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Item 1. Business

2026-03-12 compared with 2025-03-10 · 190 added, 170 removed, 556 unchanged (39% of the section changed)

OnKure Therapeutics, Inc.

(“OnKure”, “we”, “us” or the “Company”) is a clinical-stage biopharmaceutical company focused on the discovery and development of precision medicines that target biologically validated drivers of cancers underserved by available therapies.

Using a structure- and computational chemistry-driven drug design platform, we are committed to improving clinical outcomes for patients by building a robust pipeline of small molecule drugs designed to selectively target specific mutations thought to be key drivers of cancer.

By improving selectivity for the oncogenic and mutated form of these cancer-driver proteins, we aim to discover and develop drugs with improved safety and efficacy by sparing toxicity that arises from non-selective inhibition of the non-mutated (or wild-type) version of the protein.

We work under the belief that inhibiting target proteins with specific mutations instead of wild-type variants should enable precise patient selection that will, in turn, improve the probability of clinical success.

We designed our current product candidates utilizing disciplined medicinal chemistry, x-ray crystallography and computational chemistry to inhibit specified mutated versions of phosphoinositide 3-kinase alpha (“PI3K α ”), a key mediator in cancer growth signaling.

Using a structure-based drug design platform, we are committed to improving clinical outcomes for patients by building a pipeline of small molecule drugs designed to achieve optimal efficacy and tolerability by selectively targeting specific mutations shown to be key drivers of cancer and other diseases.

By selectively sparing the wild-type enzyme and preferentially targeting the mutated form of the protein, which is oncogenic and drives disease processes in both cancer and vascular overgrowth syndromes, we aim to discover and develop drugs with improved safety and efficacy by sparing toxicity that arises from non-selective inhibition of the non-mutated (or wild-type) version of the protein.

We work under the principle that inhibiting target proteins with specific mutations instead of wild-type variants should enable precise patient selection that will, in turn, improve the probability of clinical success.

Our lead product candidate, OKI-219, is a highly selective inhibitor of PI3K α harboring the H1047R mutation (“PI3Kα H1047R ”) that has a much smaller impact on wild-type PI3Kα (“PI3Kα WT ”).

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We believe we can potentially expand the application of OKI-219 by conducting appropriate clinical trials in earlier lines of treatment within breast cancer, other subtypes of breast cancer, and potentially in other solid tumors.

OKI-219 is currently being investigated in a first-in-human Phase 1a/1b open-label trial evaluating OKI-219 as a monotherapy and in combination with fulvestrant or trastuzumab in subjects with advanced solid tumors, including breast cancer harboring a PI3K a H1047R mutation (“PIKture-01”).

In Phase 1a, subjects receive escalating oral doses of OKI-219 starting at 300 mg twice daily (commonly referred to as “BID”) continuously.

In Phase 1b we are currently assessing OKI-219 in combination with fulvestrant in patients with HR+/HER2- breast cancer, and in the future, plan to assess OKI-219 in combination with HER2+ targeted agents (e.g., trastuzumab) in patients with HER2+ breast cancer.

In December 2024, we announced the preliminary safety, tolerability, and pharmacokinetic (“PK”) data from 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 only grade 1 treatment-related adverse events (“TRAEs”) were reported.

No dose interruptions, delays, reductions, or discontinuations were reported for any adverse events.

We aim to render OKI-219 as a preferred backbone therapy to which other medicines are added in the context of PI3Kα H1047R -driven disease.

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 PI3Kα H1047R 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 PI3K a H1047R 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 PI3Kα H1047R 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 PI3K a H1047R 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 PI3Kα H1047R 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 EC 80 for pAKT inhibition.

These data supported the initiation of Part 1b of PIKture-01 and we began enrolling patients in the fourth quarter of 2024 focusing initially on the evaluation of OKI-219 in combination with fulvestrant.

To date, we have completed the enrollment of patients in the Part A monotherapy arm of PIKture-01 through the 1200 mg BID cohort level with no dose limiting toxicities observed in the completed cohorts.

We are currently enrolling the last cohort with a top dose of 1500 mg BID and enrollment in Part A is almost complete.

Additionally, we have enrolled patients in the Part B fulvestrant combination arm through the 900 mg BID cohort with no dose limiting toxicities observed for all completed cohorts through 600 mg BID and enrollment in the dose escalation portion of Part B is almost complete.

We expect to report additional single-agent data and initial combination data with fulvestrant in the second half of 2025.

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.

Pharmacokinetic and Selectivity Profile

OKI-219 has shown favorable PK data (Figure 1) 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.

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.

We plan to provide updated PK data in the second half of 2025.

Steady-state concentrations of OKI-219 at Day 15 across three dose levels in PIKture-01 Part A.

Data cut off October 28, 2024.

As shown in Figure 2, 13 of the 14 patients that received a ≥600 mg dose twice a day remained in the study as of the cutoff date.

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 PIK3CA H1047R ctDNA and was on treatment for more than seven months.

Time on treatment data from PIKture-01 trial.

Data cut off October 28, 2024.

Preclinical Data

Results from preclinical in vivo models (Figure 3 and 4 below) 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.

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.

Preclinical comparison of tumor shrinkage for OKI-219 alone and in combination with fulvestrant or camizestrant vs.

fulvestrant or camizestrant in an ER+HER2- breast cancer model.

Preclinical comparison of tumor shrinkage for OKI-219 alone and in combination with fulvestrant plus CDK 4/6 inhibitors vs.

CDK 4/6 inhibitors alone and in combination with fulvestrant.

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.

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Our Development Pipeline

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

biologically validated drivers of cancers underserved by available therapies.

Currently, we are focused on delivering highly selective drug candidates that preserve wild-type PI3Kα while effectively targeting the PI3Kα-mutated cancers, initially in advanced breast cancer.

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 oncogenic mutations of PI3Kα.

We expect to announce a pan-mutant development candidate in the second quarter of 2025 targeting the most common PI3K α mutations (i.e., H1047R, E545K, and E542K).

Additionally, we are developing an allosteric inhibitor molecule designed to be highly selective by specifically targeting the PI3Kα E545K and E542K mutations ( which are also known as helical domain mutations or e-mutants) and expect to announce a development candidate in 2026 .

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 PI3K α mutations (i.e., H1047R, E545K, and E542K) in breast cancer.

Additionally, we have initiated a discovery program in vascular malformations, where mutations in the PI3K α pathway have been implicated .

Our Clinical Pipeline

Our strategic objective is to conceive, develop and commercialize one or more mutation-specific PI3Kα inhibitors to address the needs of patients in breast cancer and beyond.

With three PI3K a inhibitor programs, we are committed to developing product candidates that address the needs of patients who suffer from diseases implicated by PI3K a , a key mediator in cancer growth signaling .

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 PI3K a inhibitor programs, we are committed to developing product candidates that address the needs of patients who suffer from diseases implicated by PI3K a , 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.

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Rapidly advance and expand the clinical development of our highly selective PI3K α H1047R inhibitor, OKI-219 .

The Phase 1 dose-escalation and expansion cohort trial, OKI-219-101, known as PIKture-01, is currently enrolling two arms:

a) a monotherapy arm in patients with advanced solid tumors with a PI3Kα H1047R mutation and b) a combination arm evaluating OKI-219 in combination with fulvestrant, a selective estrogen receptor degrader (“SERD”), in patients with PI3Kα H1047R -mutated, HR+/HER2- advanced breast cancer.

We also plan to initiate additional trials or arms of PIKture-01 to evaluate OKI-219 in combination with trastuzumab in patients with PI3Kα H1047R -mutated, HER2+ advanced breast cancer, and certain combinations of OKI-219 with fulvestrant and CDK inhibitors in ER+ metastatic breast cancer.

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 PI3Kα H1047R -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 PI3Kα H1047R -mutated, HR+/HER2- advanced breast cancer.

Discover and develop a PI3K a inhibitor development candidate that selectively targets all the most common PI3K a 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 second quarter of 2025.

Discover and develop a PI3K α inhibitor development candidate specifically targeting helical domain mutations .

We are also applying our precision drug design approach and our team’s expertise to develop kinase inhibitors for PI3Kα E542K and E545K mutations (also known as helical domain mutations or e-mutants).

These mutants are well known oncogenic drivers, and highly selective inhibitors targeting these mutations have the potential to further expand our addressable patient population.

We anticipate announcing a development candidate in 2026.

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.

Expand the development of PI3K a 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.

Conduct clinical and regulatory programs to support our global regulatory and commercialization strategy .

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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 in the United States and outside 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.

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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 (Itovebi TM ) which was recently approved in combination with the SERD fulvestrant and the CDK4/6 inhibitor palbociclib (Ibrance TM ) in endocrine-resistant HR+/Her2- locally advanced or metastatic breast cancer .

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 (Itovebi TM ) which was approved in combination with the SERD fulvestrant and the CDK4/6 inhibitor palbociclib (Ibrance TM ) 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.

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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.

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 PI3Kα H1047R .

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Our lead product candidate is OKI-219, an orally administered small molecule designed to selectively bind to and inhibit PI3Kα H1047R , while avoiding inhibition of wild-type PI3Kα.

As such, OKI-219 is designed to avoid the adverse effects of inhibiting wild-type PI3Kα in patients.

OKI-219 is currently being investigated in a first-in-human Phase 1a/1b trial.

This is an open-label, international trial designed to evaluate OKI-219 for safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy with planned sites in the United States, European Union, and Asia.

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 PI3Kα H1047R metastatic 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 only grade 1 treatment-related adverse events were reported.

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 EC 80 for pAKT inhibition.

These data supported the initiation of Part 1b of PIKture-01 evaluating OKI-219 in combination with fulvestrant in the fourth quarter of 2024.

We expect to provide additional single agent data and initial combination data with fulvestrant in the second half of 2025.

We will require additional Phase 2 and Phase 3 clinical trials to demonstrate that OKI-219 is safe and effective before we can seek regulatory approvals for the commercial sale of OKI-219.

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

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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.

PI3K a is the most commonly mutated oncogene in breast cancer.

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 PI3Kα H1047R mutated tumors, suggesting that adding PI3K a inhibitors to standard of care therapies in HR+ and HER2+ breast cancer may have strong clinical benefit in patients with PI3K a -mutated cancers.

The currently approved drugs, such as inavolisib and alpelisib show strong clinical benefit in combination with fulvestrant +/- CDK inhibitors in PI3K a -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.

Notably, the activity of fulvestrant with or without CDK inhibitors in advanced or metastatic breast cancer is worse in PI3Kα H1047R 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 PI3K a is necessary to enable optimal target coverage and clinical benefit without eroding safety and quality of life due to inducing PI3K a -related toxicity.

We believe the potential market opportunity for PI3K a inhibitors is large.

Total new HR+/HER2- advanced breast cancer patients each year with the most common PI3K a mutations (i.e., H1047, E542 and E545) is approximately 29,000 in the U.S.

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 PI3K a 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

PI3K a mutation, PI3Kα H1047R , is found in approximately 14% of all breast cancers.

As a comparison, the HER2+ population in breast cancer also accounts for approximately 14% of all patients.

The other common PI3K a mutations (i.e.

PI3Kα E542K and PI3Kα E545K ) 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 PI3Kα H1047R 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 countries ( UK, Spain, Italy, Germany and France ) +Japan with PI3Kα H1047R -mutated tumors across all lines of metastatic breast cancer (see Figure 5).

The single most common PI3Kα mutation, PI3Kα H1047R , 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 PI3K a mutations, PI3Kα E542K and PI3Kα E545K , 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 PI3Kα H1047R 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 PI3Kα H1047R -mutated tumors across all lines of metastatic breast cancer (see Figure 1).

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 PI3Kα H1047R over PI3Kα WT ), we believe we have the opportunity with OKI-219 to optimize efficacy and safety in patients with PI3Kα H1047R -mutated tumors, thus being well positioned to be an important therapeutic in this sizeable patient population.

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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.

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.

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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 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:

Specifically, in the CAPItello-291

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);

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OKI-219 was well tolerated across all dose levels with no hyperglycemia, stomatitis, or rash observed with other PI3Kα inhibitors.

Additionally , only grade 1 TRAEs were reported, with no dose interruptions, delays, reductions, or discontinuations reported for any adverse events.

Additionally , all TRAEs have been grade 1, with no dose interruptions, delays, reductions, or discontinuations reported for any TRAEs.

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

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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 substances present in the rest of the body.

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.

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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 Standard-of-Care in Breast Cancer

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.

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Breast cancers are segmented diagnostically based on growth drivers, including hormonal receptors such as estrogen and progesterone receptors and the HER2/neu receptor.

Approximately 70% of breast cancers over-express an estrogen receptor (“ER”) or progesterone receptor and are classified as HR+/HER2-.

If diagnosed with early-stage disease, patients are usually treated with endocrine therapy, such as aromatase inhibitors or tamoxifen in the adjuvant setting, or they may receive chemotherapy before hormonal inhibitors if they are diagnosed with later-stage, intermediate or high-risk disease.

For patients initially diagnosed with metastatic HR+/HER2- disease, and for those who have disease that has progressed to become metastatic HR+/HER2- disease, first-line treatment includes an aromatase inhibitor plus a CDK4/6 inhibitor, or the SERD, fulvestrant, plus a CDK4/6 inhibitor.

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-/PI3K MT breast cancer are often treated with unique therapies,

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 PI3K WT 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-/PI3Ka MT 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 (ITOVEBI TM , Genentech).

HR+/HWE2-/PI3K MT 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.

For patients with ESR1 mutations, physicians may prescribe a SERD such as elacestrant, a next-generation SERD marketed by Stemline Therapeutics, a subsidiary of Menarini Group, as Orserdu ® .

ESR1 mutations commonly develop in patients who have disease that progresses on aromatase inhibitors (approximately 40% of patients).

For HR+/HER2-/PI3K MT 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+.

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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 is a critical advantage for any new therapy targeting PI3Kα-mutated HR+ breast cancer.

OKI-219 was tested in combination with a next-generation SERD known as camizestrant in a preclinical breast cancer model utilizing the T47D cell line.

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 PI3Kα H1047R mutation and is frequently utilized in research of hormonal signaling in breast cancer.

In mouse xenograft models implanted with T47D cells, 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.

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.

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Phase 1 PIKture-01 Trial

OKI-219 is currently being investigated in the PIKture-01 trial, a Phase 1a/1b trial.

This is an open-label 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 as monotherapy as well as in combination with fulvestrant or trastuzumab.

The PIKture-01 trial has three parts:

Part A is a dose-ranging basket trial of solid tumors with a target enrollment of 24 subjects testing OKI-219 as a monotherapy.

This part of the trial is enrolling patients with solid tumors with the

PI3Kα H1047R mutation for whom there is no effective available therapy.

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 PI3Kα H1047R 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 PI3Kα H1047R 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.

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Part B was initiated in the fourth quarter of 2024.

Part C will investigate OKI-219 in combination with trastuzumab in HER2+ advanced breast cancer with the PI3Kα H1047R mutation.

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 PI3Kα H1047R 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 has not been initiated.

We expect that both Part B and Part C will initially enroll patients in a single-arm dose escalation trial and then would investigate high and low doses to comply with FDA’s project OPTIMUS dose exploration requirement.

Part C was initiated in October 2025.

We expect to announce initial data from this arm of the trial in 2026.

Part E is investigating OKI-219 in combination with ribociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer with the PI3Kα H1047R 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 designed to:

Secondary endpoints include additional measures of safety and tolerability in addition to:

assess plasma PK of OKI-219;

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

For Parts B and C, the primary endpoints during dose-ranging are to assess the safety of OKI-219 when taken in combination with fulvestrant or trastuzumab and to identify two PAD doses that will be utilized during the dose optimization portion, for which the primary endpoint is to compare two PAD dose levels of OKI-219 plus a fixed dose of fulvestrant or trastuzumab 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 or trastuzumab, and are designed to:

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

assess the effect of food on the PK of OKI-219 when in combination with fulvestrant or trastuzumab;

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

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

assess the PD activity of OKI-219 and, finally, determine the impact of OKI-219 dosing in combination with fulvestrant or trastuzumab 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 and trastuzumab.

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;

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

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 parts B and C.

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.

PIKture-01 trial design, key eligibility criteria and key endpoints as of October 28, 2024.

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) ;

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.

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

OKI-219 Potential Future Trials

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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.

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 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.

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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 second quarter of 2025.

Helical Domain PI3K a Precision Kinase Inhibitor Program

Additionally, we are leveraging our discovery engine to develop a highly selective allosteric inhibitor molecule specifically targeting the PI3Kα E545K and E542K mutations ( which are also known as helical domain mutations or e-mutants) and expect to announce a development candidate in 2026.

Overall, the aim of our discovery engine is to deliver highly selective drug candidates that preserve wild-type PI3Kα while effectively targeting the vast majority of PI3Kα-mutated cancers, in breast and other cancers.

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.

The pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.

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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.

The PI3Kα-selective inhibitor inavolisib (Itovebi TM ) was recently 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.

The PI3Kα-selective inhibitor inavolisib (Itovebi TM ) 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.

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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 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.

We believe that this strategy allows us to maintain a more efficient

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 regulatory starting materials and cGMP-compliant active pharmaceutical ingredients from three different suppliers, but could contract with other CMOs for these materials as the raw materials we use are commonly used and are available from multiple sources.

We also currently rely on two CMOs, for the drug product for OKI-219, but may contract with other CMOs for the manufacture of drug product in the future.

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 the API and drug product for OKI-219 and future product candidates in order to protect against any potential supply disruptions.

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

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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 February 1, 2025, our owned and licensed patent portfolio included 150 patents and patent applications, including two licensed U.S.

issued patents and six owned U.S.

issued patents, covering various aspects of our proprietary technology, product candidates, and related inventions and improvements.

The patent portfolio also includes 36 licensed patents issued in jurisdictions outside of the United States, and 30 owned patent applications pending in jurisdictions outside of the United States that, in many cases, are counterparts to the foregoing U.S.

patents and patent applications.

Our licensed patents relate to a patent family that is no longer material to our business.

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

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Several of our current patent applications relate to and include composition of matter claims for OKI-219.

Four of the families which are at the PCT application stage also have a Taiwanese (“TW”) application.

All six of the patent families which are at the PCT application stage also have a Taiwanese (“TW”) patent application.

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.

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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.

15 applications/product and method of treatment claims/2043 expiration

PCT and TW applications/product and method of treatment claims/2043 expiration

PCT application/product and method of treatment claims/2043 expiration

PCT and TW applications/product and method of treatment claims/2043 expiration

PCT and TW applications/product and method of treatment claims/2044 expiration

USP application/product and method of treatment claims/2045 expiration

2 USP application/product and method of treatment claims/2045 expiration

USP application/product and method of treatment claims/2045 expiration

USP application/product and method of treatment claims/2046 expiration

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

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

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

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

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

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

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

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.

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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.

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.

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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 usually conducted sequentially, they may overlap or be combined.

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.

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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.

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.

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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 receipt.

The FDA must make a decision on accepting an NDA for filing within 60 days of

Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the NDA.

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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

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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 restricted, it may require such post-marketing restrictions as it deems necessary to assure safe use of the drug.

If the FDA concludes that a drug shown to be effective can be safely used only if distribution or use is

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.

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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.

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.

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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 risks or imposition of distribution restrictions, or other restrictions under a REMS program.

risks or imposition of distribution restrictions, or other restrictions under a REMS program.

Other potential consequences include, among other things:

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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.

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

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.

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.

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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.

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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, coverage and reimbursement for products can differ significantly from payor to payor.

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.

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(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;

(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.

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Further, prior to the U.S.

Supreme Court ruling, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period in 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

Supreme Court ruling, on January 28, 2021, President Biden

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.

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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, including certain pharmaceutical companies and the Pharmaceutical Research and Manufacturers of America, have initiated lawsuits against the federal government asserting that the price negotiation provisions of the IRA are unconstitutional.

The impact of these judicial challenges and other legislative, executive, and administrative actions of the government on us and the pharmaceutical industry as a whole is unclear.

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.

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.

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.

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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.

In the Merger, we assumed the lease of approximately 5,100 square feet of office space for the former Reneo headquarters in Irvine, California under a non-cancelable operating lease through November 2026.

In January 2025, we subleased this space for the remaining duration of the lease.

We lease all of our facilities and do not own any real property.

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Corporate Information

We were incorporated under the laws of the State of Delaware in December 2014.

We were incorporated under the laws of the State of Delaware in November 2014 as Reneo Pharmaceuticals, Inc.

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, we changed our name from Reneo Pharmaceuticals, Inc.

to OnKure Therapeutics, Inc.

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.

22 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business