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Item 1. Business

2025-03-18 compared with 2024-03-11 · 455 added, 221 removed, 557 unchanged (55% of the section changed)

We are a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of next generation targeted therapies for women’s cancers.

Olema is a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of next generation targeted therapies for breast cancer and beyond.

We are advancing our 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 novel, orally-available small molecule with dual activity as both a complete estrogen receptor, or ER, antagonist, or CERAN, and selective ER degrader, or SERD, currently being investigated in patients with recurrent, locally advanced or metastatic ER-positive, or ER+, human epidermal growth factor receptor 2-negative, or HER2-, breast cancer.

In preclinical models, palazestrant binds and completely blocks ER-driven transcriptional activity in both wild-type and mutant forms of metastatic ER+ breast cancer including activity in central nervous system, or CNS, metastases models.

Our lead product candidate, palazestrant (formerly known as 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), 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.

Palazestrant is currently being evaluated both as a single agent in an ongoing Phase 3 clinical trial, OPERA-01, and in Phase 2 combination studies with a CDK4/6 inhibitor (palbociclib or ribociclib) and a phosphatidylinositol 3 kinase alpha, or PI3K a, inhibitor (alpelisib).

We reported positive Phase 2 clinical results for palazestrant as a monotherapy in October 2023 at the European Society for Medical Oncology, or ESMO, Congress 2023, which demonstrated compelling progression-free survival, or PFS, a favorable tolerability profile and attractive pharmacokinetics in a heavily pretreated patient population.

These results validated the potential opportunity for palazestrant as a monotherapy agent in later lines of treatment for metastatic breast cancer, and in November 2023 we initiated OPERA-01, our pivotal Phase 3 second-, third-line monotherapy clinical trial.

We anticipate the top-line results from the OPERA-01 trial in 2026.

We are investigating palazestrant in combination with CDK4/6 inhibitors, palbociclib and ribociclib, and a PI3K a inhibitor, alpelisib.

We reported interim results of our ongoing Phase 2 dose expansion clinical studies of palazestrant in combination with each of palbociclib and ribociclib at the 2023 San Antonio Breast Cancer Symposium in December 2023.

Across both studies, the interim results demonstrated no significant drug-drug interaction, no dose-limiting toxicities and a tolerability profile consistent with the FDA-approved labels of ribociclib or palbociclib plus an endocrine therapy.

Both studies are being conducted at palazestrant recommended Phase 2 dose, or RP2D, of 120 mg combined with the full FDA-approved label doses of palbociclib 125 mg, or ribociclib 600 mg.

In October 2023, we announced the expansion of our clinical collaboration with Novartis Institutes for BioMedical Research, Inc., or Novartis, increasing the size of the ongoing Phase 1/2 clinical study testing palazestrant in combination with ribociclib to approximately 60 patients.

We will be presenting results from the Phase 2 portion of the palazestrant-ribociclib combination clinical study at the ESMO Breast Cancer Annual Congress 2024 in May 2024 in Berlin.

Furthermore, we expect the data from the Phase 2 palazestrant-ribociclib combination clinical study will enable us to prepare to initiate a pivotal Phase 3 first-line clinical trial of palazestrant in combination with ribociclib.

We also plan to initiate evaluation of palazestrant in combination with an mTOR inhibitor, everolimus, in a Phase 1b/2 clinical study, anticipated in the third quarter of 2024.

In July 2022, we were granted Fast Track designation from the U.S.

Food and Drug Administration, or the FDA, for palazestrant 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.

In addition, in October 2023 we presented new preclinical data regarding the discovery of novel compounds targeting KAT6, an epigenetic target that is dysregulated in breast and other cancers.

In January 2024, we nominated a development candidate for this program, OP-3136, and we expect to file an Investigational New Drug, or IND, application with the FDA in late 2024 and advance into clinical development.

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.

We are advancing the development of this program in collaboration with Aurigene Oncology, or Aurigene.

We are a clinical-stage biopharmaceutical company committed to transforming the standard of care and improving outcomes for women living with cancer.

Based on the clinical results we have achieved to date, we are advancing palazestrant through late-stage clinical development both as a monotherapy and in combination with other targeted agents.

In November 2023, we initiated OPERA-01, our pivotal Phase 3 clinical trial of palazestrant as a monotherapy in second/third-line ER+/HER2- metastatic breast cancer.

We anticipate top-line results in 2026.

In combination, we are 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, we 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.

We also initiated our Phase 1b/2 clinical study of palazestrant in combination with an mTOR inhibitor, everolimus, in the third quarter of 2024.

Further, in October 2024, we 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, we 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 our 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 our new clinical trial collaboration and supply agreement with Novartis Pharma AG (Novartis), which was also announced in December 2024.

Under the terms of the agreement, Novartis will provide Olema with ribociclib drug supply for the OPERA-02 trial, which we expect to initiate in 2025.

Our 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.

We believe OP-3136 presents a potential best-in-class KAT6 inhibitor in breast and other solid tumor cancers.

In October 2024, we 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.

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.

Since our inception, we have devoted substantially all of our resources to organizing and staffing our company, research and development activities, business planning, raising capital, establishing and maintaining our intellectual property portfolio, conducting non-clinical studies and clinical trials and providing general and administrative support for these operations.

We do not have any product candidates approved for commercial sale, and we have not generated any revenue from product sales.

Our ability to generate product revenue sufficient to achieve profitability, if ever, will depend on the successful development and eventual commercialization of one or more of our product candidates which we expect, if it ever occurs, will take a number of years.

We also do not own or operate, and currently have no plans to establish, any manufacturing facilities.

We rely, and expect to continue to rely, on third parties for the manufacture of our product candidates for non-clinical and clinical testing, as well as for commercial manufacturing if any of our product candidates obtain marketing approval.

We believe that this strategy allows us to maintain a more efficient infrastructure by eliminating the need for us to invest in our own manufacturing facilities, equipment and personnel while also enabling us to focus our expertise and resources on the development of our product candidates.

We are committed to transforming the standard of care and improving outcomes for women living with cancer.

Breast cancer represents approximately 30% of all new diagnoses of cancer in women.

The American Cancer Society, or ACS, estimated that in 2024 there will be approximately 310,720 new cases of female breast cancer and about 42,250 deaths from metastatic breast cancer in the United States.

The American Cancer Society (ACS), estimated that in 2025 there will be approximately 319,750 new cases of invasive breast cancer diagnosed and approximately 42,680 deaths from breast cancer in the United States.

Treatment decisions are based on a combination of individual patient characteristics and tumor biology, most importantly the expression of three proteins:

ER, progesterone receptor, or PR, and human epidermal growth factor receptor 2, or HER2.

Approximately 75% of all breast cancers are ER+, and approximately 68% are hormone receptor positive, or HR+, and HER2-, highlighting the central role of the ER in driving a large majority of breast cancer.

ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).

Approximately 79% of all breast cancers are ER+, and approximately 70% are ER+/HER2-, highlighting the central role of the ER in driving a large majority of breast cancer.

Approximately 6-10% of breast cancer patients present with metastatic disease at diagnosis and a further 20-30% of patients initially diagnosed with early-stage disease ultimately develop metastatic disease.

The current five-year survival rate for patients with ER+ metastatic breast cancer is approximately 32%.

In 2020, the breast cancer therapy market totaled $22.3 billion, and it is set to grow at a CAGR of 8.7%, reaching $51.3 billion in 2030.

All key breast cancer populations will experience strong sales growth.

We expect sales in the HR+/HER2- population to rise from $11.3 billion in 2020 to more than $30 billion by 2030.

Based on our internal estimates, we believe that the current global ER+/HER2- metastatic breast cancer market represents approximately $20 billion.

and E.U., we believe the market potential for palazestrant is up to $5 billion in the second- and third-line settings and up to $10 billion in the first-line setting.

The ER is a nuclear receptor that functions as a ligand regulated transcription factor.

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Tamoxifen is still commonly used today but is challenged by the development of acquired drug resistance, which in some cases may be due to its partial agonist activity.

In search for a different mechanism to target the estrogen pathway, aromatase inhibitors, or AIs, were developed in the 1990s to block the synthesis of estrogen and deprive the ER+ cells of its activating ligand.

In the search for a different mechanism to target the estrogen pathway, aromatase inhibitors (AIs), were developed in the 1990s to block the synthesis of estrogen and deprive the ER+ cells of its activating ligand.

However, up to 50% of patients taking AIs develop arthralgia, leading to suspension of treatment in up to 15% of patients.

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Fulvestrant was designed to be a CERAN, and later discovered to also be a SERD, and represented a breakthrough for the field with improved outcomes for patients whose disease had progressed on prior endocrine therapy.

However, fulvestrant has several limitations including its suboptimal drug exposure and route of administration as two monthly intramuscular injections.

However, fulvestrant has several limitations including its

suboptimal drug exposure and route of administration as two monthly intramuscular injections.

Despite these drawbacks, fulvestrant achieved worldwide sales of over $1.1 billion in 2019.

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Some of these oral SERD agents are CERANs, such as palazestrant, but others have partial agonist activity despite being SERDs and thus are not CERANs.

These agents can be considered selective ER modulators, or SERM/SERDs.

These agents can be considered selective ER modulators (SERM) SERDs.

SERM/SERDs reduce the levels of the ER but they do not entirely eliminate it.

Notably, naturally-occurring estrogen itself leads to ER degradation when binding the ER.

The Olema team has spent a significant amount of time designing and optimizing our lead product candidate, palazestrant, and we believe that the ability to act as a CERAN and completely block estrogen receptor signaling, combined with attractive pharmacokinetics and drug exposure, favorable tolerability, combinability with CDK4/6 inhibitors, and CNS penetration are important characteristics to enable the success of a next

generation endocrine therapy.

We believe that results from our preclinical and clinical studies demonstrate that palazestrant has shown properties supporting its potential to achieve these objectives, address an unmet need in the treatment of breast cancer, and improve upon standard of care.

We have spent a significant amount of time designing and optimizing our lead product candidate, palazestrant.

We believe that the ability to function both as a CERAN and a SERD, together with attractive pharmacokinetics and drug exposure, favorable tolerability, combinability with CDK4/6 inhibitors, and central nervous system (CNS) penetration, are important characteristics to enable the success of a next generation endocrine therapy.

We believe that results from our pre-clinical and clinical studies demonstrate that palazestrant has shown properties supporting its potential to achieve these objectives, address an unmet need in the treatment of breast cancer, and improve upon standard of care.

Based on the clinical results we have achieved to date, we are advancing palazestrant through late-stage clinical development both as a monotherapy and in combination with other targeted agents.

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We believe palazestrant’s oral formulation and dual mechanism of action directly address the limitations of current endocrine therapies, such as fulvestrant, aromatase inhibitors and tamoxifen, and position palazestrant as a potential endocrine therapy of choice for the treatment of ER+ breast cancers.

Our goal is to discover, develop and commercialize next generation targeted therapies for women’s cancers.

We are also advancing OP-3136, our newest product candidate in clinical development targeting KAT6.

Taken together, we believe our product candidates have the potential to represent the future of breast cancer care.

Our goal is to discover, develop, and commercialize next generation targeted therapies for breast and other cancers.

The key elements of our business strategy to achieve this goal include:

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Our team has spent over a decade characterizing the structure and function of the ER and its role in driving tumor cell proliferation in HR+ breast cancer.

Our knowledge of the ER’s functional domains combined with our medicinal chemistry expertise has allowed us to develop a potent and oral compound that both completely inactivates and strongly promotes degradation of the ER in nonclinical studies.

We believe palazestrant’s oral formulation and dual mechanism of action as a CERAN/SERD directly address the limitations of current endocrine therapies, such as fulvestrant, AIs, and tamoxifen, and has the potential to drive deeper, more durable responses.

• Rapidly advancing our lead product candidate, palazestrant, through clinical development as a monotherapy for ER+/HER2 breast cancer.

We are currently evaluating palazestrant in a pivotal Phase 3 trial as a monotherapy agent in the second- and third-line setting of ER+/HER2- advanced or metastatic breast cancer.

• Rapidly advancing our 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.

We are currently evaluating palazestrant in a pivotal Phase 3 trial, called OPERA-01, as a monotherapy in the second- and third-line setting of ER+/HER2- advanced or metastatic breast cancer.

We are also preparing to initiate OPERA-02, a pivotal Phase 3 trial evaluating palazestrant in combination with ribociclib in the frontline metastatic setting of ER+/HER2- breast cancer.

OP-3136 is currently in a Phase 1 clinical trial being evaluated both as a monotherapy and in combination with fulvestrant and palazestrant.

• Establishing palazestrant as the endocrine therapy of choice with targeted therapy combinations for the treatment of metastatic ER+ breast cancers.

We believe palazestrant’s differentiated product profile has the potential to overcome many of the limitations of current endocrine therapy options.

We believe palazestrant’s differentiated product profile has the potential to overcome many of the limitations of current

endocrine therapy options.

While targeted chemotherapy and other targeted anti-body drug conjugates continue to show promising data and will likely gain further favorability as a treatment option, we believe these new treatment options will replace traditional chemotherapy - not endocrine therapies.

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Metastatic breast cancer is the second most common cancer associated with brain metastases in the United States.

Of women with ER+/HER2- metastatic breast cancer, 10% to 15% will develop brain metastases, which present a significant challenge to systemic therapy.

The primary treatment for CNS metastases is typically surgery, radiation, or a combination of both and these patients tend to have a poor prognosis.

In nonclinical studies, palazestrant demonstrated robust CNS penetration, and in an intracranial breast cancer brain metastases xenograft study, palazestrant demonstrated the ability to shrink tumors and improve survival in mice.

In addition, we believe that combining palazestrant with HER2-targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2, as up to 50% of patients with metastatic HER2+ breast cancer develop CNS disease, and the majority of patients with HER2+ breast cancer also express ER.

In nonclinical studies, the addition of palazestrant to HER2 inhibitors

improved tumor growth inhibition in both ER+/HER2+ cell line-derived xenograft and patient-derived xenograft models.

• Continuing to evaluate opportunities to accelerate development timelines and enhance the commercial potential of our programs in collaboration with third parties.

We own full worldwide development and commercialization rights to palazestrant.

We have established clinical collaborations with both Novartis and Pfizer and we intend to continue evaluating opportunities to work with partners that meaningfully enhance our capabilities with respect to the development and commercialization of palazestrant.

In addition, we intend to commercialize our product candidates in key markets either alone or with partners to maximize the worldwide commercial potential of our programs.

• Expanding our portfolio of therapies focused on women’s oncology through both internal research activities and business development efforts.

We are applying our internal drug discovery capabilities to identify and evaluate novel targeted therapies that can improve the lives of women with cancer, such as with our KAT6 inhibitor program, OP-3136.

In pre-clinical studies, palazestrant demonstrated robust CNS penetration and, in an intracranial breast cancer brain metastases xenograft study, palazestrant demonstrated the ability to shrink tumors and improve survival in mice.

We believe that combining palazestrant with HER2-targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2, as up to 50% of patients with metastatic ER+/HER2+ breast cancer develop CNS disease.

In non-clinical studies, the addition of palazestrant to HER2 inhibitors improved tumor growth inhibition in ER+/HER2+ xenograft models.

• Expanding our portfolio of product candidates through both internal research activities and business development efforts.

We are applying our internal drug discovery capabilities to identify and evaluate novel targeted therapies that can improve the lives of people living with cancer.

We have an active discovery research team exploring additional opportunities for targeted therapies for breast cancer.

We will also continue to explore opportunities to acquire products and technologies that align with our core areas of expertise and complement our existing portfolio.

As summarized in our pipeline figure below, our plan is to develop our 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, in January 2024 we nominated a development candidate in our KAT6 program, OP-3136.

We successfully identified KAT6 as a novel target and entered into a collaboration with Aurigene Oncology in 2022, which led to the discovery and development of OP-3136.

We plan to continue to explore opportunities to acquire products and technologies that align with our core areas of expertise and complement our existing portfolio.

• Continuing to evaluate opportunities to accelerate clinical development timelines and enhance the commercial potential of our programs through collaboration with third parties.

We own full worldwide development and commercialization rights to both palazestrant and OP-3136.

In addition, we intend to commercialize our product candidates in key markets either alone or with partners to maximize the worldwide commercial potential of our programs.

As summarized in the figure below, our plan is to develop our 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.

our KAT6 program, OP-3136, entered clinical development in late 2024 with plans to explore its clinical development in combination with both fulvestrant and palazestrant.

Olema product pipeline

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Breast cancer is the second-most common cancer worldwide, with nearly two million new diagnoses per year.

The ACS estimates in 2024 there will be approximately 310,720 new cases of female breast cancer and approximately 42,250 deaths in the United States, making it the second-leading cause of cancer death in women.

The ACS estimates 1 in 8 women in the U.S.

will be diagnosed with invasive breast cancer in her lifetime and that, in 2025, there will be approximately 316,950 new cases of female breast cancer and approximately 42,170 deaths in the United States, making it the second-leading cause of cancer death in women.

Approximately 2,800 men are also diagnosed with breast cancer each year in the United States.

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ER, PR and HER2.

Both ER and PR are hormone receptors, and tumors that express either of

these receptors are referred to as HR+.

Both ER and PR are hormone receptors, and tumors that express either of these receptors are referred to as HR+.

It is unusual for a tumor to express PR in the absence of the ER, therefore most tumors are referred to as either ER+ or ER-.

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Second, based on the biology and characteristics of the tumor, patients may also be offered systemic therapy, referred to as adjuvant therapy, in order to decrease the risk of recurrence of breast cancer anywhere in the body.

Systemic therapy can be given either after surgery (adjuvant) or prior to surgery (neoadjuvant) or a combination of both.

Systemic therapy can be given either after surgery (adjuvant), prior to surgery (neoadjuvant), or a combination of both.

The initial standard of care for patients with early-stage ER+ breast cancer is at least five years of adjuvant endocrine therapy.

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Inhibitors of CDK4/6, such as palbociclib, ribociclib and abemaciclib, used in combination with an AI or fulvestrant, led to significant increases in progression-free survival and overall survival.

Everolimus, an mTOR inhibitor, was approved in 2012 for the treatment of postmenopausal women with advanced HR+/HER2- breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.

Alpelisib, a PI3K a inhibitor, was approved in 2019 in combination with fulvestrant for the treatment of HR+/HER2‑ breast cancers that have mutations in PIK3CA.

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The ER has three modular functional domains:

• The amino terminal domain, which contains the activation function 1, or AF1, the activity of which can be increased by multiple cell proliferative signaling pathways;

• The amino terminal domain, which contains the activation function 1 (AF1), the activity of which can be increased by multiple cell proliferative signaling pathways;

• The DNA binding domain, which directs the ER to bind to a specific set of ER-responsive genes;

• The ligand binding domain, which contains the activation function 2, or AF2, which is turned on when bound to estrogen.

• The ligand binding domain, which contains the activation function 2 (AF2), which is turned on when bound to estrogen.

Activation of either AF1 or AF2 can drive transcription and cancer cell proliferation.

Growth and proliferation mechanism driving ER+ breast cancer

Classes of endocrine therapies and their limitations

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The two major classes of endocrine therapies are AIs and ER antagonists.

In 2020, worldwide sales for endocrine and targeted therapies treating ER+ breast cancer patients totaled $20.5 billion.

Antagonists with partial agonist activity

Although tamoxifen, the first endocrine therapy for the treatment of breast cancer, directly competes with estrogen and prevents activation of the AF2 transcription factor activation domain, it does not block AF1 activity and therefore does not completely inhibit ER function (Figure 3).

As a consequence of this partial agonist activity, tamoxifen mimics estrogen in some circumstances and promotes proliferation.

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This classification arose from the observation that certain ligands bind tightly to ER leading to ER degradation.

The field shifted drug discovery efforts to SERDs based on the hypothesis that degrading ER would be more efficacious than inhibiting it.

The field shifted drug discovery efforts to SERDs based on the hypothesis that

degrading ER would be more efficacious than inhibiting it.

However, similar to tamoxifen, many compounds with SERD activity are not complete ER antagonists nor do they achieve complete degradation of the ER.

Recent experiments conducted by us and third parties in nonclinical models of breast cancer suggest that ER degradation, as achieved by many SERDs, on its own is not sufficient to effectively treat tumors and that the ability to completely inhibit ER function is best achieved through complete antagonism.

A CERAN is a molecule that completely blocks the ability of both AF1 and AF2 to stimulate gene transcription (Figure 4).

Recent experiments conducted by us and third parties in non-clinical models of breast cancer suggest that ER degradation, as achieved by many SERDs, on its own is not sufficient to effectively treat tumors and that the ability to completely inhibit ER function is best achieved through complete antagonism.

A CERAN is a molecule that completely blocks the ability of both AF1 and AF2 to stimulate gene transcription.

CERANs inhibit activation of the AF2 transcription factor activation domain and inactivate AF1 activity by recruiting nuclear receptor corepressors of the N-CoR/ SMRT family.

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• Suboptimal drug exposure limits efficacy.

In a nonclinical mouse model, an increase in antitumor activity and ER degradation was observed as the dose of fulvestrant was increased from 25 mg/kg to 200 mg/kg.

However, researchers estimated that achieving an equivalent level of fulvestrant in humans to a 200 mg/kg dose in mice would require a dose that is eight times higher than is currently clinically achievable.

In a non-clinical mouse model, an increase in antitumor activity and ER degradation was observed as the dose of fulvestrant was increased from 25 mg/kg to 200 mg/kg.

However, researchers estimated that achieving an equivalent level of fulvestrant in humans

to a 200 mg/kg dose in mice would require a dose that is eight times higher than is currently clinically achievable.

Furthermore, xenograft models created using patient-derived tumors containing ESR1 mutations show that even plasma levels substantially higher than those achievable in humans at the approved dose fail to demonstrate optimal antitumor effect.

Our Lead Product Candidate - Palazestrant

Our Lead Product Candidate:

We own worldwide development and commercialization rights to palazestrant.

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Palazestrant was designed by our 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.

We have demonstrated in nonclinical studies that palazestrant functions both as a CERAN, inactivating both AF1 and AF2 transcriptional activation functions, and a SERD, promoting degradation of the ER.

We have 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.

We believe palazestrant’s oral formulation and dual mechanism of action directly address the limitations of current endocrine therapies, such as fulvestrant and tamoxifen, and position palazestrant as a potential endocrine therapy of choice for the treatment of ER+ breast cancers.

OPERA-01, pivotal Phase 3 monotherapy trial

In October 2023 we initiated our first pivotal Phase 3 trial of palazestrant, OPERA-01:

a randomized Phase 3 trial evaluating palazestrant vs standard-of-care treatment for ER+/HER2- advanced or metastatic breast cancer (see Figure 5).

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.

Our pivotal Phase 3 monotherapy trial:

In November 2023, we initiated our 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.

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Top-line results from the trial are expected in 2026.

Design of palazestrant Phase 3 pivotal monotherapy trial, OPERA-01

OPERA-01 study design

Phase 2 monotherapy clinical study

We 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 RP2D of 120 mg.

The group was heavily pretreated with 42% of patients

being fourth-line or later at study entry, 65% of patients having received two or more prior lines of endocrine therapy for metastatic disease, and 31% having received prior chemotherapy.

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.

The group was heavily pretreated with 42% of patients being fourth-line or later at study entry, 65% of patients having received two or more prior lines of endocrine therapy for metastatic disease, and 31% having received prior chemotherapy.

Almost all patients (97%) received prior treatment with a CDK4/6 inhibitor, and 66% received prior treatment with fulvestrant.

Of 75 patients whose circulating tumor DNA, or ctDNA, was assessed, 48% had activating mutations in ESR1 at baseline.

Of 75 patients whose circulating tumor DNA (ctDNA), was assessed, 48% had activating mutations in ESR1 at baseline.

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.

Safety and Tolerability

Treatment with palazestrant at the RP2D of 120 mg was well tolerated with no dose-limiting toxicities, and the maximum tolerated dose, or MTD, was not reached.

The majority of treatment-emergent adverse events, or TEAEs, were Grade 1 or 2.

Safety and Tolerability Profile

Treatment with palazestrant at the RP2D of 120 mg was well tolerated with no dose-limiting toxicities, and the maximum tolerated dose (MTD), was not reached.

The majority of treatment-emergent adverse events (TEAEs), were Grade 1 or 2.

Of the 86 patients treated, events of Grade 4 neutropenia were observed in six patients, occurring approximately 4–6 weeks into therapy.

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All six patients had prior exposure to CDK4/6 inhibitors.

Across all 86 patients, the median PFS was 4.6 months and the clinical benefit rate, or CBR, was 40% with a 6-month PFS rate of 38%.

Efficacy Profile

Across all 86 patients, the median progression-free survival (PFS) was 4.6 months and the clinical benefit rate (CBR), was 40% with a 6-month PFS rate of 38%.

In patients with an ESR1 mutation, the median PFS was 5.6 months and the CBR was 52% with a 6-month PFS rate of 46%.

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Palazestrant Phase 1b/2 study in combination with ribociclib

We presented Phase 1b/2 data from our clinical study of palazastrant in combination with ribociclib at the 2023 San Antonio Breast Cancer Symposium, or SABCS, on December 7, 2023.

In December 2023, we presented Phase 1b/2 data from our clinical study of palazastrant 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.

Palazestrant did not affect ribociclib drug exposure in patients, and ribociclib had no clinically meaningful effect on palazestrant drug exposure.

There were no dose-limiting toxicities, the maximum tolerated dose was not reached, and the majority of treatment-emergent adverse events were grade 1 or 2, with no grade 4 events observed.

There were no dose-limiting toxicities, the maximum tolerated dose was not

reached, and the majority of treatment-emergent adverse events were grade 1 or 2, with no grade 4 events observed.

Neutropenia was reversible in all patients, and the timing was generally consistent with ribociclib-related neutropenia.

Findings from this study support the continued use of palazestrant at the RP2D of 120 mg in combination with 600mg of ribociclib, and enrollment of sixty patients in the dose-expansion portion of the

study has been completed.

We will be presenting results from the Phase 2 portion of the palazestrant-ribociclib combination clinical study at the ESMO Breast Cancer Annual Congress 2024 in May 2024 in Berlin.

Findings from this study support the continued use of palazestrant at the RP2D of 120 mg in combination with 600mg of ribociclib, and enrollment of sixty patients in the dose-expansion portion of the study has been completed.

In May 2024, we 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 our thesis that palazestrant possesses key characteristics to make it a potential backbone endocrine therapy of preference for ER+/HER2- breast cancer.

In December 2024, we 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.

62 patients with advanced or metastatic ER+/HER2- breast cancer were treated with palazestrant (n=56 at the RP2D of 120 mg once daily) plus ribociclib (600 mg once daily;

three weeks on treatment followed by one week off treatment).

The majority of participants (48 (77%)) were 2/3+ line patients;

48 (77%) patients received prior endocrine therapy for metastatic breast cancer, 46 (74%) patients received prior treatment of endocrine therapy with CDK4/6i, 12 (19%) received two prior lines of treatment with CDK4/6i, and 11 (18%) patients received chemotherapy for metastatic breast cancer.

36 (58%) patients had visceral disease;

42 (68%) patients had measurable disease at baseline.

Of 60 patients whose ctDNA was assessed, 28% had activating mutations in ESR1 at baseline.

Efficacy Profile

Palazestrant combined with ribociclib showed promising clinical activity including tumor responses, prolonged disease stabilization, and progression-free survival in patients with ESR1 wild-type and ESR1 activating mutations at baseline and in those previously treated with one or two lines of CDK4/6i.

Efficacy data continue to mature;

30 (48%) patients remained on treatment, and the longest duration on treatment is approximately 18 months (79 weeks) and was ongoing as of the data cutoff date of November 11, 2024.

With a median follow-up of 12 months, the median PFS was not reached as of the data cutoff date.

Across all patients, the 6-month PFS rate was 73%.

In those who received prior treatment with a CDK4/6i plus an endocrine therapy, the 6-month PFS rate was 68%.

The 6-month PFS rate in ESR1 mutant patients was 81% and in ESR1 wild-type patients it was 70%.

In those who were clinical benefit rate (CBR)1-eligible, the CBR was 76% (37/49) in all patients, 81% (13/16) in patients with ESR1 mutations, and 74% (23/31) in ESR1 wild-type patients.

In patients with prior CDK4/6i treatment, the CBR was 71% (25/35), 81% (13/16) in patients with ESR1 mutations, and 65% (11/17) in ESR1 wild-type patients.

As of the data cutoff date, there were 11 responses (two confirmed complete responses, eight confirmed partial responses, and one unconfirmed partial response).

Among 37 response-evaluable patients with measurable disease, the ORR was 27% (10/37).

60% of the 37 had a reduction in target lesion size.

Safety and Tolerability Profile

Across 62 treated patients, the combination of up to 120 mg of palazestrant with the approved dose for metastatic disease of 600 mg of ribociclib daily was well tolerated with no new safety signals or increase in toxicity.

The overall safety profile was consistent with the established safety profile of ribociclib 600 mg plus an endocrine therapy.

Treatment with palazestrant up to 120 mg combined with ribociclib (600 mg) was well

tolerated with no dose-limiting toxicities.

The majority of TEAEs were Grade 1 or 2, and the severity and incidence of adverse events were consistent with the expected safety profile of ribociclib plus endocrine therapy.

Pharmacokinetics

Palazestrant did not affect ribociclib drug exposure when compared with published exposure data for single-agent ribociclib.

Steady-state trough values showed no clinically significant difference between the combination and single-agent palazestrant.

Findings from this study support the advancement of palazestrant in combination with ribociclib into clinical development for the first-line treatment of ER+/HER2- advanced or metastatic breast cancer.

In March 2025, we disclosed updated median PFS (mPFS) from this study at the TD Cowen 45th Annual Health Care Conference.

As of a data cutoff date of February 18, 2025, the mPFS was 13.8 months in 56 patients treated with 120 mg of palazestrant and 600 mg of ribociclib daily.

40 of the 56 patients had received prior treatment of a CDK4/6i plus an ET;

the mPFS in this population was 13.1 months.

Our pivotal Phase 3 combination trial of palazestrant in combination with ribociclib:

Following the entry into our new clinical trial collaboration and supply agreement with Novartis and our positive data presentation at SABCS in December 2024, we announced our 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.

We expect OPERA-02 to initiate in 2025.

OPERA-02 study design

Palazestrant Phase 1b/2 study in combination with palbociclib

We presented Phase 1b/2 data from our clinical study of palazastrant 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.

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.

There was no observed drug-drug interaction between palazestrant and palbociclib, and there was no induced metabolism or increase in exposure of either palbociclib or palazestrant when administered in combination.

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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, we 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

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Clinical studies evaluating everolimus in combination with endocrine therapies has demonstrated clinical results that indicate a potential benefit for patients in later-line settings.

In the third quarter of 2024, we plan to initiate evaluation of palazestrant in combination with everolimus in a Phase 1b/2 clinical study.

Our primary objectives will be 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.

In the third quarter of 2024, we initiated evaluation of palazestrant in combination with everolimus in a Phase 1b/2 clinical study.

Our 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 we are currently evaluating palazestrant in patients with ER+/HER2- breast cancer, we believe that there is an opportunity for us 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.

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While our initial studies are focused on treating breast cancer patients with metastatic disease, we believe that if palazestrant is determined to be safe and effective in this population, there is potential for it to be used in earlier stage disease.

Based on our extensive nonclinical studies, including certain head-to-head studies, we believe that palazestrant could have superior PK properties and improved clinical outcomes than fulvestrant.

If proven in the clinic, we believe that palazestrant has the potential to not only replace fulvestrant but to become the endocrine treatment of choice for the treatment of both advanced/metastatic ER+ breast cancer as well as ultimately in early-stage ER+ breast cancer in the adjuvant setting.

OP-3136 Development

In October 2023, we presented new preclinical 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, we nominated a development candidate for this program, OP-3136, and we expect to file an IND application with the FDA in late 2024.

Based on our extensive non-clinical studies, including certain head-to-head studies, we believe that palazestrant could have superior PK properties and improved clinical outcomes than fulvestrant.

If proven in the clinic, we believe that palazestrant has the potential to not only replace fulvestrant but to become

the endocrine treatment of choice for the treatment of both advanced/metastatic ER+ breast cancer as well as ultimately in early-stage ER+ breast cancer in the adjuvant setting.

Our Second Product Candidate:

In October 2023, we 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, we 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 we 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.

We are advancing the development of this program in collaboration with Aurigene.

KAT6 is a clinically validated target and its overexpression has been shown to be correlated with worse clinical outcomes in ER+ breast cancer.

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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 nonclinical 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.

Impact of OP-3136 and positive control on tumor volume in a 25-day mouse xenograft model

Clinical Trial Collaboration and Supply Agreement with Novartis

In July 2020, we entered into a non-exclusive Clinical Collaboration and Supply Agreement, or the Novartis Agreement, with Novartis.

In October 2024, we 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.

OP-3136 demonstrates synergistic activity in combination

In December 2024, we announced that the FDA cleared our IND application for OP-3136.

The Phase 1 clinical trial initiated thereafter and is now enrolling patients.

OP-3136 Phase 1 clinical trial

Clinical Collaboration and Supply Agreement with Novartis

In July 2020, we entered into a non-exclusive Clinical Collaboration and Supply Agreement (the Novartis Agreement) with Novartis Institutes for BioMedical Research, Inc.

On January 13, 2022, we entered into an Amended and Restated Clinical Collaboration and Supply Agreement with Novartis, and on October 9, 2023, we entered into Amendment No.

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The Novartis Amendment expanded the size of the ongoing ribociclib and palazestrant study cohort to a total of approximately 60 patients.

In March 2024, we further amended the agreement and expanded the collaboration to explore 90mg of palazestrant in combination with ribociclib, bringing the total enrollment to approximately 75 patients.

We are responsible for the conduct of the clinical studies for the combined therapies in accordance with a mutually agreed development plan.

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The Novartis Agreement will terminate upon completion of all activities outlined in the development plan and the relevant protocols.

Either party may terminate the Novartis Agreement for the uncured material breach or insolvency of the other party, if it reasonably deems it necessary in order to protect the safety, health or welfare of subjects enrolled in the clinical studies for the combined therapies due to the existence of a material safety issue, or in certain circumstances for an unresolved clinical hold with respect to either the Novartis Study Drugs or palazestrant.

Novartis Agreement in the event we terminate all clinical studies of the combined therapies other than due to a material safety issue or upon a clinical hold.

Either party may terminate the Novartis Agreement for the uncured material breach or

insolvency of the other party, if it reasonably deems it necessary in order to protect the safety, health or welfare of subjects enrolled in the clinical studies for the combined therapies due to the existence of a material safety issue, or in certain circumstances for an unresolved clinical hold with respect to either the Novartis Study Drugs or palazestrant.

In addition, Novartis may terminate the Novartis Agreement if certain disputes between the parties are not resolved after following the applicable dispute resolution procedures, and we may terminate the Novartis Agreement in the event we terminate all clinical studies of the combined therapies other than due to a material safety issue or upon a clinical hold.

The Novartis Agreement does not grant any right of first negotiation to participate in future clinical trials, and each of the parties retains all rights and ability to evaluate their respective compounds in any studies or clinical trials, either as a monotherapy or in combination with any other product or compound, in any therapeutic area.

The parties retain their independent rights to commercialize their respective therapies both alone or with other parties.

New Clinical Trial Collaboration and Supply Agreement with Novartis

In November 2024, we entered into a Clinical Trial Collaboration and Supply Agreement (the Novartis

Pharma Agreement), with Novartis.

Pursuant to the Novartis Pharma

Agreement, Novartis will provide us with ribociclib drug supply for our planned Phase 3 OPERA-02

trial of palazestrant in combination with ribociclib in ER+/HER2- frontline advanced or metastatic breast

Under the Novartis Pharma Agreement, we will supply (including manufacturing, packaging and labeling)

palazestrant and letrozole for the OPERA-02 trial.

Novartis will manufacture and supply (including

primary packaging) us with a specified amount of ribociclib, which amount is expected to be sufficient for the

OPERA-02 trial.

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.

Any inventions developed in the performance of the clinical studies for the combined therapies

(other than those specific to each component study drug) are jointly owned by the parties.

otherwise specified, the Agreement does not grant any right of first negotiation to participate in future clinical

trials, and each party retains all rights and ability to evaluate their respective compounds in any studies or

clinical trials, either as a monotherapy or in combination with any other product or compound, in any

therapeutic area.

The parties retain their independent rights to commercialize their respective therapies both

alone and with third parties.

We granted Novartis a right of first negotiation with respect to (a) the grant to any person or entity any right,

license or sublicense to exploit palazestrant, in any field or territory, other than to third party service providers,

or (b) the sale or other transfer to any person or entity of palazestrant and any related assets, each referred to herein as an Olema Compound Transaction.

If we desire to or do, at any time, (a) solicit or entertain any third party proposal or indication of interest with respect to an Olema Compound Transaction, or (b) negotiate

(including in response to any proposal or indication of interest received by the Company), enter into or perform under, in each case, any written definitive agreement with a third party with respect to or that contemplates an Olema Compound Transaction, then we must provide written notice to Novartis regarding such Olema Compound Transaction, along with certain other specified information.

Novartis will have 30 days after receipt of such notice to elect to enter into exclusive good faith negotiations with respect to such Olema Compound Transaction for a period of up to 120 days.

If our board of directors (or a duly authorized board committee) determines that we should pursue or explore a change of control or sale of all or substantially all of the assets of the Company (an Olema Change of

Control Transaction), other than in response to an unsolicited bona fide acquisition proposal (a Proposed

Sale), we must promptly notify Novartis of such determination.

In the event Novartis elects to

engage in negotiations with us in respect of such Proposed Sale, then from the date such notice is given until

45 days after the later of (a) the date on which the foregoing notice is given to Novartis, (b) the date

on which Novartis is given notice that a data room has been populated as required by the Novartis

Pharma Agreement, and (c) entry by us and Novartis into a customary nondisclosure agreement,

Novartis will have the exclusive right (but no obligation) to conduct due diligence on us and our

business and negotiate with us the definitive terms and conditions of the Proposed Sale.

If the Company or its affiliates receive an unsolicited bona fide acquisition proposal from a third party, the

Company must promptly notify its board of directors (or a duly authorized board committee) of the receipt

thereof and request that they consider the merits of such acquisition proposal.

If, after such consideration, the

Company’s board of directors (or authorized committee) authorizes the Company to engage in negotiations

with regard to such acquisition proposal, then the Company must notify Novartis in writing within 24 hours of

receipt of such authorization.

To the extent possible in light of any confidentiality obligations, such notice must

include a summary of the key structural, non-financial terms of such acquisition proposal.

In the event of an Olema Compound Transaction or Olema Change of Control involving a third party other

than Novartis (the first to occur, a “Repayment Trigger Event”), the Company must promptly pay, or procure

the payment of, the Repayment Amount (as defined below) to Novartis.

Notwithstanding the foregoing, if the

Agreement is terminated as a result of certain patient safety issues, lack of product efficacy, regulatory issues

or clinical hold issues prior to the consummation of the Olema Compound Transaction or Olema Change of

Control, then the Company shall not be obligated to pay the Repayment Amount unless (a) the Olema Change of Control or Olema Compound Transaction occurs after such termination and (b) prior to the fifth anniversary of such Olema Change of Control or Olema Compound Transaction (as applicable), the Company or its affiliates (or the applicable acquirer, successor, licensee or option holder of the Company or its affiliates) enrolls a subject in any clinical study involving the combination of palazestrant and ribociclib (the Olema Combination) or submits any filing with any regulatory authority relating to the Olema Combination.

The “Repayment Amount” is the proportion of approximately $275 million that is represented by the number of

units of ribociclib actually supplied to the Company under the Supply Agreement as of immediately prior to the

Repayment Trigger Event as compared to the total number of units that could be supplied under the Agreement.

The foregoing rights of first negotiation, first offer and notice and repayment obligations remain in effect until

the first to occur of:

(a) the date that is 120 days after filing of the New Drug Application for the Olema

Combination, (b) one year after any expiration or termination of the Agreement, and (c) such time as the

Agreement is terminated by the Company due to Novartis’ material breach.

However, in the event the

Agreement is terminated due to certain patient safety issues, lack of product efficacy, regulatory issues or

clinical hold issues prior to the consummation of an Olema Change of Control or Olema Compound

Transaction, then the Repayment Obligation shall survive until the fifth anniversary of such Olema Change of

Control or Olema Compound Transaction (as applicable) or, if payment of the Repayment Amount is required,

until the next business day after the Repayment Amount has been received by Novartis.

The Agreement will terminate on the fifth anniversary of the date on which the first dose of palazestrant is

administered to the first study subject.

Either party may terminate the Agreement for the uncured material

breach or insolvency of the other party, for failure to comply with certain anti-corruption obligations, in the

event of a change of control of the other party, if it reasonably deems it necessary in order to protect the

safety, health or welfare of subjects enrolled in the clinical studies for the combined therapies due to the

existence of a material safety issue, if the parties jointly decide that the Olema Combination is not achieving

sufficiently superior levels of efficacy, if any regulatory authority action prevents a party (or the Letrozole

supplier) from supplying its product, in the event of an unresolved force majeure event, or in certain

circumstances for an unresolved clinical hold with respect to ribociclib, palazestrant or letrozole (or the

combination of ribociclib and palazestrant or ribociclib and letrozole).

In addition, Novartis may terminate the

Agreement if the Company has failed to commence the OPERA-02 trial on or prior to March 31, 2026 or if the

Company consummates an Olema Compound Transaction, and the Company may terminate the Agreement

if the Company terminates the OPERA-02 trial other than due to a material safety issue, efficacy issue,

regulatory action or upon a clinical hold.

Clinical Trial Agreement with Pfizer

In November 2020, we entered into a non-exclusive clinical trial agreement with Pfizer, or 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.

In November 2020, we 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.

Under the terms of the non-exclusive agreement, we are responsible for conducting the clinical study for the combined therapies and Pfizer is responsible for supplying IBRANCE® to us at no cost to us.

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License Agreement with Aurigene

In June 2022, we entered into an exclusive global license agreement with 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 us an exclusive license to its portfolio of novel small molecule inhibitors of the target.

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During the research term, we will contribute funding to Aurigene to facilitate Aurigene’s ongoing discovery efforts.

We and Aurigene will jointly direct further preclinical work and, if successful, we will lead clinical development as well as regulatory and commercial activities.

We and Aurigene will jointly direct further pre-clinical work and, if successful, we will lead clinical development as well as regulatory and commercial activities.

We and Aurigene jointly own collaboration compounds and rights to any inventions made during the research term.

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The Aurigene Agreement may be terminated (a) by us for convenience, in our sole discretion, upon prior written notice to Aurigene, (b) by either us or Aurigene in connection with the other party’s uncured material breach or (c) by either us or Aurigene in connection with the insolvency of the other party.

Other Licensing Agreements

On October 17, 2024, we signed an out-license of our de-prioritized TRPM4 targeted research program to Black Shadow Therapeutics LLC in exchange for potential single-digit royalties on world-wide net sales should a product be approved by regulatory authorities.

Intellectual Property

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The United States and certain other jurisdictions also have provisions that permit extension of patent term for patents that claim a drug or drug product, or its approved use, if the patent was issued before clinical trials and were completed and regulatory approval secured, so long as certain specific requirements were satisfied.

In the United States, such extension associated with regulatory approval is called a Patent Term Extension, or

PTE, and it is limited to a maximum of five years, or less if the extended patent term would exceed 14 years after the date of regulatory approval.

In the United States, such extension associated with regulatory approval is called a Patent Term Extension (PTE) and it is limited to a maximum of five years, or less if the extended patent term would exceed 14 years after the date of regulatory approval.

Only one patent can receive regulatory extension (e.g., PTE) per product approval.

The United States also offers a different form of patent term extension, known as Patent Term Adjustment, or PTA, whereby a particular patent’s term is automatically extended beyond the 20‑year date if the United States Patent and Trademark Office, or the USPTO, caused delay during its examination;

The United States also offers a different form of patent term extension, known as Patent Term Adjustment (PTA), whereby a particular patent’s term is automatically extended beyond the 20‑year date if the United States Patent and Trademark Office (USPTO) caused delay during its examination;

however, potentially available PTA is reduced by any amount of any delay caused by the patent applicant.

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Furthermore, if any changes are made to the application between the provisional and the non- provisional filings, the changed material may not be entitled to the priority filing date.

Still further, in the biopharmaceutical industry, it is common for applicants to file a so-called “international” patent application under the Patent Cooperation Treaty, or PCT, as a non-provisional filing.

Still further, in the biopharmaceutical industry, it is common for applicants to file a so-called “international” patent application under the Patent Cooperation Treaty (PCT) as a non-provisional filing.

Such an international application, often referred to as a “PCT application,” like a provisional application, cannot itself issue as a patent but rather preserves the applicant’s right to pursue patent filings in individual countries, which patent filings are referred to as “national applications” or “national phase filings” and can claim the benefit of priority to the prior PCT application (which may in turn claim priority to the prior provisional filing).

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We co-own 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 us an exclusive license to Aurigene's rights in patents and applications related to OP-3136, as well as other KAT6 inhibitors that are being evaluated.

Under the Aurigene Agreement, Aurigene has provided to us 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.

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However, there can be no assurance that we will receive or benefit from any PTE with respect to such patents.

or NCE, exclusivity, and/or for approvals related to orphan indications, or Orphan Drug designation, and/or pediatric approvals, or Pediatric Exclusivity.

Furthermore, as neither palazestrant nor OP-3136 has previously been approved in the United States for any indication, each of palazestrant and OP-3136 may be eligible for five years of NCE exclusivity upon its first approval.

In addition to patent term extension regulatory exclusivities, pharmaceutical marketing approval agencies, such as the FDA and the EMA, offer certain data exclusivities for first-approved products with a new chemical entity (NCE), exclusivity, and/or for approvals related to orphan indications (Orphan Drug designation), and/or pediatric approvals (Pediatric Exclusivity).

Should that approval be for an orphan indication for which we have received Orphan Drug designation, the NCE and Orphan Drug exclusivity would run concurrently.

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We intend to build a commercial infrastructure to support sales of any approved products.

We intend to continue evaluating opportunities to work with partners that enhance our capabilities with respect to the development and commercialization of palazestrant.

intend to continue evaluating opportunities to work with partners that enhance our capabilities with respect to the development and commercialization of palazestrant.

In addition, we intend to commercialize our product candidates, if approved, in key markets either alone or with partners in order to maximize the worldwide commercial potential of our programs.

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We currently do not own or operate any manufacturing facilities.

We rely, and expect to continue to rely for the foreseeable future, on third-party contract manufacturing organizations, or CMOs, to produce palazestrant for nonclinical and clinical testing, as well as for commercial manufacture if palazestrant receives marketing approval.

We require that our CMOs produce bulk drug substances and finished drug products in accordance with current Good Manufacturing Practices, or cGMPs, and all other applicable laws and regulations.

We rely, and expect to continue to rely for the foreseeable future, on third-party contract manufacturing organizations (CMOs) to produce palazestrant for non-clinical and clinical testing, as well as for commercial manufacture if palazestrant receives marketing approval.

We require that our CMOs produce bulk drug substances and finished drug products in accordance with current Good Manufacturing Practices (cGMPs) and all other applicable laws and regulations.

We maintain agreements with our manufacturers that include confidentiality and intellectual property provisions to protect our proprietary rights related to palazestrant.

We have engaged CMOs to manufacture and package palazestrant for nonclinical and clinical use.

We have engaged CMOs to manufacture and package palazestrant for non-clinical and clinical use.

Additional CMOs are used to label and distribute palazestrant for clinical use.

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Any product candidates that we successfully develop and commercialize will compete with current therapies and new therapies that may become available in the future.

Many of the companies against which we may compete have significantly greater financial resources and expertise in research and development, manufacturing, nonclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do.

Many of the companies against which we may compete have significantly greater financial resources and expertise in research and development, manufacturing, non-clinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do.

Mergers and acquisitions in the pharmaceutical, biotechnology and oncology industries may result in even more resources being concentrated among a smaller number of our competitors.

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If the product candidates for our priority programs are approved for the indications we are currently targeting, they will compete with the products discussed below.

Furthermore, it is possible that other companies are also engaged in discovery or nonclinical development of product candidates for the same indications.

These competitors, if successful in clinical development, may achieve regulatory approval and market adoption in advance of our product candidates, constraining our ability to gain significant market share for such product candidates.

Furthermore, it is possible that other companies are also engaged in discovery or non-clinical development of product candidates for the same indications.

competitors, if successful in clinical development, may achieve regulatory approval and market adoption in advance of our product candidates, constraining our ability to gain significant market share for such product candidates.

In addition, our product candidates, if approved, will complete with multiple approved products or products that may be approved for future indications for which we develop such product candidate.

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drug development process

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act, or FDCA, and implementing regulations.

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (FDCA), and implementing regulations.

Drugs are also subject to other federal, state and local statutes and regulations.

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The process required by the FDA before a drug may be marketed in the United States generally involves the following:

• completion of extensive nonclinical laboratory tests, nonclinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s Good Laboratory Practices, or GLP, regulations and other applicable regulations;

• submission to the FDA of an investigational new drug application, or IND, which must become effective before human clinical trials may begin;

• approval by an independent institutional review board, or IRB, at each clinical site before each trial may be initiated;

• performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including the FDA’s current good clinical practice, or GCP, regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

• submission to the FDA of a New Drug Application, or NDA, for a new drug;

• completion of extensive non-clinical laboratory tests, non-clinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s Good Laboratory Practices, or GLP, regulations and other applicable regulations;

• submission to the FDA of an investigational new drug application (IND), which must become effective before human clinical trials may begin;

• approval by an independent institutional review board (IRB) at each clinical site before each trial may be initiated;

• performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including the FDA’s current good clinical practice (GCP) regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

• submission to the FDA of a New Drug Application (NDA) for a new drug;

• a determination by the FDA within 60 days of its receipt of an NDA to file the NDA for review;

• satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with the FDA’s current good manufacturing practice, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

• potential FDA audit of the nonclinical and/or clinical trial sites that generated the data in support of the NDA;

• satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with the FDA’s current good manufacturing practice (cGMP) requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

• potential FDA audit of the non-clinical and/or clinical trial sites that generated the data in support of the NDA;

• satisfactory completion of an FDA advisory committee review, if applicable;

• FDA review and approval of the NDA prior to any commercial marketing or sale of the drug in the United States.

Before testing any compounds with potential therapeutic value in humans, the drug candidate enters the nonclinical testing stage.

Nonclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies, to assess the characteristics and potential safety and activity of the drug candidate.

The conduct of the nonclinical tests must comply with federal regulations and requirements including GLPs.

The sponsor must submit the results of the nonclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND.

Before testing any compounds with potential therapeutic value in humans, the drug candidate enters the non-clinical testing stage.

Non-clinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies, to assess the characteristics and potential safety and activity of the drug candidate.

The conduct of the non-clinical tests must comply with federal regulations and requirements including GLPs.

The sponsor must submit the results of the non-clinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND.

An IND is a request for authorization from the FDA to administer an investigational drug product to humans.

The central focus of an IND submission is on the general investigational plan and the protocol(s) for human trials.

Some nonclinical testing may continue even after the IND is submitted.

Some non-clinical testing may continue even after the IND is submitted.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the IND on clinical hold within that 30 day time period.

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For each successive clinical trial conducted with the investigational drug, a separate, new protocol submission to an existing IND must be made, along with any subsequent changes to the investigational plan.

Sponsors are also subject to ongoing reporting requirements, including submission of IND safety reports for any serious adverse experiences associated with use of the investigational drug or findings from nonclinical studies suggesting a significant risk for human subjects, as well as IND annual reports on the progress of the investigations conducted under the IND.

Sponsors are also subject to ongoing reporting requirements, including submission of IND safety reports for any serious adverse experiences associated with use of the investigational drug or findings from non-clinical studies suggesting a significant risk for human subjects, as well as IND annual reports on the progress of the investigations conducted under the IND.

Clinical trials involve the administration of the drug candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.

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Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

Further, each clinical trial must be reviewed and approved by an independent institutional review board, or IRB, at or servicing each institution at which the clinical trial will be conducted.

An IRB is charged with protecting the welfare and rights of trial

participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

Further, each clinical trial must be reviewed and approved by an IRB, at or servicing each institution at which the clinical trial will be conducted.

An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

There are also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

There are also

requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

Post-approval studies, or Phase 4 clinical trials, may be conducted after initial marketing approval.

Post-approval studies (Phase 4 clinical trials) may be conducted after initial marketing approval.

These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.

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review and approval processes

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and

other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.

Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators.

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a waiver of such fees may be obtained under certain limited circumstances.

In addition, the Pediatric Research Equity Act, or PREA, requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.

In addition, the Pediatric Research Equity Act (PREA) requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.

Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver.

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

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

Under the Prescription Drug User Fee Act (PDUFA) guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

This review typically takes twelve months from the date the NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly extended by FDA requests for additional information or clarification.

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After the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an approval letter or a Complete Response Letter.

An approval letter

authorizes commercial marketing of the drug with specific prescribing information for specific indications.

An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.

A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA.

The Complete Response Letter may require additional clinical data and/or (an) additional pivotal Phase 3 clinical trial(s), and/or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing.

The Complete Response Letter may require additional clinical data and/or (an) additional pivotal Phase 3 clinical trial(s), and/or other significant and time-consuming

requirements related to clinical trials, non-clinical studies or manufacturing.

If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.

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For example, the FDA may require Phase 4 testing, which involves clinical trials designed to further assess a drug safety and effectiveness and may require testing and surveillance programs to monitor the safety of approved products that have been commercialized.

The FDA may also determine that a risk evaluation and mitigation strategy, or REMS, is necessary to assure the safe use of the drug.

The FDA may also determine that a risk evaluation and mitigation strategy (REMS) is necessary to assure the safe use of the drug.

If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS;

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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.

As compensation for patent term lost during product development and the FDA regulatory review process, the Hatch-Waxman Amendments permit a patent restoration term, or PTE, which is limited to a maximum of five years, or less if the extended patent term would exceed 14 years after the date of the regulatory approval of the product.

As compensation for patent term lost during product development and the FDA regulatory review process, the Hatch-Waxman Amendments permit a patent restoration term (PTE), which is limited to a maximum of five years, or less if the extended patent term would exceed 14 years after the date of the regulatory approval of the product.

The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of an NDA plus the time between the submission date of an NDA and the approval of that application.

Only one patent applicable to an approved drug or drug product, or its approved use, is eligible for the extension and the application for the extension must be submitted prior to the expiration of the

Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we may intend to apply for restoration of a patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

However, we may not receive an extension if we fail to exercise due diligence during the testing phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements.

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A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application, or ANDA, or a 505(b)(2) NDA submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.

During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application (ANDA), or a 505(b)(2) NDA submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

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Five-year and three-year exclusivity will not delay the submission or approval of a full NDA.

However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the non-clinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances.

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There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.

safe harbor but the exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection.

The exceptions and safe harbors are drawn narrowly and practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor but the exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection.

Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute.

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Pharmaceutical and other healthcare companies have been prosecuted under these laws for, among other things, allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product and for causing false claims to be submitted because of the companies’ marketing of the product for unapproved, and thus non- covered, uses.

The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, also created new federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

The federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) also created new federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

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We may also be subject to data privacy and security regulations promulgated by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, impose requirements on covered entities, including certain healthcare providers, health plans, and healthcare clearinghouses, and their respective business associates that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity as well as their covered subcontractors relating to the privacy, security and transmission of individually identifiable health information.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a

service on behalf of a covered entity.

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and its implementing regulations, impose requirements on covered entities, including certain healthcare providers, health plans, and healthcare clearinghouses, and their respective business associates that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity as well as their covered subcontractors relating to the privacy, security and transmission of individually identifiable health information.

HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

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All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.

If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to significant penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security.

We are or will become subject to privacy laws in the jurisdictions in which we are established or in which we sell or market our products or run clinical trials.

For example, in Europe we are subject to the General Data Protection Regulation, or GDPR, in relation to our collection, control, processing and other use of personal data (i.e., data relating to an identified or identifiable living individual).

We process personal data in relation to participants in our clinical trials in the European Economic Area, or EEA, including the health and medical information of these participants.

The GDPR is directly applicable in each European Union Member State, however, it provides that European Union Member States may introduce further conditions that could cause our compliance costs to increase, ultimately having an adverse impact on our business.

For example, in Europe we are subject to the General Data Protection Regulation (GDPR) in relation to our collection, control, processing and other use of personal data (i.e., data relating to an identified or identifiable living individual).

We process personal data in relation to participants in our clinical trials in the European Economic Area (EEA), including the health and medical information of these participants.

The GDPR is directly applicable in each of the twenty-seven member states of the European Union (EU Member States), however, it provides that EU Member States may introduce further conditions that could cause our compliance costs to increase, ultimately having an adverse impact on our business.

We are subject to the supervision of local data protection authorities in those European Union jurisdictions where we are established or otherwise subject to the GDPR.

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up to the greater of €20 million or 4% of total global annual turnover.

Further, we must comply with both the GDPR and separately the GDPR as implemented in the United Kingdom, or UK, each regime having the ability to fine up to the greater of €20 million / £17 million or 4% of global turnover.

Further, we must comply with both the GDPR and separately the GDPR as implemented in the United Kingdom (UK), each regime having the ability to fine up to the greater of €20 million / £17 million or 4% of global turnover.

A breach of the GDPR or other applicable privacy and data protection laws and regulations could result in regulatory investigations, reputational damage, orders to cease/change our use of data, enforcement notices, or potential civil claims including class action type litigation.

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In the ordinary course of business, we may transfer personal data from Europe and other jurisdictions to the United States or other countries.

Europe and other jurisdictions have enacted laws requiring data to be localized

or limiting the transfer of personal data to other countries.

In particular, the EEA and the UK have significantly restricted the transfer of personal data to the United States and other countries whose privacy laws it believes are inadequate.

Europe and other jurisdictions have enacted laws requiring data to be localized or limiting the transfer of personal data to other countries.

In particular, the EEA and the UK have significantly restricted the transfer of personal data to the United States and other countries whose privacy laws it believes

are inadequate.

Other jurisdictions may adopt similarly stringent interpretations of their data localization and cross-border data transfer laws.

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Some European regulators have ordered certain companies to suspend or permanently cease certain transfers out of Europe for allegedly violating the GDPR’s cross-border data transfer limitations.

In the United States, the California Consumer Privacy Act, or CCPA, creates individual privacy rights for California consumers (as defined in the law) and places increased privacy and security obligations on entities handling certain personal data of consumers or households.

In the United States, the California Consumer Privacy Act (CCPA) creates individual privacy rights for California consumers (as defined in the law) and places increased privacy and security obligations on entities handling certain personal data of consumers or households.

The CCPA requires covered companies to provide new disclosure to consumers about such companies’ data collection, use and sharing practices, provide such consumers new ways to opt-out of certain sales or transfers of personal information, and provide consumers with additional causes of action.

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The CCPA may impact our business activities and exemplifies the vulnerability of our business to the evolving regulatory environment related to personal data and protected health information.

Additionally, the California Privacy Rights Act, or CPRA, significantly modifies the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information.

Additionally, the California Privacy Rights Act (CPRA) significantly modifies the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information.

The CPRA also creates a new state agency that will be vested with authority to implement and enforce the CCPA and the CPRA.

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In addition to the foregoing, any breach of privacy laws or data security laws, particularly resulting in a significant security incident or breach involving the misappropriation, loss or other unauthorized use or disclosure of sensitive or confidential patient or consumer information, could have a material adverse effect on our business, reputation and financial condition.

As a data controller, we will be accountable for any third-party service providers we engage to process personal data on our behalf, including our contract research organizations, or CROs.

As a data controller, we will be accountable for any third-party service providers we engage to process personal data on our behalf, including our contract research organizations (CROs).

We attempt to mitigate the associated risks but there is no assurance that privacy and security-related safeguards will protect us from all risks associated with the third-party processing, storage and transmission of such information.

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Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we or our collaborators obtain regulatory approval.

In the United States and markets in other countries, sales of any products for which we or our collaborators receive regulatory approval for commercial sale will depend, in part, on the extent to which third-party payors provide coverage, and establish adequate reimbursement levels for such drug products.

In the United States and markets in other countries, sales of any products for which we or our collaborators receive regulatory approval for commercial sale will depend,

in part, on the extent to which third-party payors provide coverage, and establish adequate reimbursement levels for such drug products.

In the United States, third-party payors include federal and state healthcare programs, government authorities, private managed care providers, private health insurers and other organizations.

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For example, drug manufacturers participating under the Medicaid Drug Rebate Program must pay rebates on prescription drugs to state Medicaid programs.

Under the Veterans Health Care Act, or VHCA, drug companies are required to offer certain drugs at a reduced price to a number of federal agencies, including the U.S.

Under the Veterans Health Care Act (VHCA) drug companies are required to offer certain drugs at a reduced price to a number of federal agencies, including the U.S.

Department of Veterans Affairs and Department of Defense, the Public Health Service and certain private Public Health Service designated entities in order to participate in other federal funding programs, including Medicare and Medicaid.

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To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular drug candidate to currently available therapies.

Across the European Union, member states carry out assessments of new pharmaceutical products from an economic, public health, and therapeutic perspective, through a Health Technology Assessment, or HTA, process, which is currently governed by the national laws of member states.

In December 2021, the European Parliament voted to implement a regulation regarding HTAs, or the HTA Regulation.

Across the European Union, member states carry out assessments of new pharmaceutical products from an economic, public health, and therapeutic perspective, through a Health Technology Assessment (HTA) process, which is currently governed by the national laws of EU Member States.

In December 2021, the European Parliament voted to implement a regulation regarding HTAs (the HTA Regulation).

The HTA Regulation is scheduled to apply as of January 2025, and will provide a framework for pan-EU clinical assessments, scientific consultations, identification of emerging health technologies, and further cooperation.

Entry into application of the Regulation could impose stricter and more detailed procedures to be followed by marketing authorization holders concerning conduct of HTAs in relation to their products which may influence related pricing and reimbursement decisions.

However, under the HTA Regulation, member states will still be free to make their own pricing and reimbursement decisions.

Moreover, member states may, and

do, choose to restrict the range of products for which their national health insurance systems or national healthcare systems provide reimbursement and to control the prices of such products.

Member states may impose direct controls on pricing, or otherwise adopt a system of direct or indirect controls on the profitability of the companies placing such products on the market.

Other member states allow companies to set their own prices but monitor and control prescription volumes and issue guidance to medical professionals to limit prescriptions of such products.

However, under the HTA Regulation, EU Member States will still be free to make their own pricing and reimbursement decisions.

Moreover, EU Member States may, and do, choose to restrict the range of products for which their national health insurance systems or national healthcare systems provide reimbursement and to control the prices of such products.

EU Member States may impose direct controls on pricing, or otherwise adopt a system of direct or indirect controls on the profitability of the companies placing such products on the market.

Other EU Member States allow companies to set their own prices but monitor and control prescription volumes and issue guidance to medical professionals

to limit prescriptions of such products.

The downward pressure on health care costs in general, particularly prescription drugs, has become very intense.

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For example, in March 2010, the ACA was enacted, which affected existing government healthcare programs and resulted in the development of new programs.

There have been executive, judicial and Congressional challenges to certain aspects of the ACA.

For example, on June 17, 2021, the U.S.

Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.

In addition, there have been a number of health reform initiatives by the Biden administration that have impacted the ACA.

For example, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022, or the IRA, into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

There have been executive, judicial and Congressional challenges and amendments to certain aspects of the ACA.

For example, on August 16, 2022, the Inflation Reduction Act of 2022 (IRA) was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

It is possible that the ACA will be subject to judicial or Congressional challenges in the future.

It is unclear how such challenges and the healthcare reform measures of the Biden administration will impact the ACA and our business.

It is unclear how such challenges and the healthcare reform measures of the current administration will impact the ACA and our business.

Other legislative changes have also been proposed and adopted in the United States since the ACA was enacted.

On August 2, 2011, the Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013, and will remain in effect through 2032, unless additional Congressional action is taken.

In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

Additionally, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminated the statutory Medicaid drug rebate cap, previously set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024.

There has been heightened governmental scrutiny recently over the manner in which pharmaceutical companies set prices for their marketed products, which has resulted in several Presidential executive orders, Congressional inquiries and proposed federal legislation, as well as state efforts, designed to, among other things, bring more transparency to product pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

At the federal level, in July 2021, the Biden administration

released an executive order that included multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, the U.S.

Department of Health and Human Services, or HHS, released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform.

The plan sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

In addition, the IRA, among other things (i) directs HHS to negotiate the price of certain high-expenditure, single-source drugs and biologics covered under Medicare and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions take effect progressively starting in fiscal year 2023.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the Centers for Medicare & Medicaid Services, or CMS, Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

For example, the IRA, among other things, (1) directs the U.S.

Department of Health and Human Services (HHS), to negotiate the price of certain high-expenditure, single-source drugs that have been on the market for at least seven years covered under Medicare, the Medicare Drug Price Negotiation Program, and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions began to take effect progressively in fiscal year 2023.

On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations, although the Medicare Drug Price Negotiation Program is currently subject to legal challenges.

On January 17, 2024, HHS selected fifteen additional products covered under Part D for price negotiation in 2025.

Each year thereafter, more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.

Further, on December 7, 2023, an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act was announced.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance

Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

For example, on January 5, 2024, the FDA approved Florida’s Section 804 Importation Program, or SIP, proposal to import certain drugs from Canada for specific state healthcare programs.

For example, on January 5, 2024, the FDA approved Florida’s Section 804 Importation Program (SIP) proposal to import certain drugs from Canada for specific state healthcare programs.

It is unclear how this program will be implemented, including which drugs will be chosen, and whether it will be subject to legal challenges in the United States or Canada.

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Foreign Corrupt Practices Act

Foreign Corrupt Practices Act of 1977, or FCPA, prohibits any U.S.

Foreign Corrupt Practices Act of 1977 (FCPA) prohibits any U.S.

individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business.

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Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.

In the European Union, for example, pursuant to the Clinical Trials Regulation, which came into application on January 31, 2022, a

clinical trial application, or CTA, must be submitted to via the EMA's Clinical Trials Information System, which will cover all regulatory and ethics assessments from the member states concerned.

Once the CTA is approved in accordance with a country’s requirements, clinical trial development may proceed.

Approval and monitoring of clinical trials in the European Union is the responsibility of individual member states but, compared to the position prior to the applicability of the Clinical Trials Regulation, there is likely to be more collaboration, information-sharing, and decision-making between member states.

In the European Union, for example, clinical trials are governed by the Clinical Trials Regulation (EU) No 536/2014 (CTR), which entered into application on January 31, 2022 repealing and replacing the former Clinical Trials Directive 2001/20 (CTD).

The CTR is intended to harmonize and streamline clinical trial authorizations, simplify adverse-event reporting procedures, improve the supervision of clinical trials and increase transparency.

Specifically, the Regulation, which is directly applicable in all EU Member States, introduces a streamlined application procedure through a single-entry point, the "EU portal", the Clinical Trials Information System (CTIS);

a single set of documents to be prepared and submitted for the application;

as well as simplified reporting procedures for clinical trial sponsors.

A harmonized procedure for the assessment of applications for clinical trials has been introduced and is divided into two parts.

Part I assessment is led by the competent authorities of a reference Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to be scientifically harmonized across EU Member States.

This assessment is then submitted to the competent authorities of all concerned EU Member States in which the trial is to be conducted for their review.

Part II is assessed separately by the competent authorities and Ethics Committees in each concerned EU Member State.

Individual EU Member States retain the power to authorize the conduct of clinical trials on their territory.

The CTR foresaw a three-year transition period that ended on January 31, 2025.

Since this date, all new or ongoing trials are subject to the provisions of the CTR.

The requirements and processes governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

In all major territories, including the European Union, clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

The European Union and the European Economic Area consist, at the time of writing, of the twenty-seven Member States of the European Union, plus Norway, Iceland and Liechtenstein which are Member States of the European Economic Area.

The European Union and the European Economic Area consist, at the time of writing, of the EU Member States, plus Norway, Iceland, and Liechtenstein which are member states of the European Economic Area.

To obtain regulatory approval of an investigational drug or biological product under European Union regulatory systems, we must submit a marketing authorization application either under the so-called centralized or national authorization procedures.

There are three procedures for a marketing authorization to be obtained:

There are three procedures for a marketing authorization (MA) to be obtained:

• The Centralized marketing authorization, which is issued by the European Commission through the Centralized Procedure, based on the scientific opinion of the EMA’s Committee for Medicinal Products for Human Use, and which is valid throughout the entire territory of the European Economic Area.

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The Centralized Procedure is optional for products containing a new active substance not yet authorized in the European Union, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the European Union.

Under the centralized procedure, the EMA’s Committee for Medicinal Products for Human Use (CHMP), conducts the initial assessment of a product.

The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing MA.

The maximum timeframe for the evaluation of an MAA under the centralized procedure is 210 days, excluding clock stops when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP.

• Decentralized Procedure marketing authorizations are available for products not falling within the mandatory scope of the Centralized Procedure.

An identical dossier is submitted to the competent authorities of each of the Member States in which the marketing authorization is sought, one of which is selected by the applicant as the Reference Member State, or RMS, to lead the evaluation of the regulatory submission.

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics, or SmPC, and a draft of the labeling and package leaflet as distilled from the preliminary evaluation, which are sent to the other Member States (referred to as the Concerned Member States) for their approval.

An identical dossier is submitted to the competent authorities of each of the Member States in which the marketing authorization is sought, one of which is selected by the applicant as the Reference Member State (RMS), to lead the evaluation of the regulatory submission.

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics (SmPC), and a draft of the labeling and package leaflet as distilled from the preliminary evaluation, which are sent to the other Member States (referred to as the Concerned Member States) for their approval.

If the Concerned Member States raise no objections, based on a potential serious risk to public health, to the assessment, SmPC, labeling, or packaging proposed by the RMS, the RMS records the agreement, closes the procedure and informs the applicant accordingly.

Each Member State concerned by the procedure is required to adopt a national decision to grant a national marketing authorization in conformity with the approved assessment report, SmPC and the labeling and package leaflet as approved.

Where a product has already been authorized for marketing in a Member State of the European Economic Area, the granted national marketing authorization can be used for mutual recognition in other Member States through the Mutual Recognition Procedure, or MRP, resulting in progressive national approval of the product in the European Economic Area.

Where a product has already been authorized for marketing in a Member State of the European Economic Area, the granted national marketing authorization can be used for mutual recognition in other Member States through the Mutual Recognition Procedure (MRP), resulting in progressive national approval of the product in the European Economic Area.

• National marketing authorizations, which are issued by a single competent authority of the member states of the European Economic Area and only covers such authority’s respective territory, are also available for products not falling within the mandatory scope of the Centralized Procedure.

Once a product has been authorized for marketing in a Member State of the European Economic Area through the National Procedure, this National marketing authorization can also be recognized in other Member States through the Mutual Recognition Procedure.

The EMA grants orphan drug designation to promote the development of products that may offer therapeutic benefits for life-threatening or chronically debilitating conditions affecting not more than five in 10,000 people in the European Union.

An MA has, in principle, an initial validity of five years.

The MA may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the EU Member State

in which the original MA was granted.

To support the application, the MA holder must provide the EMA or the competent authority with a consolidated version of the Common Technical Document providing up-to-date data concerning the quality, safety and efficacy of the product, including all variations introduced since the MA was granted, at least nine months before the MA ceases to be valid.

The European Commission or the competent authorities of the EU Member States may decide on justified grounds relating to pharmacovigilance, to proceed with one further five year renewal period for the MA.

Once subsequently definitively renewed, the MA shall be valid for an unlimited period.

Any authorization which is not followed by the actual placing of the medicinal product on the EU market (for a centralized MA) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).

The EU provides opportunities for data and market exclusivity related to MAs.

Upon receiving an MA, innovative medicinal products are generally entitled to receive eight years of data exclusivity and 10 years of market exclusivity.

Data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial MA of the reference product in the EU.

The overall ten-year period may, occasionally, be extended for a further year to a maximum of 11 years if, during the first eight years of those ten years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical/biological entity, and products may not qualify for data exclusivity.

The European Commission may also grant orphan drug designation to promote the development of products that may offer therapeutic benefits for life-threatening or chronically debilitating conditions affecting not more than five in 10,000 people in the European Union.

In addition, orphan drug designation can be granted if the drug is intended for a life threatening, seriously debilitating or serious and chronic condition in the European Union and without incentives it is unlikely that sales of the drug in the European Union would be sufficient to justify developing the drug.

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The exclusivity period may be reduced to six years if the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

In the EU, pricing and reimbursement schemes vary widely from country to country.

Some EU Member States may approve a specific price for a product, or they may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market.

Other EU Member States allow companies to fix their own prices for products but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.

In addition, some EU Member States may require the completion of additional studies that compare the cost-effectiveness of a particular medicinal product candidate to currently available therapies.

This Health Technology Assessment (HTA), process is the procedure according to which the assessment of the public health impact, therapeutic impact and the economic and societal impact of use of a given medicinal product in the national healthcare systems of the individual country is conducted.

The outcome of HTA regarding specific medicinal products will often influence the pricing and reimbursement status granted to these medicinal products by the competent authorities of individual EU Member States.

In December 2021, Regulation No 2021/2282 on Health Technology Assessment, or HTA Regulation, was adopted.

The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including new medicinal products, and providing the basis for cooperation at EU level for joint clinical assessments in these areas.

The HTA Regulation has applied from January 12, 2025 although it will enter into force iteratively and

initially apply to new active substances to treat cancer and to all advanced therapy medicinal products (ATMPs), it will then be expanded to orphan medicinal products in January 2028, and to all centrally authorized medicinal products as of 2030.

Selected high-risk medical devices will also be assessed under the HTA Regulation as of 2026.

The HTA Regulation is intended to harmonize the clinical benefit assessment of HTA across the European Union.

Much like the Anti-Kickback Statute prohibition in the United States, as described below, the provision of benefits or advantages to physicians and other health care professionals to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the E.U.

Interactions between pharmaceutical companies and health care professionals are governed by strict laws, such as national anti-bribery laws of European countries, national sunshine rules, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct.

Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

Infringement of related laws could result in substantial fines and imprisonment.

Payments made to physicians and other health care professionals in certain EU Member States must be publicly disclosed.

Moreover, agreements with health care professionals may require prior notification or approval by the health care professional’s employer, his or her competent professional organization and/or the regulatory authorities of the individual EU Member States.

Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

The United Kingdom’s, or UK, withdrawal from the EU on January 31, 2020, commonly referred to as Brexit,

has changed the regulatory relationship between the UK and the EU.

The Medicines and Healthcare products Regulatory Agency, or MHRA, is now the UK’s standalone regulator for medicinal products and medical devices.

The United Kingdom is now a third country to the EU.

The UK regulatory framework in relation to clinical trials is governed by the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, which is derived from the CTD, as implemented into UK national law through secondary legislation.

On January 17, 2022, the MHRA launched an eight-week consultation on reframing the UK legislation for clinical trials, and which aimed to streamline clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.

The UK Government published its response to the consultation on March 21, 2023 confirming that it would bring forward changes to the legislation.

The UK Government published its response to the consultation on March 21, 2023 confirming that it would bring forward changes to the legislation and such changes were laid in parliament on December 12, 2024.

These resulting legislative amendments will, if implemented in their current form, bring the UK into closer alignment with the CTR.

In October 2023, the MHRA announced a new Notification Scheme for clinical trials which enables a more streamlined and risk-proportionate approach to initial clinical trial applications for Phase 4 and low-risk Phase 3 clinical trial applications.

Marketing authorizations in the United Kingdom are governed by the Human Medicines Regulations (SI

2012/1916), as amended.

Since January 1, 2021, an applicant for the EU’s centralized procedure marketing

authorization can no longer be established in the United Kingdom.

As a result, since this date, companies

established in the United Kingdom cannot use the EU’s centralized procedure.

In order to obtain a United

Kingdom MA to commercialize products in the United Kingdom, an applicant must be established in the

United Kingdom and must follow one of the United Kingdom national authorization procedures or one of the

remaining post-Brexit international cooperation procedures.

Applications are governed by the Human

Medicines Regulations (SI 2012/1916) and are made electronically through the MHRA Submissions Portal.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, a 150-day assessment (subject to clock-stops) and a rolling review procedure.

The rolling-review procedure permits the separate or joint submission of quality, non-clinical, and clinical data to the MHRA which can be reviewed on a rolling basis.

After an application under the rolling-review procedure has been validated, the decision should be received within 100 days (subject to clock-stops).

In addition, since January 1, 2024, the MHRA may rely on the International Recognition Procedure (“IRP”),

when reviewing certain types of MAAs.

Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (e.g., the regulatory in Australia, Canada, Switzerland,

Singapore, Japan, the U.S.A.

The MHRA will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust.

The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update a MA in the United Kingdom.

Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60 day period and the approval from the trusted regulatory partner selected has been granted within the previous 2 years or if there are such major objections identified or such approval hasn’t been granted within the previous 2 years within 110 days.

Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals.

There is no pre-marketing authorization orphan designation for medicinal products in the UK.

MHRA reviews applications for orphan designation in parallel to the corresponding marketing authorization

The criteria are essentially the same as those in the EU, but have been tailored for the market.

This includes the criterion that prevalence of the condition in the United Kingdom, rather than the EU, must not be more than five in 10,000.

Upon the grant of a marketing authorization with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication.

The start of this market exclusivity period will be set from the date of first approval of the product in the United Kingdom.

For other countries outside of the European Union, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

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Employees and Human Capital

As of January 31, 2024, we had 74 employees, all of whom were full time, consisting of clinical, research, operations, regulatory, finance and business development personnel.

Thirty-two of our employees hold Ph.D.

Our commitment to innovation begins with the dedication to creating an environment that attracts and retains highly skilled people, including top scientific talent.

This is a critical factor for us in delivering on our mission and creating value for our stakeholders.

We have grown significantly since our initial public offering in November 2020 and have since built a diverse organization, both in our Board of Directors where three global biotech female leaders are seated, and across our employee base.

We have been successful in hiring employees with broad experience and backgrounds while facing significant competition for biotechnology talent from both established and early-stage biotechnology companies.

Further, we are headquartered in the San Francisco Bay area and have operations in Cambridge, Massachusetts - both of which are global biotechnology hubs with many employment choices.

Despite the competition, we have been successful in hiring highly qualified staff to join Olema.

As of January 31, 2025, we had 96 employees, all of whom were full time, consisting of clinical, research, operations, regulatory, and administrative personnel.

Twenty eight of our employees hold Ph.D.

41% of our employee population is male and 59% is female.

None of our employees is subject to a collective bargaining agreement.

We consider our relationship with our employees to be good.

Our commitment to innovation begins with the commitment to creating an environment with the ability to attract and retain highly skilled people, including top scientific talent, as a critical factor for us to deliver on our mission and create value.

As we have grown significantly since our initial public offering in November 2020, we have focused on diversity, inclusion and belonging both at the level of our Board of Directors, where we appointed three global biotech female leaders to our Board of Directors, and for all employees.

We have been successful in hiring employees with a broad diversity of experiences and backgrounds.

We face significant competition for biotechnology talent from both established and early-stage biotechnology companies.

Further, we are headquartered in the San Francisco Bay Area and have operations in Cambridge, Massachusetts, both global biotechnology hubs with many employment choices.

Despite our early stage, we have been successful in hiring highly qualified staff to join Olema.

As of January 31, 2024, 39% of our employee population is male, and 61% is female.

We strive to create a positive employee experience by fostering an inclusive and equitable culture.

We are committed to the health, safety, and well-being of our employees.

We strive to create a positive employee experience and we are committed to the health, safety, and well-being of our employees.

This commitment is reflected in our ability to attract and retain high performers.

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The principal purposes of our equity incentive plans are to attract, motivate, and retain our employees and directors through the granting of stock-based compensation awards.

From time to time, we may offer additional stock-based compensation awards to our employees to continue to motivate them and support retention, particularly at times when our stock price, or the stock price of biotechnology companies generally, is volatile.

From time to time, we may offer additional stock-based compensation awards to our employees to continue to motivate them and support retention, particularly at times when our stock price, or

the stock price of biotechnology companies generally, is volatile.

We grant stock options to all full-time employees to foster alignment and promote a spirit of ownership.

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

What changed 10-K

Item 1. Business