OKUR 8-K
OnKure Therapeutics, Inc. (OKUR)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.
Item 7.01 Regulation FD Disclosure.
On December 10, 2024, OnKure Therapeutics, Inc. (the “Company”) issued a press release announcing preliminary safety, tolerability, and pharmacokinetic data from its first-in-human PIKture-01 trial of OKI-219. The press release is attached hereto as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
On December 10, 2024, the Company also posted a presentation to its Investor Relations website (https://investors.onkuretherapeutics.com). A copy of the presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.
The information in this Item 7.01, including Exhibits 99.1 and 99.2 attached hereto, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, except as expressly set forth by specific reference in such filing.
Item 8.01 Other Events.
On December 10, 2024, the Company announced preliminary safety, tolerability, and pharmacokinetic (“PK”) data from its first-in-human PIKture-01 trial of OKI-219. OKI-219 was well tolerated across all dose levels with no hyperglycemia, and only grade 1 treatment-related adverse events (“TRAEs”) were reported. No dose interruptions, delays, reductions, or discontinuations were reported for any adverse events. OKI-219 dosed at 900 mg twice daily shows steady-state exposure levels with near-continuous coverage of the in vivoEC 80 for pAKT inhibition. These data support initiation of Part 1b of PIKture-01 evaluating OKI-219 in combination with fulvestrant, and the first patients have been dosed. The Company expects to provide additional single agent data and initial combination data with fulvestrant in the second half of 2025. In addition, the Company announced new pre-clinical data that show OKI-219’s synergistic activity, inducing regressions, in combination with SERD + CDK4/6 inhibitors.
Preliminary Safety Data (Data cutoff date for announcement: October 28, 2024)
Patients have been treated with OKI-219 at three dose levels as a single agent: 300 mg BID, 600 mg BID, and 900 mg BID. Across all three levels, a total of 17 patients have been dosed, including 11 patients with HER2- breast cancer, two with HR+/HER2+ breast cancer, two with colorectal cancer, one with triple negative breast cancer and one with squamous cell carcinoma in the single-agent dose escalation. OKI-219 has been generally well tolerated, with no dose-limiting toxicities, dose interruptions, or dose reductions required. The most common TRAEs were Grade 1 diarrhea (N=4), Grade 1 nausea (N=2) and Grade 1 pruritus (N=2).
Pharmacokinetic and Selectivity Profile
OKI-219 has shown favorable PK data that support pharmacologically relevant exposures, even at the lowest assessed dose levels, with a safety profile that suggests 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.
There are 13 patients who have received a ≥600 mg dose twice a day that remain in the study. In addition, two patients with HR+/HER2- breast cancer (BR) who received the 300 mg dose showed prolonged stable disease, including one patient that sustained >95% reduction in PIK3CAH1047R ctDNA and remains on treatment for more than seven months.
Pre-Clinical Data
Preclinical in vivo data show that OKI-219 used in combination with standard-of-care therapies for mutant-selected solid tumors, including breast cancers, showed potent anti-tumor activity with excellent tolerability at doses well above those needed for tumor regressions in those models. Specifically, OKI-219 shows strong combination activity in doublet with SERDs and in triplet with SERD + CDK4/6 inhibitors. Additional preclinical combination studies are ongoing.
Pipeline Progress
OnKure is actively pursuing multiple additional early-stage discovery programs that target oncogenic mutations of PI3Kα. The Company has broadened the expectations of its next-generation program beyond PI3KαH1047mutations to target all the most common PI3Kα mutations (i.e., H1047R, E545K, and E542K). The Company expects to announce a pan-mutant development candidate in the first half of 2025. Additionally, the Company is developing a highly selective allosteric inhibitor molecule specifically targeting the PI3Kα E545K and E542K mutations (a/k/a helical domain mutations or e-mutants) and expects to announce a development candidate in 2026.
Forward Looking Statements
The Company cautions you that statements contained in this report regarding matters that are not historical facts are forward-looking statements. These statements are based on the Company’s current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding the potential of, and expectations and plans regarding, the Company’s product candidates and programs, including OKI-219; the timing of data release for the ongoing clinical trial of OKI-219; and the Company’s ability to advance additional programs, including the Company’s discovery programs and the timing of announcement of development candidates for such programs. Actual results may differ from those set forth in this presentation due to the risks and uncertainties inherent in the Company’s business, including, without limitation: the Company’s limited operating history; the significant net losses incurred since inception; the ability to raise additional capital to finance operations; the ability to advance product candidates through preclinical and clinical development; the ability to obtain regulatory approval for, and ultimately commercialize, the Company’s product candidates; the outcome of preclinical testing and early clinical trials for the Company’s product candidates, including the ability of those trials to satisfy relevant governmental or regulatory requirements and the potential that the outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials; the Company’s limited resources; the risk of adverse events, toxicities or other undesirable side effects; potential delays or difficulties in the enrollment or maintenance of patients in clinical trials; the decision to develop or seek strategic collaborations to develop the Company’s current or future product candidates in combination with other therapies and the cost of combination therapies; the Company’s limited experience in designing clinical trials and lack of experience in conducting clinical trials; the substantial competition the Company faces in discovering, developing, or commercializing products; the ability to attract, hire, and retain highly skilled executive officers and employees; the ability of the Company to protect its intellectual property and proprietary technologies; the scope of any patent protection the Company obtains or the loss of any of the Company’s patent protection; developments relating to the Company’s competitors and its industry, including competing product candidates and therapies; reliance on third parties, contract manufacturers, and contract research organizations; legislative, regulatory, political and economic developments and general market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section titled “Risk Factors” in documents that the
Company files from time to time with the Securities and Exchange Commission (“SEC”), including the Quarterly Report on Form 10-Q for the period ended September 30, 2024, filed on November 7, 2024, the final 424B3 proxy statement/prospectus filed with the SEC on August 26, 2024, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and the Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
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Description |
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99.1 |
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99.2 |
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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ONKURE THERAPEUTICS, INC. |
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Date: |
December 10, 2024 |
By: |
/s/ Jason Leverone |
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Name: Jason Leverone |
Exhibit 99.1
OnKure Announces Encouraging Preliminary Safety, Tolerability, and Pharmacokinetic (PK) Data from its First-In-Human PIKture-01 Trial of OKI-219
-- OKI-219 is well-tolerated across all doses, and no dose interruptions, delays, reductions, or discontinuations were reported
-- Initial patient data show exposures of OKI-219 exceeding levels associated with robust antitumor activity in preclinical models
-- Data support the initiation of Part 1b of PIKture-01 evaluating OKI-219 in combination with fulvestrant; first patients dosed, and initial data are expected in 2H-2025
-- Management to host conference call today, December 10, 2024 at 7:00 a.m. CT
BOULDER, CO, December 10, 2024 (GLOBE NEWSWIRE) – OnKure Therapeutics, Inc. (NASDAQ: OKUR), a clinical-stage biopharmaceutical company focused on the development of novel precision medicines in oncology, today announced encouraging safety, tolerability, and pharmacokinetic data from the ongoing first-in-human trial of OKI-219, a potential best-in-class, mutant-selective PI3KαH1047R inhibitor. OKI-219 was well tolerated across all dose levels with no hyperglycemia, and only grade 1 treatment-related adverse events (TRAEs) were reported. No dose interruptions, delays, reductions, or discontinuations were reported for any adverse events (AEs). OKI-219 dosed at 900 mg twice daily shows steady-state exposure levels with near-continuous coverage of the in vivo EC 80 for pAKT inhibition. These data are consistent with the Company’s preclinical data and support the continued development of OKI-219.
In addition, the Company announced new pre-clinical data that show OKI-219’s synergistic activity, inducing regressions, in combination with SERD + CDK4/6 inhibitors, potentially paving the way for clinical trials in multiple lines of therapy. These clinical and preclinical data are scheduled to be presented during poster sessions at the 2024 San Antonio Breast Cancer Symposium (SABCS) on December 12, 2024.
“We are thrilled to present the first clinical data for our lead program, OKI-219, which is the only highly selective PI3KαH1047R inhibitor molecule in the clinic,” said Nicholas Saccomano, Ph.D., President and Chief Executive Officer of OnKure.“ These preliminary data show that OKI-219 was very well tolerated and presents a favorable safety profile. In addition, the clinical PK data show consistent steady-state exposure with near-continuous target coverage at levels where clinical activity is consistently observed. These initial clinical data support our initiation of Part 1b of the PIKture-01 trial to evaluate OKI-219 in combination with fulvestrant. We look forward to providing mature single agent and initial fulvestrant data in the second half of 2025.”
Preliminary Safety Data (Data cutoff date for announcement: October 28, 2024)
Patients have been treated with OKI-219 at three dose levels as a single agent: 300 mg BID, 600 mg BID, and 900 mg BID. Across all three levels, a total of 17 patients have been dosed, including 11 patients with HR+/HER2- breast cancer, two with HER2+ breast cancer, two with colorectal cancer, one with triple negative breast cancer and one with squamous cell carcinoma in the single-agent dose escalation. OKI-219 has been generally well tolerated, with no dose-limiting toxicities, dose interruptions, or dose
reductions required. The most common TRAEs were Grade 1 diarrhea (N=4), Grade 1 nausea (N=2) and Grade 1 pruritus (N=2).
Pharmacokinetic and Selectivity Profile
OKI-219 has shown favorable PK data that support pharmacologically relevant exposures, even at the lowest assessed dose levels, with a safety profile that suggests 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.
There are 13 patients who have received a ≥600 mg dose twice a day that remain in the study. In addition, two patients with HR+/HER2- breast cancer (BR) who received the 300 mg dose showed prolonged stable disease, including one patient that sustained >95% reduction in PIK3CAH1047R ctDNA and remains on treatment for more than seven months.
PIKture-01 Trial
PIKture-01 is a global, multi-center, first-in-human phase 1a/1b study evaluating OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab in subjects with advanced solid tumors including breast cancer harboring a PI3KαH1047R mutation. In Phase 1a, subjects receive escalating oral doses of OKI-219 starting at 300 mg BID continuously. Phase 1b is assessing OKI-219 in combination with fulvestrant in patients with HR+/HER2- breast cancer, or with trastuzumab in patients with HER2+ breast cancer. The study also includes a dose optimization phase to evaluate the optimal combination doses of OKI-219 with fulvestrant or trastuzumab. Additional information about PIKture-01 may be found at www.ClinicalTrials.gov, using Identifier: NCT06239467.
Poster presentation details: Title: Preliminary results from PIKture-01, a First-in-Human Study of OKI-219, a mutant selective inhibitor of PI3KαH1047R, in mutant selected solid tumors including breast cancer; Presentation ID: P3-08-19; Abstract Number: SESS-3634; Date and Time: Thursday, December 12, 2024 at 12:30 PM to 2:00 PM CST; Presenter: Alexander Spira, MD, PhD, et al. The poster is available on the Publications page of the OnKure website (click here).
Pre-Clinical Data
Preclinical in vivo data show that OKI-219 used in combination with standard-of-care therapies for mutant-selected solid tumors, including breast cancers, showed potent anti-tumor activity with excellent tolerability at doses well above those needed for tumor regressions in those models. Specifically, OKI-219 shows strong combination activity in doublet with SERDs and in triplet with SERD + CDK4/6 inhibitors. Additional preclinical combination studies are ongoing. The Company believes OKI-219’s selectivity could provide increased safety both as a single agent and in combination.
Poster presentation details: Title: OKI-219 enhances activity of SOC therapies in double and triple combinations in pre-clinical PI3KαH1047R mutant breast cancer models; Presentation ID: P4-12-20; Abstract Number: SESS-2240; Date and Time: Thursday, December 12, 2024 at 05:30 PM to 7:00 PM CST; Presenter: Molly Taylor, PhD, et al. The poster is available on the Publications page of the OnKure website (click here).
Pipeline Progress
OnKure is actively pursuing multiple additional early-stage discovery programs that target oncogenic mutations of PI3Ka. The Company has broadened the expectations of its next-generation program beyond PI3KαH1047 mutations to target all the most common PI3Ka mutations (i.e., H1047R, E545K, and E542K). The Company expects to announce a pan-mutant development candidate in the first half of 2025.
Additionally, the Company is developing a highly selective allosteric inhibitor molecule specifically targeting the PI3Kα E545K and E542K mutations (a/k/a helical domain mutations or e-mutants) and expects to announce a development candidate in 2026. Overall, the aim of the Company’s discovery engine is to deliver highly selective drug candidates that preserve wild-type PI3Kα while effectively targeting the majority of PI3Kα-mutated cancers, in breast and other cancers.
Conference Call
OnKure will host a conference call and live webcast today, December 10, 2024 at 7:00 a.m. CT (8:00 a.m. ET) to discuss the preliminary data from the PIKture-01 trial of OKI-219, which will be presented at
SABCS. To participate, please dial 877-407-0789 (domestic), 201-689-8562 (international) and refer to conference ID 13750009. To access the webcast, click here. Following the live event, a replay will be also available on the Events page of the Investors section of the Company’s website.
About OnKure
OnKure is a clinical-stage biopharmaceutical company focused on the discovery and development of best-in-class precision medicines that target biologically validated drivers of cancers that are underserved by available therapies. Using a structure-based drug design platform, OnKure is building a pipeline of tumor-agnostic candidates that are designed to achieve optimal efficacy and tolerability. OnKure is currently developing OKI-219, a selective PI3KαH1047R inhibitor, as its lead program. OnKure aims to become a leader in targeting oncogenic PI3Kα and has multiple programs designed to enable best-in-class targeting of this key oncogene.
For more information about OnKure, visit us at www.onkure.com and follow us on LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this press release, including statements regarding our business strategy and plans, and objectives of management for future operations, as well as statements regarding industry trends, are forward-looking statements. Such forward-looking statements include, among other things, statements regarding the potential of, and expectations and plans regarding, OnKure’s product candidates and programs, including OKI-219; the timing of data release for the ongoing clinical trial of OKI-219; OnKure’s ability to advance additional programs, including OnKure’s discovery programs and the timing of announcement of development candidates for such programs; and statements by the Company’s President and Chief Executive Officer. In some cases, you can identify forward-looking statements by terminology such as “estimate,” “intend,” “may,” “plan,” “potentially” “will” or the negative of these terms or other similar expressions.
The Company based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including, among other things, the Company’s limited operating history; the significant net losses incurred since inception; the ability to raise additional capital to finance operations; the ability to advance product candidates through preclinical and clinical development; the ability to obtain regulatory approval for, and ultimately commercialize, the Company’s product candidates; the outcome of preclinical testing and early clinical trials for the Company’s product candidates, including the ability of those trials to satisfy relevant governmental or regulatory requirements and the potential that the outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials; the Company’s limited resources; the risk of adverse events, toxicities or other undesirable side effects; potential delays or difficulties in the enrollment or maintenance of patients in clinical trials; the decision to develop or seek strategic collaborations to develop the Company’s current or future product candidates in combination with other therapies and the cost of combination therapies; the Company’s limited experience in designing clinical trials and lack of experience in conducting clinical trials; the substantial competition the Company faces in discovering, developing, or commercializing products; the ability to attract, hire, and retain highly skilled executive
officers and employees; the ability of the Company to protect its intellectual property and proprietary technologies; the scope of any patent protection the Company obtains or the loss of any of the Company’s patent protection; developments relating to the Company’s competitors and its industry, including competing product candidates and therapies; reliance on third parties, contract manufacturers, and contract research organizations; legislative, regulatory, political and economic developments and general market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section titled “Risk Factors” in documents that OnKure files from time to time with the Securities and Exchange Commission (“SEC”), including the Quarterly Report on Form 10-Q filed with the SEC on November 7, 2024, the final 424B3 proxy statement/prospectus filed with the SEC on August 26, 2024, and any subsequent filings with the SEC. These risks are not exhaustive. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. Except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this press release.
This press release contains hyperlinks to information that is not deemed to be incorporated by reference into this press release.
Contact:
Dan Ferry
LifeSci Advisors
[email protected]
Corporate Overview December 2024 Exhibit 99.2
Legends Forward-Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties of OnKure Therapeutics, Inc. (“OnKure” or the “Company”). All statements other than statements of historical facts contained in this presentation, including statements regarding our future financial condition, results of operations, business strategy and plans, and objectives of management for future operations, as well as statements regarding industry trends, are forward-looking statements. Such forward-looking statements include, among other things, statements regarding the potential of, and expectations and plans regarding, OnKure’s product candidates and programs, including OKI-219; the potential of PI3KaMUT inhibitor-based therapies; OnKure’s ability to advance additional programs; planned expansion combination arms; the expected milestones and timing of such milestones, including for OKI-219 and its discovery programs; and statements regarding OnKure’s financial position, including its cash runway. In some cases, you can identify forward-looking statements by terminology such as “estimate,” “intend,” “may,” “plan,” “potentially” “will” or the negative of these terms or other similar expressions. We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including, among other things: OnKure’s limited operating history; the significant net losses incurred since inception; the ability to raise additional capital to finance operations; the ability to advance product candidates through preclinical and clinical development; the ability to obtain regulatory approval for, and ultimately commercialize, OnKure’s product candidates; the outcome of preclinical testing and early clinical trials for OnKure’s product candidates, including the ability of those trials to satisfy relevant governmental or regulatory requirements and the potential that the outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials; OnKure’s limited resources; the risk of adverse events, toxicities or other undesirable side effects; potential delays or difficulties in the enrollment or maintenance of patients in clinical trials; the decision to develop or seek strategic collaborations to develop OnKure’s current or future product candidates in combination with other therapies and the cost of combination therapies; OnKure’s limited experience in designing clinical trials and lack of experience in conducting clinical trials; the substantial competition OnKure faces in discovering, developing, or commercializing products; the ability to attract, hire, and retain highly skilled executive officers and employees; the ability of OnKure to protect its intellectual property and proprietary technologies; the scope of any patent protection OnKure obtains or the loss of any of OnKure’s patent protection; developments relating to OnKure’s competitors and its industry, including competing product candidates and therapies; reliance on third parties, contract manufacturers, and contract research organizations; legislative, regulatory, political and economic developments and general market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section titled “Risk Factors” in documents that OnKure files from time to time with the Securities and Exchange Commission. These risks are not exhaustive. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. Except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. These data involve a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk.
Investment Highlights OnKure is developing a best-in-class portfolio of highly mutant-selective PI3Kα inhibitors designed to preserve wild-type PI3Kα while effectively targeting the majority of PI3Kα-mutated cancers PI3Kα is the most frequently mutated oncogene Highly selective, targeted therapies offer the potential for significant improvement in patient outcomes OKI-219 is a PI3KaH1047R mutant selective inhibitor being evaluated in a Phase 1 trial as a monotherapy and in combination with other agents in breast cancer Preclinical pipeline includes: PI3Ka PAN and PI3Ka E542K, E545K programs Cash and investments expected to provide funding through multiple clinical milestones and runway into Q4 2026
Nicholas Saccomano, Ph.D. President and Chief Executive Officer Leadership Team with Proven Experience Samuel Agresta, M.D., MPH Chief Medical Officer Duncan Walker, Ph.D. Chief Development Officer Dylan Hartley, Ph.D. Chief Scientific Officer Rogan Nunn, J.D. General Counsel and Secretary James Blake, Ph.D. SVP of Computational Drug Discovery Mark L. Boys, Ph.D. SVP of Discovery Chemistry Ann Howell, Pharm.D. VP of Regulatory Affairs Robbie Alton, Pharm VP of Clinical Operations Kevin S. Litwiler, Ph.D. SVP of DMPK and Clinical Pharmacology Jason Leverone Chief Financial Officer Jim Wong, Ph.D. VP of Biological Sciences
Mutant-Selective PI3Ka Inhibitors Targeting the Majority of PI3Ka-mutated Cancers While Preserving Wild-type PI3Ka Program/Target Indication(s) Discovery Preclinical Clinical Current Status Next Anticipated Milestone OKI-219 PI3KaH1047R mutant-selective inhibitor Breast cancer & solid tumors Phase 1 enrolling Data Update (2H 2025) OKI-TBD PI3KaPAN mutant-selective inhibitor Solid tumors & breast cancer Candidate selection Select candidate (1H 2025) OKI-TBD PI3Ka E542K, E545K mutant-selective inhibitor Solid tumors & breast cancer Active discovery Select candidate (2026) PIKture-01 Trial PI3Ka mutant specific portfolio
PI3Ka: A validated target in HR+ MBC Three approved drugs (alpelisib, capivasertib, and inavolisib) However, on-target toxicity of inhibiting wild type significantly limits dosing and decreases quality of life5,6 OnKure is developing mutant-selective inhibitors designed to preserve wild-type PI3KaH1047R* OKI-219, in Phase 1 PI3Ka PAN candidate selection 1H 2025 PI3Ka E542K, E545K active discovery PI3Ka: The Most Commonly Mutated Oncogene A Need for Highly Selective Mutant Inhibitors that Improve Efficacy and Safety 1. Data from Tumor portal; ACS Cancer Facts and Figures; Sanger COSMIC database and cBioPortal and Independent market analysis. 2. Estimate of Salvage Therapy patients based on cancer Deaths (US Patients; ACS cancer facts and figures, Globecan) 3. 1 Kandoth, C., McLellan, M., Vandin, F. et al. Nature 502, 333–339 (2013); http://www.tumorportal.org/#gene 4. https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=PIK3CA#references 5. Fritsch et al Mol Cancer Ther; 13(5) May 2014, 6. Juric et al, JCO, 36 (13), 2018 US Patient Population1 *PI3KaH1047R is the most common hot spot mutation3 present in ~15% of breast and ~4% of all human cancers4
Alpelisib approved Inavolisib approved Phase 1: Relay & Scorpion Single-digit selectivity Initial proof of concept data Compound H1047R Alpelisib1 1 STX-4781 8.8 RLY-26082 3.8 OKI-2193 ~100 Next-Gen PI3Ka Mutant-Targeting Landscape Mutant-Selectivity is Necessary to Drive Improved Efficacy and Safety 1 Buckbinder et al Cancer Discov 2023;13:2432–47 2 Varkaris et al Cancer Discov 2024;14:1–18 3 OnKure internal data PI3KαH1047R Inhibitors ATP Site Competitive Inhibitors Phase 1: OKI-219, previously LOXO-783 Highly selective; wide therap. index preclinically Non-Mutation Site Allosteric Inhibitors PI3KαE-mutant Inhibitors E-mutation-specific No known clinical trials OnKure preclinical program Reported Cell-Based Selectivity for PI3KaH1047R vs PI3KaWT
PI3KaMUT Inhibitors: Potential Backbone Therapy in Combination with Approved Agents in Breast Cancer SERM: Selective Estrogen Receptor Modulator SERD: Selective Estrogen Receptor Degrader AI: Aromatase Inhibitor ADC: Antibody Drug Conjugate HER2 Cancer Cell Survival & Proliferation PI3Ka AKT Estrogen Receptor Transcription PI3Kai AKTi SERMs SERDs AI CDK4/6i G1 G2 M Cell Cycle S RTK ADCs Her2 mAb Her2-inhibitors
1https://seer.cancer.gov/statfacts/html/breast-subtypes.html 2Third party research Current & Near-Term Treatments INAVOLISIB + palbociclib + fulvestrant ALPELISIB + fulvestrant CAPIVASERTIB + fulvestrant Treatable US Population2 ~25K ~9K ~5.5K NONE HR+ accounts for ~70% of all BrCa cases1 PI3Kα Mutated HR+ MBC: A Major Market Opportunity PI3KaH1047R Mutated HR+ Metastatic Breast Cancer: Significant Unmet Need OKI-219: Targeted for Development Across Adjuvant & MBC Properties of OKI-219 suggest potential to demonstrate safety and efficacy in both adjuvant and metastatic settings Adjuvant 1st Line 2nd Line
Current & Near-Term Treatments PI3KaH1047R Mutant-Selective Drugs: Development into Poorly Served Markets INAVOLISIB + palbociclib + fulvestrant 2nd Line NONE (AI +/- CDK4/6) 1st Line OKI-219 vs. Placebo (SOC) (AI+CDK4/6 Combo) OKI-219 vs. alpelisib/capivasertib OKI-219 + next gen SERD OKI-219 Development Opportunities (Start in Metastatic and Advance to Adjuvant) OKI-219: Multiple Development Opportunities The Potential to Reach Across Multiple Lines of Therapy ALPELISIB + fulvestrant CAPIVASERTIB + fulvestrant OKI-219 vs. Inavolisib <12 months prior AI+ CDK4i (AI+CDK4/6 Combo) OKI-219 vs. Placebo (SOC) >12 months prior AI+ CDK4i (AI+CDK4/6 Combo) OKI-219 vs. Placebo (SOC) prior inavolisib or alpelisib OKI-219 + SERD OKI-219 Approval Strategy Adjuvant SOC: Standard of Care
Preclinical Safety and Efficacy Profile Shows High Potential Demonstrated excellent brain exposure & CNS activity OKI-219 highly mutant-selective (~100X for H1047R vs. wt) inhibition leads to superior efficacy Potential for superior target coverage at accessible tolerated doses Selectivity/ Efficacy Brain Penetration OKI-219 has been well-tolerated with lack of glycemic effects Wide therapeutic margin in GLP studies Safety OKI-219 shows preclinical efficacy at low doses in single-agent, SOC combinations and with novel therapeutics approaching approval Combinability Overcomes PI3KαH1047R driven resistance in combination with tucatinib or trastuzumab Overcomes Resistance
Preclinical Safety and Efficacy Profile Shows High Potential Safety Combinability Overcomes Resistance Brain Penetration Selectivity/ Efficacy
OKI-219 Single Agent Tumor Agnostic Part A Backfill (High Dose) Backfill (Low Dose) Dose Ranging (n=24) N= up to 15 OKI-219 + fulvestrant HR+/HER2- Advanced Breast Cancer Part B RP2D Expansion (High dose) Expansion (Low dose) Dose ranging (N~9) N=20 each RP2D OKI-219 + trastuzumab HER2+ Advanced Breast Cancer Part C Expansion (High dose) Expansion (Low dose) Dose ranging (N~9) N=20 each PIKture-01 Phase 1 Clinical Trial Additional expansion combination arms are being planned An Open-Label, Multicenter, Dose-Escalation First-in-Human Trial of OKI-219 RP2D: Recommended Phase 2 Dose
PIKture-01 Study Design BOIN: Bayesian Optimal Interval Design; DOR: Duration of Response; ORR: Objective Response Rate; PFS: Progression Free Survival; PAD: Pharmacologically Active Dose; PD: Pharmacodynamics, PK: Pharmacokinetics; R: Randomization; RP2D: Recommended Phase 2 Dose; SOC: Standard of Care. NCT:06239467 As of October 28, 2024 Metastatic HER2+Breast Cancer PI3KH1047R mutation Metastatic HR+HER2-Breast Cancer PI3KH1047R mutation 300 mg* OKI-219 Monotherapy Dose Escalation Advanced Solid Tumors PI3KH1047R mutation Back-fill | N = 5-15 per PAD Part A 600 mg* 1200 mg* 900 mg* 1500 mg* BOIN Design N = 24 *Doses are BID Part B Part C OKI-219 + Fulvestrant Dose Ranging R OKI-219 PAD 1 + Fulvestrant (N=20) Dose Optimization OKI-219 PAD 2 + Fulvestrant (N=20) OKI-219 + Trastuzumab Dose Ranging R OKI-219 PAD 1 + Trastuzumab (N=20) Dose Optimization OKI-219 PAD 2 + Trastuzumab (N=20) Key Eligibility Criteria: PI3KαH1047R advanced solid tumors who received prior SOC Prior PIK3 inhibitors of any kind allowed Treated or untreated asymptomatic brain metastasis allowed HbA1C < 8% allowed Key Endpoints: Safety and tolerability PK, PD, RP2D incorporating Project Optimus1 Anti-tumor activity assessed by ORR by RECIST v1.1, DOR, PFS Patient reported outcomes via EORTC QLQ-C30 score during dose optimization only dosed 1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases
Pharmacokinetics: Highly Developable Candidate Profile EC80 0.1 1.0 10.0 0 2 4 6 8 10 12 Time (hr) OKI-219 Plasma Concentration (µg/mL) 300 mg (n=3) 900 mg (n=4) 600 mg (n=4) Values are geometric means with 90% CI; 12 hr point based on Day 15 pre-dose 0 10 20 30 0 200 400 600 800 1000 AUC AUClast (hr*µg/mL) 0 2 4 6 8 0 200 400 600 800 1000 Cmax Dose (mg) Clast (µg/mL) Parameter 300 mg BID 600 mg BID 900 mg BID Tmax (hr) 2.0 4.0 3.0 Cmax (µg/mL) 1.47 5.33 5.94 AUCtau (hr*µg/mL) 7.55 26.0 30.5 Steady-State OKI-219 PK Estimates Values are geometric means except for Tmax which is median Dose Proportionality (Single Dose) Steady-State OKI-219 Concentrations (Day 15) Steady-state exposures (900 mg BID) show near-continuous coverage Single dose, dose proportional exposure (Cmax, AUC) OKI-219 is rapidly absorbed with modest accumulation CI: Confidence Interval
Only Grade 1 TRAEs Observed Across All Dose Levels No Hyperglycemia, Stomatitis, or Rash Observed at Any Dose OKI-219 is well tolerated across all doses Adverse events were mild and infrequent No DLTs observed No dose interruptions, delays, reductions, or discontinuations for any AEs 300 mg BID n = 3 600 mg BID n = 8 900 mg BID n = 6 ALL Pts n=17 Preferred Term Grade 1 Grade 1 Grade 1 Grade 1 Diarrhoea 0 (0%) 3 (38%) 1 (17%) 4 (24%) Nausea 0 (0%) 1 (13%) 1 (17%) 2 (12%) Pruritus 1 (33%) 1 (13%) 0 (0%) 2 (12%) Anaemia 0 (0%) 1 (13%) 0 (0%) 1 (6%) Fatigue 0 (0%) 1 (13%) 0 (0%) 1 (6%) Data cut-off - October 28, 2024 TRAEs: Treatment Related Adverse Events; DLT: Dose Limiting Toxicities; AEs: Adverse Events
Time on Treatment As of October 28, 2024 Patient 1 Patient 2 13/14 patients at doses ≥600 mg BID remain on study 2/3 patients at 300 mg showed prolonged stable disease Sustained >95% reduction in PIK3CAH1047R ctDNA in 300 mg BID patient who remains on study after >7 months
OKI-219 Strategy: Combine with Targeted Agents Across Breast Cancer HER2 Cancer Cell Survival & Proliferation PI3Ka AKT Estrogen Receptor Transcription G1 G2 M Cell Cycle S RTK Fulvestrant (generic) Camizestrant (AZ) Vepdegestrant (Pfizer) Palazestrant (Olema) Giredestrant (Roche) Imlunestrant (Lilly) OKI-219 OnKure PI3Ka Franchise Trastuzumab (Roche) Pertuzamab (Roche) Tucatinib (Pfizer) Ribociclib (Novartis) Palbociclib (Pfizer) Abemaciclib (Lilly) There are several next-generation agents in addition to the drugs noted here
Financial Overview Stock Symbol Investors Participants in Private Placement (Oct 2024) Common Stock Outstanding Approximately 13.3 million shares outstanding October 4, 2024 (after the close of the merger/private placement, and post-reverse split) Cash and investments expected to provided funding through multiple clinical data readouts and runway into 4Q 2026 Approximately $139 million at close of the merger/private placement Acorn Bioventures, Cormorant Asset Management, Surveyor Capital (a Citadel company), Perceptive Advisors, Deep Track Capital, Samsara BioCapital, Vestal Point Capital and other undisclosed investors NASDAQ: OKUR Cash Runway Cash and Investments As of October 4, 2024
Summary: OnKure is Developing Innovative Precision Medicines for Patients Focused team with remarkable success in precision medicine Ongoing PIKture-01 trial evaluating OKI-219 single agent and in combination with other agents Supported by committed investors Mutation-specific approach to a validated target (PI3Ka) in a large patient population
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