Olema Pharmaceuticals, Inc. (Olema), a clinical-stage biopharmaceutical company, focuses on the discovery, development, and commercialization of next generation targeted therapies for breast cancer and beyond.
The company is advancing its pipeline of novel therapies by leveraging its deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance.
The company’s lead product candidate, palazestrant, is a novel, orally-available small molecule with dual a...
Olema Pharmaceuticals, Inc. (Olema), a clinical-stage biopharmaceutical company, focuses on the discovery, development, and commercialization of next generation targeted therapies for breast cancer and beyond.
The company is advancing its pipeline of novel therapies by leveraging its deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance.
The company’s lead product candidate, palazestrant, is a novel, orally-available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD), 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 pre-clinical models, palazestrant binds and completely blocks ER-driven transcriptional activity in both wild-type and mutant forms of metastatic ER+ breast cancer. In clinical studies across more than 400 patients, palazestrant has demonstrated strong anti-tumor activity, attractive pharmacokinetics, and prolonged drug exposure, favorable tolerability, and combinability with CDK4/6 inhibitors, with no significant drug-drug interaction. Based on the clinical results the company has achieved to date, it is advancing palazestrant through late-stage clinical development both as a monotherapy and in combination with other targeted agents.
In November 2023, the company initiated OPERA-01, its pivotal Phase 3 clinical trial of palazestrant as a monotherapy in second/third-line ER+/HER2- metastatic breast cancer. It anticipates top-line results in 2026.
In combination, the company is investigating palazestrant in multiple Phase 1/2 studies with CDK4/6 inhibitors (palbociclib or ribociclib), a phosphatidylinositol 3 kinase alpha (PI3Ka) inhibitor (alpelisib), and with an mTOR inhibitor (everolimus). In March 2024, the company increased the size of the ongoing Phase 1/2 clinical study of palazestrant in combination with ribociclib by an additional 15 patients to explore 90 mg of palazestrant in combination with 600 mg of ribociclib. It also initiated its Phase 1b/2 clinical study of palazestrant in combination with an mTOR inhibitor, everolimus, in the third quarter of 2024. Further, in October 2024, the company presented new pre-clinical data at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, showing that the combination of palazestrant with both everolimus and capivasertib may be synergistic and have the potential to result in significant tumor regression.
Most recently, the company presented updated results from the ongoing Phase 1b/2 clinical trial of palazestrant in combination with ribociclib in patients with ER+/HER2- advanced or metastatic breast cancer at the San Antonio Breast Cancer Symposium (SABCS) in December 2024. These data further support the company’s thesis that palazestrant possesses key characteristics to make it a potential backbone endocrine therapy of preference for ER+/HER2- breast cancer, while also providing the basis for a new pivotal Phase 3 clinical trial of palazestrant in combination with ribociclib in front-line ER+/HER2- metastatic breast cancer, called OPERA-02. The execution of OPERA-02 will be supported by the company’s new clinical trial collaboration and supply agreement with Novartis Pharma AG (Novartis), which was also announced in December 2024.
The company’s second product candidate in clinical development, called OP-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 October 2024, the company presented new pre-clinical data at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, demonstrating OP-3136's robust anti-tumor activity as a single agent, as well as potential synergy and enhanced anti-tumor activity in combination with palazestrant. The Investigational New Drug (IND) application for OP-3136 was cleared by the U.S Food and Drug Administration (FDA) in late 2024, and the Phase 1 clinical trial is now enrolling patients.
Strategy
The company’s strategies are applying its deep understanding of nuclear receptors — particularly the ER — and mechanisms of resistance to develop novel therapeutic approaches for endocrine-driven cancers; rapidly advancing its product candidates, including palazestrant, through late-stage clinical development for the treatment of ER+/HER2- metastatic breast cancer, and OP-3136 through early-stage clinical development in breast and other cancers; establishing palazestrant as the endocrine therapy of choice with targeted therapy combinations for the treatment of metastatic ER+ breast cancers; exploring additional clinical opportunities for palazestrant, including metastatic breast cancer with brain metastases and other hormone-sensitive tumors; expanding its portfolio of product candidates through both internal research activities and business development efforts; and continuing to evaluate opportunities to accelerate clinical development timelines and enhance the commercial potential of its programs through collaboration with third parties.
The company’s plan is to develop its wholly-owned lead product candidate, palazestrant, in a number of ER+ breast cancer indications, both as a monotherapy and in combination with approved targeted therapies that have shown improved outcomes with other endocrine therapies. In addition, the company’s KAT6 program, OP-3136, entered clinical development in late 2024, with plans to explore its clinical development in combination with both fulvestrant and palazestrant.
Lead Product Candidate: Palazestrant
The company owns worldwide development and commercialization rights to palazestrant. Its plan is to develop palazestrant for the treatment of a number of ER+ breast cancer indications, both as monotherapy and in combination with approved targeted therapies that have shown improved outcomes with other endocrine therapies.
Palazestrant is an oral small molecule clinical-stage product candidate for the treatment of endocrine-driven cancers. It was designed by the company’s scientific team based both on a detailed structural understanding of the ER and on known alterations to this structure induced by fulvestrant and other ER ligands. The company has demonstrated in non-clinical studies that palazestrant functions both as a CERAN, inactivating both AF1 and AF2 transcriptional activation functions, and a SERD, promoting degradation of the ER.
In July 2022, palazestrant was granted Fast Track designation from the FDA in patients with 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.
The company’s pivotal Phase 3 monotherapy trial: OPERA-01
In November 2023, the company initiated its first pivotal Phase 3 trial of palazestrant, OPERA-01, which is a randomized Phase 3 trial evaluating palazestrant versus standard-of-care treatment for ER+/HER2- advanced or metastatic breast cancer. The trial is expected to enroll approximately 510 second/third-line metastatic breast cancer patients randomized one-to-one with either palazestrant or standard-of-care endocrine therapy. Key inclusion criteria for the trial include evaluable disease and prior exposure to endocrine therapy in combination with a CDK4/6 inhibitor in the advanced setting.
Phase 2 monotherapy clinical study
The company presented positive Phase 2 monotherapy clinical results in an oral presentation at ESMO in October 2023. As of the data cut-off of July 7, 2023, 86 patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer were treated at the recommended Phase 2 dose (RP2D) of 120 mg.
Pharmacokinetics
Palazestrant demonstrated favorable pharmacokinetics characterized by high oral bioavailability, dose-proportional exposure, and a long half-life of eight days, with steady-state plasma levels showing minimal peak-to-trough variability, enabling consistent inhibition of the ER for the full dosing interval.
Palazestrant Phase 1b/2 study in combination with ribociclib
In December 2023, the company presented Phase 1b/2 data from its clinical study of palazestrant in combination with ribociclib at SABCS. With a data cutoff of November 1, 2023, across 19 patients who had completed at least one cycle of treatment as of the data cutoff date, the combination of up to 120 mg of palazestrant with 600 mg of ribociclib daily was well tolerated, with no safety signals or enhancement of toxicity, and an overall safety profile consistent with the expected safety profile of ribociclib plus an endocrine therapy.
In May 2024, the company presented interim results from this combination clinical trial at the ESMO Breast Cancer Annual Congress in Berlin, Germany. As of the data cut-off date of March 13, 2024, the combination of the palazestrant RP2D of 120 mg in combination with the full FDA-approved label dose of 600 mg of ribociclib was well tolerated, with no new safety signals or enhancement of toxicity, and palazestrant did not affect ribociclib drug exposure while ribociclib had no clinically meaningful effect on palazestrant drug exposure. Furthermore, the results for the maturing dataset showed anti-tumor activity and prolonged disease stabilization, and a CBR of 85% across 13 CBR-eligible patients. These data further supported the company’s thesis that palazestrant possesses key characteristics to make it a potential backbone endocrine therapy of preference for ER+/HER2- breast cancer.
In December 2024, the company presented updated clinical results from this study at SABCS 2024, as of a data cut-off date of November 22, 2024. Palazestrant, in combination with ribociclib, demonstrated promising clinical activity, a safety profile consistent with ribociclib and endocrine therapy, and favorable tolerability in patients with ER+/HER2- advanced or metastatic breast cancer.
Pivotal Phase 3 combination trial of palazestrant in combination with ribociclib: OPERA-02
Following the entry into the company’s new clinical trial collaboration and supply agreement with Novartis and its positive data presentation at SABCS in December 2024, it announced its intention to initiate a new pivotal Phase 3 clinical trial of palazestrant in combination with ribociclib in patients with frontline advanced or metastatic ER+/HER2- breast cancer. The trial is expected to enroll approximately 1,000 patients, half of whom will receive palazestrant plus ribociclib; the other half will receive letrozole, a standard-of-care aromatase inhibitor, plus ribociclib. The trial will enroll first-line patients who have received no prior systemic therapy for the treatment of advanced or metastatic breast cancer. Progression-free survival will be the primary endpoint; overall survival is a key secondary endpoint. The company expects OPERA-02 to initiate in 2025.
Palazestrant Phase 1b/2 study in combination with palbociclib
The company presented Phase 1b/2 data from its clinical study of palazestrant in combination with palbociclib at SABCS on December 7, 2023. With a data cutoff of September 15, 2023, across 46 patients as of the cutoff date of September 15, 2023, the combination of palazestrant (120 mg) with palbociclib (125 mg) daily was well tolerated, with an overall safety profile consistent with the expected safety profile of palbociclib plus an endocrine therapy.
Most treatment-emergent adverse events were grade 1 or 2. Neutropenia incidence was similar to the PALOMA-3 study; it was reversible in all patients, and the timing was generally consistent with the palbociclib-related neutropenia.
Tumor responses and prolonged disease stabilization were observed in this patient group, including in those previously exposed to CDK4/6 inhibitors, in both ESR1 mutant and ESR1 wild-type tumors. Partial responses were observed in seven patients, with two confirmed partial responses and five unconfirmed partial responses.
Twenty-two (48%) patients remained on treatment, and efficacy data were still maturing. Findings from this study were consistent with previously reported data and support the ongoing clinical development of palazestrant in combination with CDK4/6 inhibitors for the treatment of ER+/HER2- metastatic breast cancer. Enrollment of sixty patients in the Phase 2 portion of the palazestrant-palbociclib combination clinical study is complete.
Additional palazestrant pre-clinical combination data
In October 2024, the company presented new pre-clinical data at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, showing that the combination of palazestrant with both everolimus and capivasertib are synergistic and have the potential to result in significant tumor regression. Palazestrant and everolimus demonstrated synergy in vitro and in vivo and resulted in greater anti-proliferative activity than either agent alone; this combination also caused gene signature transcriptional changes, downregulating cell cycle progression and upregulating apoptosis. Palazestrant and capivasertib in combination worked synergistically to inhibit proliferation of multiple ER+ breast cancer models, both in vitro and in vivo.
Clinical development plan for palazestrant and additional clinical opportunities
Everolimus, an mTOR inhibitor, is a targeted therapy that is often used by oncologists in the treatment of advanced breast or other cancers. Clinical studies evaluating everolimus in combination with endocrine therapies have demonstrated clinical results that indicate a potential benefit for patients in later-line settings. In the third quarter of 2024, the company initiated evaluation of palazestrant in combination with everolimus in a Phase 1b/2 clinical study. The company’s primary objectives are to determine the safety, tolerability, and PK profile of the combination with palazestrant, and secondarily to determine efficacy and duration of response in patients with ER+/HER2- metastatic breast cancer.
Furthermore, though the company is evaluating palazestrant in patients with ER+/HER2- breast cancer, there is an opportunity for it to study palazestrant in patients with ER+/HER2+ breast cancer, which represents approximately 11% of breast cancer patients and more than 50% of the patients with HER2+ breast cancer. In particular, up to 50% of patients with metastatic HER2+ breast cancer develop CNS disease.
Second Product Candidate: OP-3136
In October 2023, the company presented new pre-clinical data regarding the discovery of novel compounds targeting KAT6, an epigenetic target that is dysregulated in breast and other cancers at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. In January 2024, it nominated a development candidate for this program, OP-3136, and in late 2024, the IND application for OP-3136 was cleared by the FDA, and it initiated a Phase 1 clinical trial evaluating OP-3136 in patients with ER+/HER2- metastatic breast cancer and other cancers.
In a non-clinical xenograft model, OP-3136 caused dose-dependent tumor growth inhibition and tumor regression comparable to or better than a positive-control patented KAT6 inhibitor and demonstrated synergy in combination with CDK4/6 inhibitors or palazestrant.
In KAT6-amplified and overexpressing ER+ breast cancer cell lines, OP-3136 strongly inhibited cell proliferation, whereas KAT6-low cell lines were insensitive to the compounds. In a non-clinical xenograft model, OP-3136 caused dose-dependent tumor growth inhibition and tumor regression comparable to or better than a positive-control patented KAT6 inhibitor and demonstrated synergy in combination with CDK4/6 inhibitors or an endocrine therapy, palazestrant. In addition, OP-3136 demonstrated activity in both ESR1 wild-type and mutant breast cancer cell lines.
In October 2024, the company presented compelling new pre-clinical data at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, demonstrating OP-3136's robust anti-tumor activity as a single agent, as well as potential synergy and enhanced anti-tumor activity in combination with palazestrant. OP-3136 inhibited cell proliferation and synergized with anti-estrogens (fulvestrant and palazestrant) and a CDK4/6 inhibitor (ribociclib) in a breast cancer cell line. OP-3136 led to either tumor growth inhibition or tumor regression in vivo in xenograft models across all treatment groups. In combination with OP-3136, palazestrant was consistently superior to fulvestrant and led to improved anti-tumor activity and tumor regression; OP-3136 also showed robust synergistic anti-tumor activity when combined with fulvestrant or palazestrant as doublet therapy in breast cancer models.
In December 2024, the company announced that the FDA cleared its IND application for OP-3136. The Phase 1 clinical trial initiated thereafter and is now enrolling patients.
Clinical Collaboration and Supply Agreement with Novartis
In July 2020, the company entered into a non-exclusive Clinical Collaboration and Supply Agreement (the Novartis Agreement) with Novartis Institutes for BioMedical Research, Inc. (Novartis). On January 13, 2022, it entered into an Amended and Restated Clinical Collaboration and Supply Agreement with Novartis, and on October 9, 2023, it entered into Amendment No. 1 (the Novartis Amendment) to Amended and Restated Clinical Collaboration and Supply Agreement with Novartis (as amended, the Novartis Agreement). The collaboration is focused on the evaluation of the safety, tolerability, and efficacy of palazestrant in combination with Novartis’ proprietary CDK4/6 inhibitor KISQALI (ribociclib) and/or Novartis’ proprietary phosphatidylinositol 3-kinase inhibitor PIQRAY (alpelisib), or collectively the Novartis Study Drugs, as part of the company’s planned Phase 1b clinical study of palazestrant in patients with metastatic ER+ breast cancer. The Novartis Amendment expanded the size of the ongoing ribociclib and palazestrant study cohort to a total of approximately 60 patients. In March 2024, the company further amended the agreement and expanded the collaboration to explore 90 mg of palazestrant in combination with ribociclib, bringing the total enrollment to approximately 75 patients. The company is responsible for the conduct of the clinical studies for the combined therapies in accordance with a mutually agreed development plan. As part of the collaboration, the parties granted to each other a non-exclusive, royalty-free license under certain of the parties’ respective background patent rights and other technology to use the parties’ respective study drugs in research and development, solely to the extent reasonably needed for the other party’s activities in the collaboration.
The company is responsible for manufacturing, packaging, and labeling palazestrant, and for packaging and labeling all drugs used in the clinical studies for the combined therapies (other than the Novartis Study Drugs). In accordance with an agreed budget, Novartis is reimbursing the company for a portion of the direct outside costs, but no more than an amount in the low single-digit millions of the U.S. dollars, that it incurs related to conducting the activities under the agreed development plan in conducting the clinical trials for the combined therapies.
New Clinical Trial Collaboration and Supply Agreement with Novartis
In November 2024, the company entered into a Clinical Trial Collaboration and Supply Agreement (the Novartis Pharma Agreement) with Novartis.
Clinical Trial Agreement with Pfizer
In November 2020, the company entered into a non-exclusive clinical trial agreement with Pfizer (the Pfizer Agreement) to evaluate the safety and tolerability of palazestrant in combination with Pfizer’s proprietary CDK4/6 inhibitor IBRANCE (palbociclib) in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer in a clinical trial.
License Agreement with Aurigene
In June 2022, the company entered into an exclusive global license agreement with Aurigene, to research, develop, and commercialize novel small molecule inhibitors of an undisclosed oncology target (the Aurigene Agreement).
Other Licensing Agreements
On October 17, 2024, the company signed an out-license of its de-prioritized TRPM4 targeted research program to Black Shadow Therapeutics LLC in exchange for potential single-digit royalties on worldwide net sales should a product be approved by regulatory authorities.
Intellectual Property
The company has granted patents and pending applications relating to palazestrant, including granted claims that encompass the palazestrant compound, pharmaceutical compositions that include palazestrant, and certain methods of using palazestrant, including in treatment which may involve combination therapy. The 20-year term for these patents expires in 2036. In the United States, it is uncertain whether any PTE will be available, and if so, how much. Additional applications are pending, including ones that relate to dosing regimens and treatment of particular cancers and patient populations, and, if granted, will have 20-year terms that expire between 2040 and 2043.
The company co-owns with Aurigene a pending patent application related to OP-3136, which includes claims that encompass the OP-3136 compound, pharmaceutical compositions that include OP-3136, and certain methods of using OP-3136. Under the Aurigene Agreement, Aurigene has provided to the company an exclusive license to Aurigene's rights in patents and applications related to OP-3136 and other KAT6 inhibitor compounds. The 20-year term for the pending patent application related to OP-3136 expires in 2044.
The company has also applied to register the ‘Olema,’ ‘Olema Oncology,’ ‘Olema Oncology and design,’ and ‘Olema Therapeutics’ trademarks with the USPTO.
Sales and Marketing
Given the company’s stage of development, it has not yet established a commercial organization or distribution capabilities. It intends to build a commercial infrastructure to support sales of any approved products. The company intends to continue evaluating opportunities to work with partners that enhance its capabilities with respect to the development and commercialization of palazestrant. In addition, it intends to commercialize its product candidates, if approved, in key markets either alone or with partners in order to maximize the worldwide commercial potential of its programs.
Government Regulation and Product Approval
Any drug candidates that the company develops must be approved by the U.S Food and Drug Administration (FDA) before they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in foreign countries.
Any drug products for which the company receives FDA approvals are subject to continuing regulation by the FDA.
Depending upon the timing, duration, and specifics of the FDA approval of the use of the company’s product candidates, some of its U.S. patents, if granted, may be eligible for limited PTE under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.
The company relies, and expects to continue to rely, on third parties for the production of clinical and commercial quantities of its products in accordance with Good Manufacturing Practice (cGMP) regulations.
In Europe, the company is subject to the General Data Protection Regulation (GDPR) in relation to its collection, control, processing, and other use of personal data (i.e., data relating to an identified or identifiable living individual). It processes personal data in relation to participants in its clinical trials in the European Economic Area (EEA), including the health and medical information of these participants.
The company is subject to the supervision of local data protection authorities in those European Union jurisdictions where it is established or otherwise subject to the GDPR. Further, it must comply with both the GDPR and separately the GDPR as implemented in the United Kingdom (UK).
Research and Development
The company’s research and development expenses for the year ended December 31, 2024, were $124.5 million.
History
The company was incorporated in Delaware in 2006 under the legal name of CombiThera, Inc. and renamed Olema Pharmaceuticals, Inc. in 2009.
