Olema Pharmaceuticals Stock

Olema Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company, focuses on the discovery, development and commercialization of targeted therapies for women’s cancers.

The company’s lead product candidate, OP-1250, is a novel oral therapy with combined activity as both a complete ER antagonist, or CERAN, and a selective ER degrader, or SERD, which will drive deeper, more durable responses than existing therapies. OP-1250, both as a monotherapy and in combination with inhibitors of cyclin-dependent kinase 4 and 6, or CDK4/6, demonstrated robust anti-tumor activity in a range of preclinical xenograft models of breast cancer, including in ESR1 and PIK3CA mutations and central nervous system, or CNS, metastasis. In August 2020, the company initiated an ongoing Phase 1/2 monotherapy dose escalation and expansion study evaluating OP-1250 for the treatment of recurrent, locally advanced or metastatic ER-positive, or ER+, human epidermal growth factor receptor 2-negative, or HER2-, breast cancer. The company reported initial data from the Phase 1a dose escalation portion of this study in November 2021, which provided proof-of-concept for OP-1250 as a monotherapy treatment for ER+/HER2- breast cancer. The company reported additional monotherapy data from the Phase 1b dose expansion portion of this study in October 2022 and initiated the Phase 2 portion of the study. In 2022, the company also initiated Phase 1b/2 dose escalation and expansion studies evaluating OP-1250 in combination with CDK4/6 inhibitors palbociclib and ribociclib and phosphatidylinositol 3 kinase alpha, or PI3Ka inhibitor, alpelisib. In December 2022, the company reported initial data from the Phase 1a dose escalation portion of the study in combination with Palbociclib, which demonstrated attractive combinability including no drug-drug interaction, or DDI, between the two agents. In July 2022, the company was granted Fast Track designation from the U.S. Food and Drug Administration, or FDA, for OP-1250 for 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. Based on the clinical results it has achieved to date, it is advancing OP-1250 through to late-stage clinical development both as a monotherapy and in combination with other targeted agents. The company owns worldwide development and commercialization rights to OP-1250.

The company is initially focused on developing therapies for the treatment of breast cancer, which represents approximately 30% of all new diagnoses of cancer in women. The company designed its lead product candidate, OP-1250, based both on a detailed structural understanding of the ER and on known alterations to this structure induced by fulvestrant and other ligands. The company has demonstrated in nonclinical studies that OP-1250 functions both as a CERAN and a SERD, but is distinguished from fulvestrant in several noteworthy ways, including:

OP-1250 is orally bioavailable while fulvestrant is a highly insoluble compound that must be administered monthly by intramuscular injection into the buttocks;

OP-1250 has favorable biodistribution properties leading to significantly higher drug concentrations in the plasma and tumor than those achieved with fulvestrant; and

OP-1250 has demonstrated the ability to shrink tumors in head-to-head nonclinical studies with fulvestrant, in contrast to fulvestrant, which has only been shown to inhibit tumor growth.

Based on these differences, the company’s OP-1250 has the potential to demonstrate clinical outcomes superior to fulvestrant. Furthermore, OP-1250 has the potential to benefit patients with metastatic breast cancer, initially for patients who have previously received endocrine therapy, as well as those who are treatment naïve in the metastatic setting, and advance into the adjuvant setting for early-stage ER+ breast cancer. In multiple nonclinical animal models of anti-cancer activity, including patient-derived xenografts with tumors containing activating mutations in the ER, OP-1250 monotherapy led to tumor shrinkage or in some cases tumor eradication, as well as long-term post-treatment survival. In each of these nonclinical models, the effect of OP-1250 was superior to that of fulvestrant, an effect which it determined was driven both by improved pharmacokinetics, or PK, properties, and higher plasma and tumor drug concentrations. In nonclinical studies, OP-1250 demonstrated robust CNS penetration, and in an intracranial breast cancer brain metastases xenograft study, OP-1250 demonstrated the ability to shrink tumors and improve survival in mice. OP-1250 has the potential to address a critical unmet medical need as 10-15% of ER+ breast cancer patients develop brain metastases for which there are limited treatment options. In nonclinical studies, the addition of OP-1250 to HER2 inhibitors improved tumor growth inhibition in both ER+/HER2+ cell line-derived xenograft and patient-derived xenograft models.

The company’s plan is to develop its wholly-owned lead product candidate, OP-1250, 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 August 2020, the company initiated a Phase 1/2 clinical study of OP-1250 in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer whose disease has progressed on endocrine therapy. Phase 1a consisted of monotherapy dose escalation to evaluate the safety and PK of OP-1250 and to determine the maximum tolerated dose, or MTD, and/or the recommended Phase 2 dose, or RP2D. In November 2021, the company reported interim Phase 1a data, with OP-1250 demonstrating attractive PK with oral bioavailability and dose-proportional exposures supporting once daily dosing; favorable tolerability with no maximum tolerated dose defined, and no clinically significant bradycardia, ocular toxicity or diarrhea; and evidence of single-agent activity in patients who had advanced on multiple prior therapies in the advanced setting, including CDK4/6 inhibitors, and confirmed partial responses in patients with baseline estrogen receptor 1, or ESR1, activating mutations.

In 2022, the company completed enrollment in its Phase 1b dose expansion at two dose levels (60 mg and 120 mg daily) and selected 120 mg daily as its RP2D to advance into Phase 2 efficacy evaluation. Phase 2 efficacy evaluation initiated in the second half of 2022 with approximately 80 patients expected to be enrolled across three cohorts: patients with measurable disease (n=50), patients with non-measurable disease (n=15), and patients with CNS metastasis (n=15). The first two primary cohorts, patients with measurable disease and patients with non-measurable disease, were fully enrolled in the fourth quarter of 2022.

In October 2022, the company reported preliminary Phase 1b clinical data at the 34th EORTC-NCI-AACR Symposium, with OP-1250 demonstrating attractive PK with oral bioavailability and high drug exposure, supporting once daily dosing; favorable tolerability with no dose-limiting toxicities and no maximum tolerated dose defined; and strong anti-tumor activity and durable benefit with 41% of patients seeing reductions in target tumor lesions, a 39% clinical benefit rate, or CBR, at its RP2D of 120 mg (seven out of 18 CBR-eligible patients) and six partial responses (four confirmed and two unconfirmed) out of 57 efficacy-evaluable patients. The company anticipates presenting Phase 2 clinical data for OP-1250 as a monotherapy in the second half of 2023.

In January 2022, the company initiated a Phase 1b dose escalation study evaluating OP-1250 in combination with the CDK4/6 inhibitor palbociclib for the treatment of recurrent, locally advanced or metastatic ER+/HER2 breast cancer. The company presented preliminary results from this Phase 1b study in December 2022 at the 2022 San Antonio Breast Cancer Symposium. In the third quarter of 2022, the company initiated the Phase 2 dose expansion portion of this study with 120 mg of OP-1250 in combination with 125 mg of palbociclib. The company anticipates presenting results from this Phase 2 study in the second quarter of 2023.

Concurrently, in the third quarter of 2022, the company initiated a Phase 1b dose escalation study of OP-1250 in combination with CDK4/6 inhibitor, ribociclib, and PI3Ka inhibitor, alpelisib, which have both been shown to lead to improvements in both progression-free and overall survival.

In July 2020, the company entered into a non-exclusive agreement with Novartis Institutes for BioMedical Research, Inc., or Novartis, to evaluate the combination of OP-1250 and Novartis’ KISQALI (ribociclib), a CDK4/6 inhibitor, as well as PIQRAY (alpelisib), their PI3Ka inhibitor. In November 2020, the company entered into a non-exclusive agreement with Pfizer Inc., or Pfizer, to evaluate the safety and tolerability of OP-1250 in combination with Pfizer’s CDK4/6 inhibitor IBRANCE (palbociclib) in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer.

Strategy

The key elements of the company’s strategy include 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 lead product candidate, OP-1250, through clinical development as a monotherapy for ER+/HER2 breast cancer; establishing OP-1250 as the endocrine therapy of choice with targeted therapy combinations for the treatment of metastatic ER+ breast cancers; exploring additional clinical opportunities for OP-1250, including metastatic breast cancer with brain metastases and other hormone sensitive tumors; continuing to evaluate opportunities to accelerate development timelines and enhance the commercial potential of its programs in collaboration with third parties; and expanding its portfolio of therapies focused on women’s oncology through both internal research activities and business development efforts.

Product Candidate

The company owns worldwide development and commercialization rights to OP-1250. The company’s plan is to develop OP-1250 for the treatment of 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.

OP-1250 is an oral small molecule clinical-stage product candidate for the treatment of endocrine-driven cancers. OP-1250 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 nonclinical studies that OP-1250 functions both as a CERAN, inactivating both AF1 and AF2 transcriptional activation functions, and a SERD, promoting degradation of the ER. OP-1250’s oral formulation and dual mechanism of action directly address the limitations of endocrine therapies, such as fulvestrant and tamoxifen, and position OP-1250 as a potential endocrine therapy of choice for the treatment of ER+ breast cancers.

The company’s Phase 1/2 monotherapy clinical development plan for OP-1250 is outlined. The company initiated the Phase 1a dose escalation portion of its Phase 1/2 monotherapy clinical study in July 2020 and reported initial results across 41 patients in November 2021. In December 2021, the company initiated the Phase 1b dose expansion portion of its monotherapy clinical development plan by expanding enrollment at two doses of 60 mg and 120 mg once daily. The company enrolled a total of 68 patients across these two doses through the end of July 2022 and reported interim results in October 2022. In the third quarter of 2022, the company selected 120 mg as its recommended Phase 2 dose, or RP2D, and initiated enrollment in the Phase 2 portion of its monotherapy study, including targeting a total enrollment of 50 patients with measurable disease, 15 patients with non-measurable disease, and 15 patients with CNS metastasis. The company’s first two primary cohorts of 50 patients with measurable disease and 15 patients with non-measurable disease were fully enrolled in the fourth quarter of 2022.

The company reported the first clinical data from the Phase 1a dose-escalation portion of the ongoing Phase 1/2 clinical study of OP-1250 in November 2021, with a data cut-off of November 1, 2021. The company reported interim clinical results from the Phase 1b monotherapy dose expansion portion of the Phase 1/2 study of OP-1250 in October 2022 at a poster session of the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, with a data cut-off of September 2, 2022.

The company anticipates presenting Phase 2 clinical data for OP-1250 as a monotherapy in the second half of 2023 The company’s clinical development strategy for OP-1250 includes exploring the potential for combination treatment of advanced or metastatic breast cancer with other targeted therapies. The company initially focuses on exploring the potential for OP-1250 in combination with CDK4/6 inhibitors palbociclib and ribociclib and PI3Ka inhibitor, alpelisib. In December 2021, the company initiated the Phase 1b dose escalation portion of its Phase 1b/2 combination clinical study in combination with palbociclib and reported preliminary results in December 2022. The company is enrolling patients in the Phase 2 dose expansion portion of this study. The company anticipates presenting results from this Phase 2 clinical study in the second quarter of 2023. In the third quarter of 2022, the company initiated the Phase 1b dose escalation portion of its Phase 1b/2 combination clinical study in combination with both ribociclib and alpelisib. The company anticipates presenting data from the Phase 1b clinical study for OP-1250 in combination with ribociclib in the second half of 2023.

In December 2021, the company initiated a Phase 1b/2 clinical study of OP-1250 in combination with palbociclib, a CDK4/6 inhibitor. The company reported preliminary clinical data from the Phase 1b dose escalation portion of the clinical study in December 2022 at the 2022 San Antonio Breast Cancer Symposium in San Antonio, Texas.

The company is exploring the potential for OP-1250 to combine with CDK4/6 inhibitors palbociclib and ribociclib in Phase 1b/2 dose escalation and expansion studies. Subject to positive results from these ongoing studies, the company anticipates initiating a pivotal Phase 3 clinical trial in combination with a CDK4/6 inhibitor in 2024 for the treatment of advanced or metastatic ER+/HER2- breast cancer in the first-line setting.

The company is conducting a series of pharmacology studies for OP-1250, including DDI fed/fast and bioequivalence to a tablet formulation, and expect to complete these studies in 2023. In addition to breast cancer, the company intends to explore the use of OP-1250 in various gynecological malignancies, beginning with endometrial cancer. Approximately 80% of endometrial tumors are endometriod in nature and these tumors are driven by estrogen.

In addition to the favorable efficacy profile of OP-1250 in the Phase 1a dose-escalation portion of the ongoing Phase 1/2 clinical study of OP-1250 for the treatment of ER+/HER2- breast cancer, the company has shown that OP-1250 can also function in combination with HER2 inhibition in ER+/HER2+ breast cancer cell lines and patient-derived xenograft models.

Clinical Trial Collaboration and Supply Agreement with Novartis

In July 2020, the company entered into a non-exclusive Clinical Collaboration and Supply Agreement, or the Novartis Agreement, with Novartis. The collaboration focuses on the evaluation of the safety, tolerability and efficacy of OP-1250 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 its planned Phase 1b clinical study of OP-1250 in patients with metastatic ER+ breast cancer.

The company is responsible for manufacturing, packaging and labeling OP-1250, and for packaging and labeling all drugs used in the clinical studies for the combined therapies (other than the Novartis Study Drugs).

Clinical Trial Agreement with Pfizer

In November 2020, the company entered into a non-exclusive clinical trial agreement with Pfizer, or the Pfizer Agreement, to evaluate the safety and tolerability of OP-1250 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.

The company is responsible for manufacturing, packaging and labeling OP-1250, and for packaging and labeling all drugs used in the clinical trials for the combined therapies (other than IBRANCE (palbociclib)). Pfizer is responsible for manufacturing and delivering to it IBRANCE (palbociclib) in such quantities as reasonably needed for the clinical studies for the combined therapies.

License Agreement with Aurigene

In June 2022, the company entered into an exclusive global license agreement with Aurigene Discovery Technologies Limited, or Aurigene, to research, develop and commercialize novel small molecule inhibitors of an undisclosed oncology target, or the Aurigene Agreement.

Under the terms of the Aurigene Agreement, Aurigene will provide to the company an exclusive license to its portfolio of novel small molecule inhibitors of the target.

Intellectual Property

The company has granted patents and pending applications relating to OP-1250, including granted claims that encompass the OP-1250 compound, pharmaceutical compositions that include OP-1250, and certain methods of using OP-1250, including in treatment which may involve combination therapy. The 20-year term for these patents expires in 2036.

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

The company 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 OP-1250. In addition, the company 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.

Research and Development Expenses

For the year ended December 31, 2022, the company’s research and development expenses were $82.3 million.

Regulation

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.

In Europe, the company is subject to Regulation (EU) 2016/679, 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

History

The company was incorporated in Delaware in 2006 under the legal name of CombiThera, Inc. and renamed Olema Pharmaceuticals, Inc. in 2009.