Palbociclib

Inavolisib获批用于乳腺癌治疗 近日，Nat. Rev. Drug. Disc.上发文报道，FDA已批准基因泰克的 inavolisib（Itovebi）与 CDK4/6 抑制剂 palbociclib 和雌激素受体拮抗剂 fulvestrant 联合用于内分泌耐药、PIK3CA 突变、激素受体阳性、HER2 阴性乳腺癌（doi: https://doi.org/10.1038/d41573-024-00176-3）。Inavolisib 与诺华的首个PI3K抑制剂 alpelisib相比，增加了一种单体降解机制，可能扩展其适用性。 “基于 Itovebi 的治疗方案使无进展生存期翻倍，并保持了可管理的安全性和耐受性，确立了 PIK3CA 突变乳腺癌治疗的新标准，”来自纪念斯隆凯特琳癌症中心的肿瘤学家 Komal Jhaveri 说，她是获得该药物批准的试验的主要研究者。 药物开发者长期以来一直致力于抑制 PI3K，这是一种驱动细胞生长、增殖和存活的蛋白质。在基因泰克，研究人员意识到一些阻断该蛋白激酶功能的小分子也会使该蛋白不稳定，导致其泛素化和随后的降解。 inavolisib 能够降解突变的 PI3Kα，同时保护野生型蛋白，可能导致更适合联合使用的安全性特征。其降解 PI3Kα的能力也被认为依赖于 HER2 及相关受体，可能使该药物在 HER2 阳性癌症中有效。 FDA 基于 II/III 期 INAVO120 试验批准了 inavolisib，该试验涉及 325 名患有内分泌耐药、PIK3CA 突变、激素受体阳性、HER2 阴性局部晚期或转移性乳腺癌的患者。主要终点是中位无进展生存期，inavolisib 加 palbociclib 加 fulvestrant 为 15.0 个月，而安慰剂加 palbociclib 加 fulvestrant 为 7.3 个月。治疗组的总体反应率为 58%，对照组为 25%。治疗组的中位反应持续时间为 18.4 个月，对照组为 9.6 个月。总体生存数据尚未成熟。 常见副作用包括中性粒细胞减少、血红蛋白减少、空腹血糖升高、血小板减少、淋巴细胞减少、口腔炎、腹泻、钙减少、疲劳、钾减少、肌酐升高、ALT 升高、恶心、钠减少、镁减少、皮疹、食欲减退、感染和头痛。 降解活性带来的潜在优势 2022年，Genentech团队在JMC上报道了Inavolisib的发现（J. Med. Chem. 2022, 65, 24, 16589–16621）。 文章中提到了 Inavolisib 的降解活性带来的优势，主要体现在以下几个方面： 突变体选择性降解: GDC-0077 能够选择性降解突变体 p110α 蛋白，而不影响野生型 p110α 或 p85α 的水平。这种选择性降解被认为是其疗效的关键，因为突变体 PI3Kα 是癌症发展的主要驱动因素。 抑制通路再激活: 突变体 p110α 的降解使得肿瘤细胞即使在 RTK 上调的情况下也无法重新激活 PI3K 通路，从而更有效地抑制肿瘤生长。传统的 PI3K 抑制剂往往会面临通路再激活的问题，导致耐药性的产生。 提高疗效和耐受性: 文章假设，相比于不具有降解活性的 PI3K 抑制剂，GDC-0077 对突变体 p110α 的选择性降解及其较长的半衰期可能带来更强的疗效和更好的耐受性，从而提高治疗指数。在小鼠模型中，GDC-0077 的疗效优于其他不具有降解活性的抑制剂（如alpelisib），这与该假设相符。 支持联合用药: 文章提到，GDC-0077 良好的特性使其可以与化疗、激素疗法和靶向药物联合使用，从而更好地治疗 PIK3CA 突变的癌症患者。 总而言之，GDC-0077 兼具 PI3Kα 抑制和突变体降解的双重功能，使其在疗效、选择性和耐受性方面比单纯的 PI3K 抑制剂更具优势，有望成为治疗 PIK3CA 突变癌症的更有效药物。 Inavolisib的后续研究及市场展望 inavolisib 的 III 期头对头对比试验正在进行中。一项对照试验正在测试 inavolisib 加 fulvestrant 与 alpelisib 加 fulvestrant 在激素受体阳性、HER2 阴性、PIK3CA 突变乳腺癌中的疗效，经过 CDK4/6 抑制剂和内分泌联合治疗。另一项试验正在测试 inavolisib 与双重 HER2 阻断相比，双重 HER2 阻断和可选的医生选择的内分泌治疗作为 HER2 阳性疾病的维持治疗。 Genentech预测该药物的峰值销售潜力约为 24 亿至 36 亿美元。 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓

Presented compelling new preclinical data demonstrating anti-tumor activity for OP-3136, a novel KAT6 inhibitor, with enhanced activity of palazestrant combinations at EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (ENA 2024) New clinical data for palazestrant (OP-1250) in combination with ribociclib to be presented at the San Antonio Breast Cancer Symposium (SABCS) in DecemberIND submission for OP-3136 expected before year end; clinical study to initiate early 2025Cash, cash equivalents, and marketable securities of $214.8 million as of September 30, 2024 SAN FRANCISCO, Nov. 12, 2024 (GLOBE NEWSWIRE) -- Olema Pharmaceuticals, Inc. (“Olema”, “Olema Oncology”, Nasdaq: OLMA), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of targeted therapies for breast cancer and beyond, today reported financial results for the third quarter ended September 30, 2024, and provided a corporate update. “We look forward to presenting updated data from our ongoing Phase 2 clinical study of palazestrant in combination with ribociclib in frontline metastatic breast cancer patients at SABCS in December. The OPERA-01 Phase 3 clinical trial of palazestrant as a monotherapy in second/third-line patients continues to advance and we remain on track for top-line readout in 2026,” said Sean P. Bohen, M.D., Ph.D., President and Chief Executive Officer of Olema Oncology. “At ENA 2024, we presented three new, robust preclinical data sets. Palazestrant demonstrated combinability and enhanced tumor suppression with both everolimus and capivasertib. OP-3136, our potent and selective KAT6 inhibitor, demonstrated robust anti-tumor activity as a single agent, as well as synergy and enhanced anti-tumor activity in combination with palazestrant. These data reinforce our belief in the potential of OP-3136 as an exciting new therapy for breast and other cancers, and we remain on track to submit the IND application before year end.” Recent Progress Continued enrollment of patients in OPERA-01, the pivotal Phase 3 clinical trial of palazestrant as a monotherapy in second/third-line ER+/HER2- metastatic breast cancer.Presented preclinical data for OP-3136 and palazestrant at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (ENA 2024) in Barcelona, Spain.Initiated Phase 1b/2 clinical study of palazestrant in combination with everolimus.Successfully completed Investigational New Drug (IND)-enabling studies for OP-3136. Anticipated Upcoming Milestones Present updated Phase 2 data showing palazestrant in combination with ribociclib at the San Antonio Breast Cancer Symposium (SABCS) in December 2024.Submit the IND application for OP-3136 to the U.S. Food and Drug Administration (FDA) before year-end; initiate the Phase 1 clinical study for OP-3136 in early 2025. Third Quarter 2024 Financial ResultsCash, cash equivalents, and marketable securities as of September 30, 2024, were $214.8 million. Net loss for the quarter ended September 30, 2024, was $34.6 million, as compared to $21.5 million for the quarter ended September 30, 2023. The increase in net loss for the third quarter was primarily related to increased spending on clinical development and research activities as a result of late-stage clinical trials for palazestrant and the advancement of our KAT6 inhibitor program, as well as general and administrative (G&A) activities. The increase was partially offset by higher interest income earned from marketable securities. GAAP research and development (R&D) expenses were $33.2 million for the quarter ended September 30, 2024, as compared to $19.5 million for the quarter ended September 30, 2023. The increase in R&D expenses was primarily related to increased spending on clinical operations and development-related activities as we continue to advance palazestrant through late-stage clinical trials, research-related activities associated with the advancement of our KAT6 inhibitor program, and personnel related costs, including an increase in non-cash stock-based compensation expense of $1.5 million. Non-GAAP R&D expenses were $28.9 million for the quarter ended September 30, 2024, which excluded $4.3 million non-cash stock-based compensation expense. Non-GAAP R&D expenses were $16.7 million for the quarter ended September 30, 2023, excluding $2.8 million non-cash stock-based compensation expense. A reconciliation of GAAP to non-GAAP financial measures used in this press release can be found at the end of this press release. GAAP G&A expenses were $4.4 million for the quarter ended September 30, 2024, as compared to $3.9 million for the quarter ended September 30, 2023. The increase in G&A expenses was primarily due to increased spending on corporate-related costs and an increase in non-cash stock-based compensation expense of less than $0.1 million. Non-GAAP G&A expenses were $3.0 million for the quarter ended September 30, 2024, excluding $1.3 million non-cash stock-based compensation expense. Non-GAAP G&A expenses were $2.6 million for the quarter ended September 30, 2023, excluding $1.3 million non-cash stock-based compensation expense. A reconciliation of GAAP to non-GAAP financial measures used in this press release can be found at the end of this press release. About Palazestrant (OP-1250)Palazestrant (OP-1250) is a novel, orally available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD). It is currently being investigated in patients with recurrent, locally advanced or metastatic ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In clinical studies, palazestrant completely blocks ER-driven transcriptional activity in both wild-type and mutant forms of metastatic ER+ breast cancer and has demonstrated anti-tumor efficacy along with attractive pharmacokinetics and exposure, favorable tolerability, CNS penetration, and combinability with CDK4/6 inhibitors. Palazestrant has been granted U.S. Food and Drug Administration (FDA) Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor. It is being evaluated both as a single agent in an ongoing Phase 3 clinical trial, OPERA-01, and in Phase 1/2 combination studies with CDK4/6 inhibitors (palbociclib and ribociclib), a PI3Ka inhibitor (alpelisib), and an mTOR inhibitor (everolimus). For more information on OPERA-01, please visit www.opera01study.com. About OP-3136OP-3136 is a novel, orally available small molecule that potently and selectively inhibits KAT6, an epigenetic target that is dysregulated in breast and other cancers. In preclinical studies, OP-3136 has demonstrated significant anti-proliferative activity in ER+ breast cancer models and is combinable and synergistic with endocrine therapies including palazestrant and CDK4/6 inhibitors. Olema has successfully completed IND-enabling studies in support of a potential Investigational New Drug (IND) application with the FDA and expects to initiate Phase 1 clinical trials for OP-3136 in early 2025. About Olema OncologyOlema Oncology is a clinical-stage biopharmaceutical company committed to transforming the standard of care and improving outcomes for women living with cancer. Olema is advancing a pipeline of novel therapies by leveraging our deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance. Our lead product candidate, palazestrant (OP-1250), is a proprietary, orally available complete estrogen receptor (ER) antagonist (CERAN) and a selective ER degrader (SERD), currently in a Phase 3 clinical trial called OPERA-01. In addition, Olema is developing a potent KAT6 inhibitor (OP-3136). Olema is headquartered in San Francisco and has operations in Cambridge, Massachusetts. For more information, please visit us at www.olema.com. Non-GAAP Financial InformationThe results presented in this press release include both GAAP information and non-GAAP information. As used in this release, non-GAAP R&D expense is defined by Olema as GAAP R&D expense excluding stock-based compensation expense, and non-GAAP G&A expense is defined by Olema as GAAP G&A expense excluding stock-based compensation expense. We use these non-GAAP financial measures to evaluate our ongoing operations and for internal planning and forecasting purposes. We believe that non-GAAP financial information, when taken collectively, may be helpful to investors because it provides consistency and comparability with past financial performance. However, non-GAAP financial information is presented for supplemental informational purposes only, has limitations as an analytical tool, and should not be considered in isolation or as a substitute for financial information presented in accordance with GAAP. Other companies, including companies in our industry, may calculate similarly titled non-GAAP measures differently or may use other measures to evaluate their performance, all of which could reduce the usefulness of our non-GAAP financial measures as tools for comparison. Investors are encouraged to review the related GAAP financial measures and the reconciliation of these non-GAAP financial measures to their most directly comparable GAAP financial measures and not rely on any single financial measure to evaluate our business. Forward Looking StatementsStatements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Words such as “anticipate,” “believe,” “could,” “expect,” “goal,” “may,” “potential,” “upcoming,” “will” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These statements include those related to the timelines for initiation and enrollment for potential clinical studies and for results of clinical trials of palazestrant (OP-1250) and OP-3136, each as a monotherapy and in combination trials, Olema’s financial condition and resources, results of operations, cash position, potential beneficial characteristics including but not limited to safety, tolerability, activity, efficacy and therapeutic effects of palazestrant, the potential of palazestrant to advance the standard of care for women living with cancer, combinability with other drugs, palazestrant, or OP-3136, and the sufficiency and timing of Olema’s preclinical program, including the potential beneficial characteristics of its KAT6 inhibitor compounds and the timing of a potential IND application and advancement into clinical development for OP-3136. Because such statements deal with future events and are based on Olema’s current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of Olema could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including, without limitation, those discussed in the section titled “Risk Factors” in Olema’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, and future filings and reports that Olema makes from time to time with the U.S. Securities and Exchange Commission. Except as required by law, Olema assumes no obligation to update these forward-looking statements, including in the event that actual results differ materially from those anticipated in the forward-looking statements. Olema Pharmaceuticals, Inc. Condensed Consolidated Balance Sheets Data (in thousands) September 30,December 31, 2024 2023 Cash, cash equivalents and marketable securities $214,763$261,807 Total assets 230,173 276,945 Total current liabilities 30,700 21,621 Total liabilities 31,262 23,050 Total stockholders’ equity 198,911 253,895 Total liabilities and stockholders’ equity $ 230,173$ 276,945 Olema Pharmaceuticals, Inc. Condensed Consolidated Statements of Operations (In thousands, except share and per share data) Three Months Ended September 30, Nine Months Ended June 30, 2024 2023 2024 2023 Operating expenses: Research and development (1)$33,226 $19,453 $92,218 $60,268 General and administrative (2) 4,395 3,889 13,272 14,277 Total operating expenses 37,621 23,342 105,490 74,545 Loss from operations (37,621) (23,342) (105,490) (74,545) Other income: Interest income 2,928 1,919 9,388 4,774 Other income (expense) 138 (79) 195 (112) Total other income 3,066 1,840 9,583 4,662 Net loss$ (34,555)$ (21,502) $ (95,907)$ (69,883) Net loss per share, basic and diluted$(0.60)$(0.48) $(1.80)$(1.66) Weighted average shares used to compute net loss per share, basic and diluted 57,262,803 44,977,161 53,194,081 41,999,978 Reconciliation of GAAP to Non-GAAP Information (In thousands) Three Months Ended September 30, Nine Months Ended June 30, 2024 2023 2024 2023 (1) Research and development reconciliation GAAP research and development (3)$33,226 $19,453 $92,218 $60,268 Less: share-based compensation expense 4,280 2,801 11,925 8,858 Non-GAAP research and development$ 28,946 $ 16,652 $ 80,293 $ 51,410 (2) General and administrative reconciliation GAAP general and administrative$4,395 $3,889 $13,272 $14,277 Less: share-based compensation expense 1,346 1,304 4,334 4,047 Non-GAAP general and administrative$ 3,049 $ 2,585 $ 8,938 $ 10,230 (3) Research and development expenses for the nine-months ended September 30, 2024 include a $5.0 million milestone payment in connection to the Aurigene Agreement. IR and Media ContactCourtney O’Konek, Vice President, Corporate Communicationsmedia@olema.com