existing policies and rules that limit access to health insurance coverage through Medicaid or the ACA, among others. It is possible that the ACA will be subject to judicial or congressional challenges in the future. It is unclear how any such challenges and healthcare measures promulgated by the Biden administration will impact the ACA, our business, financial condition, and results of operations. Complying with any new legislation or reversing changes implemented under the ACA could be time-intensive and expensive, resulting in a material adverse effect on our business.

Other legislative changes have been proposed and adopted since the ACA was enacted. These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, effective April 1, 2013, which, due to subsequent legislative amendments, will stay in effect through 2032, unless additional congressional action is taken. In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. These laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our drugs, if approved, and accordingly, our financial operations.

Additionally, there has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketed products, which has resulted in several congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for drug products. For example, the American Rescue Plan Act of 2021 eliminated the statutory cap on Medicaid Drug Rebate Program rebates that manufacturers pay to state Medicaid programs. Elimination of this cap may require pharmaceutical manufacturers to pay more in rebates than they receive on the sale of products, which could have a material impact on our business. In August 2022, Congress passed the IRA, which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries, including allowing the federal government to negotiate a maximum fair price for certain high-priced single-source Medicare drugs, imposing penalties and excise tax for manufacturers that fail to comply with the drug price negotiation requirements, requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug prices increase faster than inflation, and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries, among other changes. Only high-expenditure, single-source drugs that have been approved for at least seven years (11 years for single-source biologics) qualify for negotiation, with the negotiated price taking effect two years after the selection year. For 2026, the first year in which negotiated prices become effective, CMS selected 10 high-cost Medicare Part D drugs in 2023, negotiations began in 2024, and the negotiated maximum fair price for each drug has been announced. CMS has selected 15 additional Medicare Part D drugs for negotiated maximum fair pricing in 2027. For 2028, up to an additional 15 drugs, which may be covered under either Medicare Part B or Part D, will be selected, and for 2029 and subsequent years, up to 20 additional Part B or Part D drugs will be selected. Various industry stakeholders have initiated lawsuits against the federal government asserting that the price negotiation provisions of the IRA are unconstitutional. Further, the current administration has issued executive orders focused on decreasing prescription drug prices, including directing the Secretary of HHS to establish a mechanism through which American patients can buy drugs directly from manufacturers who sell at a most-favored-nation price and directing the U.S. Trade Representative and Secretary of Commerce to take action to ensure foreign countries are not engaged in practices that purposefully and unfairly undercut market prices and drive price hikes in the United States. In November 2025, CMS announced a voluntary initiative called the GENEROUS Model (GENErating cost Reductions fOr U.S. Medicaid Model) to introduce the option of most-favored-nation pricing to the Medicaid program, whereby a drug manufacturer may voluntarily offer supplemental rebates to participating state Medicaid programs for a manufacturer’s covered outpatient drugs. Government agreements with pharmaceutical companies and other government measures that use most-favored-nation pricing targets for prescription drugs, including the use of international pricing reference to set drug prices in the United States, or that increase generic and biosimilar drug entry sooner than expected can have a material adverse effect on our industry, ability to set adequate pricing for new drugs to recover research and development costs, ability to attract potential investors and potential buyers in the future. The impact of these legislative, executive, and administrative actions of the government on us and the pharmaceutical industry as a whole is unclear.

31

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical 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. A number of states are considering or have recently enacted state drug price transparency and reporting laws that could substantially increase our compliance burden and expose us to greater liability under such state laws once we begin commercialization after obtaining regulatory approval for any of our products. Further, the FDA has authorized the state of Florida to develop an importation program to import certain prescription drugs from Canada for a limited period to help reduce drug costs, provided that Florida’s Agency for Health Care Administration meets the requirements set forth by the FDA. Other states may follow Florida. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our drug candidates or additional pricing pressures. We are unable to predict the future course of federal or state healthcare legislation in the United States directed at broadening the availability of healthcare and containing or lowering the cost of healthcare. If we or any third parties we may engage are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we or such third parties are not able to maintain regulatory compliance, our product candidates may lose regulatory approval that may have been obtained and we may not achieve or sustain profitability.

Foreign Regulation

In addition to regulations in the United States, we will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of our product candidates to the extent we choose to develop or sell any product candidates outside of the United States. The approval process varies from country to country and the time may be longer or shorter than that required to obtain FDA approval. The requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from country to country.

Employees and Human Capital Resources

As of March 11, 2026, we had 45 employees, 34 of whom were engaged in research and development activities. We also engage contractors and consultants. None of our employees are represented by a labor union or covered under a collective bargaining agreement. We have not experienced any work stoppages due to employee disputes, and 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 and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success of OnKure by motivating such individuals to perform to the best of their abilities and achieve our objectives.

Facilities

Our corporate headquarters is located in Boulder, Colorado, and consists of approximately 15,000 square feet of office and laboratory space pursuant to a lease that expires in December 2026, with the option to extend for a five-year period.

We lease all of our facilities and do not own any real property. We believe that our existing facilities are adequate and suitable for our current needs and that, should it be needed, suitable additional or alternative space will be available as and when needed.

32

Corporate Information

We were incorporated under the laws of the State of Delaware in November 2014 as Reneo Pharmaceuticals, Inc. (“Reneo”). On October 4, 2024 (the “Closing Date”), we consummated a merger pursuant to the terms of the Agreement and Plan of Merger, dated as of May 10, 2024 (the “Merger Agreement”), by and among Reneo, Radiate Merger Sub I, Inc., a Delaware corporation and a direct, wholly-owned subsidiary of Reneo (“Merger Sub I”), Radiate Merger Sub II, LLC, a Delaware limited liability company and a direct, wholly-owned subsidiary of Reneo, and OnKure, Inc., a Delaware corporation (“Legacy OnKure”). Legacy OnKure was incorporated under the laws of the State of Delaware in March 2011.

Pursuant to the Merger Agreement, on the Closing Date, (i) Reneo effected a reverse stock split of Reneo’s issued common stock at a ratio of 1:10, (ii) Reneo changed its name to “OnKure Therapeutics, Inc.”, (iii) Reneo reclassified all of its common stock as Class A Common Stock or Class B Common Stock, and (iv) Merger Sub I merged with and into Legacy OnKure (the “Merger”), with Legacy OnKure as the surviving company in the Merger and, after giving effect to such Merger, Legacy OnKure became a wholly owned subsidiary of OnKure Therapeutics, Inc. (together, the “Combined Company”.

Our principal executive offices are located at 6707 Winchester Circle, Suite 400, Boulder, CO 80301, and our telephone number is (720) 307-2892.

Our website address is www.onkure.com. The information on, or that can be accessed through, our website is not part of this Annual Report or our other filings with the SEC. We have included our website address in this Annual Report solely as an inactive textual reference.

We use the OnKure logo and other marks as trademarks in the United States and other countries. This Annual Report contains references to our trademarks and service marks and to those belonging to other entities. Solely for convenience, trademarks and trade names referred to in this Annual Report, including logos, artwork and other visual displays, may appear without a trademark symbol, but such references are not intended to indicate in any way that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entity.

Emerging Growth Company

We are an emerging growth company as defined in the Jumpstart Our Business Startups Act of 2012 (the “JOBS Act”). We will remain an emerging growth company until the earliest to occur of: the last day of the fiscal year in which we have more than $1.235 billion in annual revenues; the date we qualify as a “large accelerated filer,” with at least $700 million of equity securities held by non-affiliates; the issuance, in any three-year period, by us of more than $1.0 billion in non-convertible debt securities; and the last day of the fiscal year ending after the fifth anniversary of Reneo’s initial public offering (i.e., December 31, 2026).

Section 107 of the JOBS Act provides that an emerging growth company can take advantage of the extended transition period provided in Section 7(a)(2)(B) of the Securities Act of 1933, as amended (the “Securities Act”), for complying with new or revised accounting standards. In other words, an emerging growth company can delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. We have elected not to opt out of such extended transition period, which means that when a standard is issued or revised and it has different application dates for public or private companies, we, as an emerging growth company, can adopt the new or revised standard at the time private companies adopt the new or revised standard. This may make comparison of our financial statements with certain other public companies difficult or impossible because of the potential differences in accounting standards used.

33

Smaller Reporting Company

Additionally, we are a “smaller reporting company” as defined in Item 10(f)(1) of Regulation S-K. Smaller reporting companies may take advantage of certain reduced disclosure obligations, including, among other things, providing only two years of audited financial statements. We may continue to be a smaller reporting company in any given year if either (i) the market value of our stock held by non-affiliates is less than $250 million as of June 30th in the most recently completed fiscal year, or (ii) our annual revenue is less than $100 million during the most recently completed fiscal year and the market value of our stock held by non-affiliates is less than $700 million as of June 30th in the most recently completed fiscal year.

34