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Item 1. Business

2024-03-11 compared with 2023-03-09 · 239 added, 444 removed, 539 unchanged (56% 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.

Our team has spent the past decade characterizing the structure and function of the estrogen receptor, or ER, a key driver of breast cancer in approximately 75% of patients, in order to develop more potent, oral therapies that completely inactivate this signaling pathway.

Our lead product candidate, OP-1250, is a novel oral therapy with combined activity as both a complete ER antagonist, or CERAN, and a selective ER degrader, or SERD, which we believe will drive deeper, more durable responses than existing therapies.

OP-1250, both as a monotherapy and in combination with inhibitors of cyclin-dependent kinase 4 and 6, or CDK4/6, demonstrated robust anti-tumor activity in a range of preclinical xenograft models of breast cancer, including in ESR1 and PIK3CA mutations and central nervous system, or CNS, metastasis.

In August 2020, we initiated an ongoing Phase 1/2 monotherapy dose escalation and expansion study evaluating OP-1250 for the treatment of recurrent, locally advanced or metastatic ER-positive, or ER+, human epidermal growth factor receptor 2-negative, or HER2-, breast cancer.

We reported initial data from the Phase 1a dose escalation portion of this study in November 2021, which provided proof-of-concept for OP-1250 as a monotherapy treatment for ER+/HER2- breast cancer.

We reported additional monotherapy data from the Phase 1b dose expansion portion of this study in October 2022 and initiated the Phase 2 portion of the study.

In 2022, we also initiated Phase 1b/2 dose escalation and expansion studies evaluating OP-1250 in combination with CDK4/6 inhibitors palbociclib and ribociclib and phosphatidylinositol 3 kinase alpha, or PI3K a inhibitor, alpelisib.

In December 2022, we reported initial data from the Phase 1a dose escalation portion of the study in combination with palbociclib which demonstrated attractive combinability including no drug-drug interaction, or DDI, between the two agents.

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.

In clinical studies across more than 250 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 FDA, for OP-1250 for patients with ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor.

Based on the clinical results we have achieved to date, we are advancing OP-1250 through to late-stage clinical development both as a monotherapy and in combination with other targeted agents.

We own worldwide development and commercialization rights to OP-1250.

We believe OP-1250’s oral formulation and dual mechanism of action directly address the limitations of current endocrine therapies, such as fulvestrant and tamoxifen, and position OP-1250 as a potential endocrine therapy of choice for the treatment of ER+ breast cancers.

Our goal is to transform the standard of care for women living with cancers by developing more effective therapies that apply our deep understanding and collective expertise in endocrine-driven cancers, nuclear receptor activities and mechanisms of acquired resistance.

We are initially focused on developing therapies for the treatment of breast cancer, which represents approximately 30% of all new diagnoses of cancer in women.

In 2022, the American Cancer Society, or ACS, estimated there were approximately 288,000 new cases of female breast cancer and over 43,250 deaths from metastatic breast cancer in the United States.

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.

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.

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 HR+/HER2-, highlighting the central role of the ER in driving a large majority of breast cancer.

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.

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.

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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 $30.6 billion in 2030.

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

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

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Additionally, most patients with metastatic breast cancer have been shown to ultimately develop resistance to AIs, the most common of which is the development of a ligand-independent activating mutation in the estrogen receptor gene, ESR1.

AIs are also not used to treat pre-menopausal women without the addition of ovarian suppression.

In 2002, fulvestrant was approved as a treatment for hormone receptor positive, or HR+, metastatic breast cancer patients and is typically used as a second- or third-line endocrine agent.

In pre-menopausal women, treatment with AIs must also be accompanied by ovarian suppression.

In 2002, fulvestrant was approved as a treatment for HR+ metastatic breast cancer patients and is typically used as a second- or third-line endocrine agent.

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 a monthly intramuscular injection.

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.

More recently, the field has focused on the discovery and development of oral agents that have fulvestrant’s dual mechanism of action to completely inactivate and degrade the ER.

Some of these oral SERD agents are CERANs, such as OP-1250, but others have partial agonist activity despite being SERDs and thus are not CERANs.

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.

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

We designed our lead product candidate, OP-1250, based both on a detailed structural understanding of the ER and on known alterations to this structure induced by fulvestrant and other ligands.

We have demonstrated in nonclinical studies that OP-1250 functions both as a CERAN and a SERD, but is distinguished from fulvestrant in several noteworthy ways, including:

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

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

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

Based on these differences, we believe that OP-1250 has the potential to demonstrate clinical outcomes superior to fulvestrant.

Furthermore, OP-1250 has the potential to benefit patients with metastatic breast cancer, initially for patients who have previously received endocrine therapy, as well as those who are treatment naïve in the metastatic setting, and advance into the adjuvant setting for early-stage ER+ breast cancer.

In multiple nonclinical animal models of anti-cancer activity, including patient-derived xenografts with tumors containing activating mutations in the ER, OP-1250 monotherapy led to tumor shrinkage or in some cases tumor eradication, as well as long-term post-treatment survival.

In each of these nonclinical models, the effect of OP-1250 was superior to that of fulvestrant, an effect which we determined was driven both by improved pharmacokinetics, or PK, properties, and higher plasma and tumor drug concentrations.

In nonclinical studies, OP-1250 demonstrated robust CNS penetration, and in an intracranial breast cancer brain metastases xenograft study, OP-1250 demonstrated the ability to shrink tumors and improve survival in mice.

the potential to address a critical unmet medical need as 10-15% of ER+ breast cancer patients develop brain metastases for which there are currently limited treatment options.

In addition, we believe that combining OP-1250 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 OP-1250 to HER2 inhibitors improved tumor growth inhibition in both ER+/HER2+ cell line-derived xenograft and patient-derived xenograft models.

As summarized in our pipeline figure below, our plan is to develop our wholly-owned lead product candidate, OP-1250, in a number of ER+ breast cancer indications, both as a monotherapy and in combination with approved targeted therapies that have shown improved outcomes with other endocrine therapies.

Olema product pipeline

In August 2020, we initiated a Phase 1/2 clinical study of OP-1250 in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer whose disease has progressed on endocrine therapy.

Phase 1a consisted of monotherapy dose escalation to evaluate the safety and PK of OP-1250 and to determine the maximum tolerated dose, or MTD, and/or the recommended Phase 2 dose, or RP2D.

In November 2021, we reported interim Phase 1a data, with OP-1250 demonstrating attractive PK with oral bioavailability and dose-proportional exposures supporting once daily dosing;

favorable tolerability with no maximum tolerated dose defined, and no clinically significant bradycardia, ocular toxicity or diarrhea;

and evidence of single-agent activity in patients who had advanced on multiple prior therapies in the advanced setting, including CDK4/6 inhibitors, and confirmed partial responses in patients with baseline estrogen receptor 1, or ESR1, activating mutations.

In 2022, we completed enrollment in our Phase 1b dose expansion at two dose levels (60 mg and 120 mg daily) and selected 120 mg daily as our RP2D to advance into Phase 2 efficacy evaluation.

Phase 2 efficacy

evaluation initiated in the second half of 2022 with approximately 80 patients expected to be enrolled across three cohorts:

patients with measurable disease (n=50), patients with non-measurable disease (n=15), and patients with CNS metastasis (n=15).

The first two primary cohorts, patients with measurable disease and patients with non-measurable disease, were fully enrolled in the fourth quarter of 2022.

In October 2022, we reported preliminary Phase 1b clinical data at the 34 th EORTC-NCI-AACR Symposium, with OP-1250 demonstrating attractive PK with oral bioavailability and high drug exposure, supporting once daily dosing;

favorable tolerability with no dose-limiting toxicities and no maximum tolerated dose defined;

and strong anti-tumor activity and durable benefit with 41% of patients seeing reductions in target tumor lesions, a 39% clinical benefit rate, or CBR, at our RP2D of 120 mg (seven out of 18 CBR-eligible patients) and six partial responses (four confirmed and two unconfirmed) out of 57 efficacy-evaluable patients.

We believe that with this profile, OP-1250 has the potential to become the endocrine therapy of choice for the treatment of ER+/HER2- breast cancer.

We anticipate presenting Phase 2 clinical data for OP-1250 as a monotherapy in the second half of 2023.

Based on our clinical results to date, we intend to discuss plans to initiate a pivotal Phase 3 monotherapy trial in second- and third-line advanced or metastatic breast cancer patients at an End of Phase 2 meeting with the FDA and the European Medicines Agency, or EMA, prior to initiating such trial in what we expect to be the second half of 2023.

In January 2022, we initiated a Phase 1b dose escalation study evaluating OP-1250 in combination with the CDK4/6 inhibitor palbociclib for the treatment of recurrent, locally advanced or metastatic ER+/HER2 breast cancer.

We presented preliminary results from this Phase 1b study in December 2022 at the 2022 San Antonio Breast Cancer Symposium.

Across 12 patients, the combination of up to 120 mg of OP-1250 with 125 mg of palbociclib was shown to be well tolerated with no DDI, no induced metabolism of palbociclib, and exposure of OP-1250 in combination with palbociclib was consistent with the observed monotherapy OP-1250 exposure levels.

In addition, there was no dose-related increase in the incidence or severity of adverse events, and neutropenia events observed were consistent with the expected profile of palbociclib plus an endocrine therapy.

In the third quarter of 2022, we initiated the Phase 2 dose expansion portion of this study with 120 mg of OP-1250 in combination with 125 mg of palbociclib.

We anticipate presenting results from this Phase 2 study in the second quarter of 2023.

Concurrently, in the third quarter of 2022, we initiated a Phase 1b dose escalation study of OP-1250 in combination with CDK4/6 inhibitor, ribociclib, and PI3K a inhibitor , alpelisib, which have both been shown to lead to improvements in both progression-free and overall survival.

These studies are ongoing and we anticipate presenting data from the Phase 1b clinical study for OP-1250 in combination with ribociclib in the second half of 2023.

In July 2022, we were granted Fast Track designation from the FDA for OP-1250 for the treatment of ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor.

In July 2020, we entered into a non-exclusive agreement with Novartis Institutes for BioMedical Research, Inc., or Novartis, to evaluate the combination of OP-1250 and Novartis’ KISQALI® (ribociclib), a CDK4/6 inhibitor, as well as PIQRAY® (alpelisib), their PI3K a inhibitor.

Under the terms of the collaboration, Novartis will be responsible for funding a capped majority of the costs for the Phase 1b clinical study, as well as supplying their drugs.

In November 2020, we entered into a non-exclusive agreement with Pfizer Inc., or Pfizer, to evaluate the safety and tolerability of OP-1250 in combination with Pfizer’s CDK4/6 inhibitor IBRANCE® (palbociclib) in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer.

Under the terms of the non-exclusive agreement, we will be responsible for conducting the clinical study for the combined therapy and Pfizer is responsible for supplying IBRANCE® (palbociclib) at no cost to us.

As part of the collaboration, the parties granted to each other a non-exclusive, royalty- free license under certain of the parties’ respective patent rights in the combination of IBRANCE® and OP-1250 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.

All inventions and data developed in the performance of the clinical trials for the combined therapies (other than those specific to each component study drug), will be jointly owned by the parties.

We expect to present additional monotherapy and combination therapy data in 2023 and initiate a pivotal Phase 3 monotherapy trial of OP-1250 in the second- and third-line settings of ER+/HER2- advanced or metastatic breast cancer in the second half of 2023, subject to feedback from the FDA and EMA.

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.

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.

We own worldwide development and commercialization rights to palazestrant.

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.

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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 OP-1250’s oral formulation and dual mechanism of action as a CERAN/SERD directly address the limitations of current endocrine therapies, such as fulvestrant and tamoxifen, and has the potential to drive deeper, more durable responses.

● Rapidly advancing our lead product candidate, OP-1250, through clinical development as a monotherapy for ER+/HER2 breast cancer.

We are currently evaluating OP-1250 monotherapy in a Phase 1/2 dose escalation and expansion clinical study in patients with recurrent, locally advanced or metastatic ER+/HER2 breast cancer whose disease has progressed on endocrine therapy.

We plan to initiate a pivotal Phase 3 trial for OP-1250 as a monotherapy agent in the second- and third-line setting of ER+/HER2- advanced or metastatic breast cancer in the second half of 2023, subject to feedback from the FDA and EMA.

● Establishing OP-1250 as the endocrine therapy of choice with targeted therapy combinations for the treatment of metastatic ER+ breast cancers.

We believe OP-1250’s differentiated product profile has the potential to overcome many of the limitations of current endocrine therapy options.

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.

• 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.

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.

Our goal is to successfully demonstrate improved efficacy and a favorable tolerability profile in combination with other targeted therapies in order to position OP-1250 as the endocrine therapy of choice in the first-line setting for advanced or metastatic ER+/HER2- breast cancer.

● Exploring additional clinical opportunities for OP-1250, including metastatic breast cancer with brain metastases and other hormone sensitive tumors.

Our goal is to successfully demonstrate improved efficacy and a favorable tolerability profile in combination with other targeted therapies to position palazestrant as the endocrine therapy of choice in the first-line setting for advanced or metastatic ER+/HER2- breast cancer.

• Exploring additional clinical opportunities for palazestrant, including metastatic breast cancer with brain metastases and other hormone sensitive tumors.

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

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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, the addition of OP-1250 to HER2 inhibitors improved tumor growth inhibition in both ER+/HER2+ cell line-derived xenograft and patient-derived xenograft models.

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 OP-1250.

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 OP-1250.

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

We own full worldwide development and commercialization rights to 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.

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.

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.

Olema product pipeline

Our Opportunity

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

In 2022, the ACS estimated there were approximately 288,000 new cases of female breast cancer and over 43,250 deaths in the United States, making it the second-leading cause of cancer death in women.

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.

Approximately 2,700 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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Approximately 78% of all breast cancers are HR+, and approximately 68% are HR+/HER2-, highlighting the central role of ER signaling in driving a large majority of breast cancer.

The percentage breakdown of all breast cancers by subtype are shown in Figure 2.

Types of breast cancer

Treating breast cancer

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In addition, approximately 20-30% of patients diagnosed with early-stage breast cancer will develop metastatic disease.

In contrast to the goals of

adjuvant therapy, treatments for metastatic disease are palliative with the desired outcome of controlling symptoms and extending survival as long as possible.

In contrast to the goals of adjuvant therapy, treatments for metastatic disease are palliative with the desired outcome of controlling symptoms and extending survival as long as possible.

The current five-year survival rate for patients with ER+ metastatic breast cancer is approximately 30%.

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Figure 2 shows the endocrine treatment options available for ER+ metastatic breast cancer, and an example of the sequence of treatments, by agent and line of therapy.

Available endocrine options and example of sequential alternating of endocrine

based therapy in ER+ metastatic breast cancer

Available endocrine options and example of sequential alternating of endocrine based therapy in ER+ metastatic breast cancer

When moving a patient from one line of therapy to the next, the standard of care is to switch to an endocrine agent with a different mechanism of action depending upon last therapy, co-morbidities, and individual patient characteristics.

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

ER is a tripartite protein with two distinct transcription factor activation domains,

Classes of endocrine therapies and their limitations

For more than four decades, researchers have been developing new approaches and therapies to prevent activation of the ER pathway, thereby inhibiting the ability of the ER to drive tumor cell growth.

Figure 5 describes the two major classes of endocrine therapies, AIs and ER antagonists.

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.

Classes of endocrine therapies

Antagonists with partial agonist activity

In 1977, the first endocrine therapeutic, tamoxifen, was approved by the FDA for the treatment of breast cancer.

Although tamoxifen 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 6).

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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In the search for more potent ER antagonists, researchers focused on another class of ER drugs that were described as SERDs.

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

leading to ER degradation.

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.

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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 Product Candidate

We own worldwide development and commercialization rights to OP-1250.

Our plan is to develop OP-1250 for the treatment of a number of ER+ breast cancer indications, both as a monotherapy and in combination with approved targeted therapies that have shown improved outcomes with other endocrine therapies.

Our solution, OP-1250

OP-1250 is an oral small molecule clinical-stage product candidate for the treatment of endocrine-driven cancers.

OP-1250 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 OP-1250 functions both as a CERAN, inactivating both AF1 and AF2 transcriptional activation functions, and a SERD, promoting degradation of the ER.

Our Lead Product Candidate - Palazestrant

We own worldwide development and commercialization rights to palazestrant.

Our plan is to develop palazestrant for the treatment of a number of ER+ breast cancer indications, both as monotherapy and in combination with approved targeted therapies that have shown improved outcomes with other endocrine therapies.

Palazestrant is an oral small molecule clinical-stage product candidate for the treatment of endocrine-driven cancers.

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 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).

The trial is expected to enroll approximately 510 second/third-line metastatic breast cancer patients randomized one-to-one with either palazestrant or standard-of-care endocrine therapy.

Key inclusion criteria for the trial include evaluable disease and prior exposure to endocrine therapy in combination with a CDK4/6 inhibitor in the advanced setting.

One additional line of endocrine therapy in the advanced or metastatic setting is permitted.

The trial consists of two parts:

a three-arm dose selection part followed by assessment of the selected dose of palazestrant versus standard of care.

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

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

Phase 2 monotherapy clinical study

Our Phase 1/2 monotherapy clinical development plan for OP-1250 is outlined in Figure 8 below.

We initiated the Phase 1a dose escalation portion of our Phase 1/2 monotherapy clinical study in July 2020 and reported initial results across 41 patients in November 2021.

In December 2021, we initiated the Phase 1b dose expansion portion of our monotherapy clinical development plan by expanding enrollment at two doses of 60 mg and 120 mg once daily.

We enrolled a total of 68 patients across these two doses through the end of July 2022 and reported interim results in October 2022.

In the third quarter of 2022, we selected 120 mg as our recommended Phase 2 dose, or RP2D, and initiated enrollment in the Phase 2 portion of our monotherapy study including targeting a total enrollment of 50 patients with measurable disease, 15 patients with non-measurable disease, and 15 patients with CNS metastasis.

Our first two primary cohorts of 50 patients with measurable disease and 15 patients with non-measurable disease were fully enrolled in the fourth quarter of 2022.

Design of the Phase 1/2 OP-1250-001 monotherapy study for OP-1250

* Fully-enrolled.

Phase 1a dose-escalation results

We reported the first clinical data from the Phase 1a dose-escalation portion of the ongoing Phase 1/2 clinical study of OP-1250 in November 2021, with a data cut-off of November 1, 2021.

These initial data provide proof-

of-concept for OP-1250 as a once-daily oral monotherapy in women with recurrent, locally advanced or metastatic ER+/HER2- breast cancer.

PK, safety, tolerability, and anti-tumor activity of once-daily OP-1250 monotherapy were evaluated in the open-label, dose-escalation portion of the ongoing Phase 1/2 clinical study (NCT04505826).

As of November 1, 2021, a total of 41 patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer were enrolled across seven dose cohorts (30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 210 mg, and 300 mg once-daily).

This was a heavily pretreated population with 95% of patients previously treated with a CDK4/6 inhibitor (nine patients, or 22%, received two or more prior CDK4/6 inhibitor regimens), 68% of patients received prior fulvestrant, and 42% received prior chemotherapy in the advanced setting.

Overall, patients received a median of three prior lines of anti-cancer therapy and two prior lines of endocrine therapy in advanced settings.

Of 39 patients whose circulating tumor DNA, or ctDNA, was assessed, ESR1 mutations were detected in 49% at baseline.

PK analyses demonstrated dose-proportional increases in OP-1250 exposures across all evaluated doses, high oral bioavailability and steady-state plasma levels with minimal peak-to-trough variability.

OP-1250 was generally well tolerated, and no dose-limiting toxicities were reported at any of the seven dose levels studied.

A maximum tolerated dose was not reached.

The majority of reported adverse events were grade 1 or 2 at all dose levels, and the most common treatment-related adverse events, or TRAEs, as assessed by study investigator were nausea (49%), fatigue (34%), vomiting (22%) and headache (17%).

No clinically significant bradycardia, ocular toxicities or diarrhea occurred.

As of the data cut-off of November 1, 2021, three patients had grade 4 neutropenia attributed to study drug by the investigator.

Two of these patients presented with fever and neutropenia.

A RP2D range of 60 mg to 120 mg was identified for further evaluation based on PK, favorable tolerability, and initial evidence of anti-tumor activity.

Early evidence of anti-tumor activity was observed in patients across all dose levels tested in the Phase 1a dose escalation portion of the study.

Patients were scheduled for tumor assessments at eight-week intervals.

Patients were considered efficacy-evaluable for overall response rate, or ORR, if they had response evaluation criteria in solid tumors, or RECIST,-measurable disease at baseline and at least one post-baseline tumor assessment or discontinued treatment prior to their first post-baseline assessment, and for CBR if they were enrolled at least 24 weeks prior to the data cut-off date.

As of the data cut-off date of November 1, 2021, three partial responses were observed among 24 efficacy-evaluable patients, including two confirmed partial responses and one unconfirmed partial response.

The patient with the unconfirmed partial response demonstrated robust target lesion reduction of 100% but remained unconfirmed due to progressive disease with a new lesion appearing at a follow-up visit.

All three responses occurred in patients with ESR1 mutations and who had previously received CDK4/6 and aromatase inhibitors, and fulvestrant.

As of the data cut-off date, 32% of patients (13/41) remained on treatment with efficacy data continuing to mature, including both patients with confirmed partial responses.

Phase 1b/2 monotherapy dose expansion clinical study

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

The results continued to demonstrate that at doses of 60 mg and 120mg once daily, OP-1250 is well-tolerated, achieves high drug exposure, and has encouraging anti-tumor activity across both wild-type and ESR1 mutant tumors.

PK, safety, tolerability, and anti-tumor activity of once-daily OP-1250 monotherapy were evaluated in the ongoing Phase 1/2 clinical study (NCT04505826).

As of September 2, 2022, 68 patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer were treated across two doses of 60 mg and 120 mg orally once per day.

This group was heavily pretreated with 69% having received 2 or more prior lines of therapy and 32% having received prior chemotherapy in the advanced setting.

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.

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

Of 46 patients whose ctDNA was assessed, 59% had activating mutations in ESR1 at baseline.

We anticipate presenting Phase 2 clinical data for OP-1250 as a monotherapy in the second half of 2023.

Baseline patient characteristics for OP-1250 monotherapy Phase 1b expansion study

Pharmacokinetics

OP-1250 demonstrated favorable PK characterized by high oral bioavailability and dose proportional exposure.

With an approximately 8-day half-life, OP-1250 exhibited the desired low peak-to-trough variability in a 24-hour period at steady state, supporting once daily dosing with complete inhibition of the ER for the full dosing interval.

A RP2D of 120 mg once per day orally was selected based on overall PK, tolerability and efficacy.

Dosing at the RP2D yielded drug exposure that exceeded targeted efficacy thresholds based on pre-clinical models.

OP-1250 steady-state plasma concentration-time profiles

Treatment with OP-1250 was well tolerated at both the 60 mg and 120 mg dose levels with no dose-limiting toxicities.

The most common TRAEs that occurred in at least 15% of subjects as assessed by the treating physician were nausea (42%), fatigue (25%) and vomiting (15%).

Of the 68 patients treated, one patient experienced Grade 3 neutropenia concurrent with progressive disease, and three patients experienced Grade 4 neutropenia at the 120 mg dose.

Of these cases, one patient had dosing interrupted for one week, restarted therapy at 60 mg and subsequently had a confirmed response with no further incidence of neutropenia.

The two other patients discontinued treatment with recovery of their neutrophil counts.

These events have occurred at a low rate and are manageable and reversible.

Treatment-related adverse events for OP-1250 monotherapy Phase 1b expansion study

Six partial responses across the two doses had been observed as of the data cut-off date of September 2, 2022 among 57 efficacy-evaluable patients (per RECIST measurable lesions and at least one on-treatment tumor assessment), including four confirmed partial responses and two unconfirmed partial responses awaiting confirmation at a follow-up scan.

Strong anti-tumor activity was observed with 41% of patients demonstrating reduction in target lesions and evidence of activity in both wild-type and mutant estrogen receptors across both doses.

As of the data cut-off date , 31% of patients (21/68) remained on treatment with efficacy data continuing to mature.

Meaningful anti-tumor activity in OP-1250 Phase 1b dose expansion study

a Patient had an unconfirmed partial response and later progressed at a subsequent scan.

b Dark shaded boxes indicate ESR mutation present, light shaded boxes indicate wild-type, and the absence of a box indicates missing data.

AI, aromatase inhibitor;

CDK4/6i, CDK4/6 inhibitor;

Chemo, chemotherapy;

Fulv, fulvestrant;

PD, progressive disease;

PR, partial response;

QD, once daily;

SD, stable disease;

uPR, unconfirmed partial response.

Treatment duration and response for OP-1250 Phase 1b monotherapy dose expansion

b Solid boxes indicate ESR mutation present, open boxes indicate wild-type, and the absence of a box indicates missing data.

*Unconfirmed partial responses awaiting confirmation at a subsequent scan.

AI, aromatase inhibitor;

CDK4/6i, CDK4/6 inhibitor;

Chemo, chemotherapy;

Fulv, fulvestrant;

PD, progressive disease;

PR, partial response.

Phase 1b/2 combination dose escalation and expansion clinical studies

Our clinical development strategy for OP-1250 includes exploring the potential for combination treatment of advanced or metastatic breast cancer with other targeted therapies.

We are initially focused on exploring the potential for OP-1250 in combination with CDK4/6 inhibitors palbociclib and ribociclib and PI3K a inhibitor, alpelisib.

In December 2021, we initiated the Phase 1b dose escalation portion of our Phase 1b/2 combination clinical study in combination with palbociclib and reported preliminary results in December 2022.

We are currently enrolling patients in the Phase 2 dose expansion portion of this study.

We anticipate presenting results from this Phase 2 clinical study in the second quarter of 2023.

In the third quarter of 2022, we initiated the Phase 1b dose escalation portion of our Phase 1b/2 combination clinical study in combination with both ribociclib and alpelisib.

We anticipate presenting data from the Phase 1b clinical study for OP-1250 in combination with ribociclib in the second half of 2023.

Phase 1b/2 combination dose escalation and expansion clinical study with palbociclib

In December 2021, we initiated a Phase 1b/2 clinical study of OP-1250 in combination with palbociclib, a CDK4/6 inhibitor.

We reported preliminary clinical data from the Phase 1b dose escalation portion of the clinical study in December 2022 at the 2022 San Antonio Breast Cancer Symposium in San Antonio, Texas.

The preliminary results demonstrated attractive combinability with no dose-limiting toxicities, no dose-related increase in the incidence or severity of adverse events and no DDI with exposure levels of each drug consistent with monotherapy or standard of care combinations.

As of the data cut-off of September 12, 2022, 12 patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer were treated across four dose escalation cohorts:

three patients per cohort dosed at 30, 60, 90, and 120 mg in combination with palbociclib 125 mg.

Ten of the 12 patients received prior therapy for advanced disease, including eight patients who had received prior CDK4/6 inhibitors and nine patients who received prior endocrine therapy for advanced disease.

Of 11 patients whose ctDNA was assessed, 36% had activating mutations in ESR1 at baseline.

Baseline patient characteristics from Phase 1b study in combination with palbociclib

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

Pharmacokinetics

OP-1250 demonstrated favorable PK 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 ER for the full dosing interval.

There was no observed DDI between palbociclib and OP-1250 in the dose range of 30 mg to 120 mg.

Palbociclib did not affect OP-1250 drug exposures compared to monotherapy dosing, and OP-1250 had no effect on palbociclib 125 mg drug exposures when compared to published concentrations.

Steady state C max of OP–1250 combination vs.

Steady state AUC (0-24) of OP-1250 combination vs.

Steady state AUC 0-24 and C max of palbociclib vs.

published concentrations

Treatment with OP-1250 up to the RP2D of 120 mg was well tolerated with no dose-limiting toxicities, and maximum tolerated dose, or MTD, was not reached.

The majority of treatment-emergent adverse events, or TEAEs, were Grade 1 or 2 and increasing the dose did not show an increase in frequency of events.

OP-1250 was not dose-reduced in any patients, and no patients discontinued treatment with OP-1250 due to an adverse event, including neutropenia.

Neutropenia events observed were consistent with the expected profile of palbociclib plus an endocrine therapy.

There was no Grade 4 neutropenia, and eight of 12 patients reported Grade 3 neutropenia, a rate which is consistent with the FDA-approved label of palbociclib plus an endocrine agent.

Treatment-emergent adverse events for OP-1250 in combination with palbociclib

Treatment duration and response for OP-1250 Phase 1b in combination with palbociclib

Clinical development plan for OP-1250 and additional clinical opportunities

In the third quarter of 2022, we selected 120 mg once daily as the RP2D.

We completed enrollment in the two primary cohorts of our Phase 2 monotherapy expansion study in the fourth quarter of 2022 (50 patients with measurable disease and 15 patients with non-measurable disease) at the RP2D.

Based on our clinical results to date, we are actively planning to initiate a monotherapy pivotal Phase 3 trial in the second half of 2023 in the second- and third-line setting for locally advanced or metastatic ER+/HER2- breast cancer, subject to feedback from the FDA and EMA.

We are currently exploring the potential for OP-1250 to combine with CDK4/6 inhibitors palbociclib and ribociclib in Phase 1b/2 dose escalation and expansion studies.

Subject to positive results from these ongoing studies, we anticipate initiating a pivotal Phase 3 clinical trial in combination with a CDK4/6 inhibitor in 2024 for the treatment of advanced or metastatic ER+/HER2- breast cancer in the first-line setting.

While all populations described above are in patients with ER+/HER2- breast cancer, we believe that there is an opportunity for us to study OP-1250 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.

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.

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

Of these patients, three had a dose interruption with recovery and subsequent dose reduction (two continued at 90 mg and one continued at 60 mg) without any recurrence, and three had dose discontinuation followed by recovery.

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%.

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%.

In ESR1 wild-type patients, the median PFS was 3.5 months and the CBR was 32% with a 6-month PFS rate of 35%.

In a subset analysis of 49 patients that received palazestrant as a second- or third-line therapy with or without prior chemotherapy, the median PFS was 7.2 months and the CBR was 48% across all patients with a 6-month PFS rate of 54%.

In patients with an ESR1 mutation, the median PFS was 7.3 months and CBR was 59% with a 6-month PFS rate of 62%.

In ESR1 wild-type patients the median PFS was 5.5 months and the CBR was 38% with a 6-month PFS rate of 44%.

Anti-tumor activity was observed in this heavily pretreated population, with 40% of patients demonstrating reduction in target lesions and evidence of activity in both ESR1 wild-type and ESR1-mutant patients.

Given the advanced and heavily pretreated nature of the patients, many of these patients are expected to be resistant to monotherapy endocrine treatment.

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.

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.

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.

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.

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.

Most treatment-emergent adverse events were grade 1 or 2.

Neutropenia incidence was similar to the PALOMA-3 study;

it was reversible in all patients and the timing was generally consistent with the palbociclib-related neutropenia.

Tumor responses and prolonged disease stabilization were observed in this patient group, including in those previously exposed to CDK4/6 inhibitors, in both ESR1 mutant and ESR1 wild-type tumors.

Partial responses were observed in seven patients, with two confirmed partial responses and five unconfirmed partial responses.

The clinical benefit rate was 46% in all patients and 60% in patients with an ESR1 mutation at baseline.

In patients naïve to prior CDK4/6 inhibitor treatment, the CBR was 71%.

53% of patients had any reduction in target lesion size.

Twenty-two (48%) patients remained on treatment, and efficacy data were still maturing.

Findings from this study were consistent with previously reported data and support the ongoing clinical development of palazestrant in combination with CDK4/6 inhibitors for the treatment of ER+/HER2− metastatic breast cancer.

Enrollment of sixty patients in the Phase 2 portion of the palazestrant-palbociclib combination clinical study is complete.

Clinical development plan for palazestrant and additional clinical opportunities

Everolimus, an mTOR inhibitor, is a targeted therapy that is often used by oncologists in the treatment of advanced breast or other cancers.

Clinical studies evaluating everolimus in combination with endocrine therapies 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.

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.

In particular, up to 50% of patients with metastatic HER2+ breast cancer develop CNS disease.

We believe that combining OP-1250 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.

We are conducting a series of pharmacology studies for OP-1250, including DDI fed/fast and bioequivalence to a tablet formulation, and expect to complete these studies in 2023.

We believe that the conversion from

capsule to tablet formulation of OP-1250 may have certain clinical advantages and we expect to transition to tablet administration prior to initiation of a pivotal trial in what we expect to be the second half of 2023.

While our initial studies are focused on treating breast cancer patients with metastatic disease, we believe that if OP-1250 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 OP-1250 could have superior PK properties and improved clinical outcomes than fulvestrant.

If proven in the clinic, we believe that OP-1250 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.

In addition to breast cancer, we intend to explore the use of OP-1250 in various gynecological malignancies, beginning with endometrial cancer.

Approximately 80% of endometrial tumors are “endometriod” in nature and these tumors are driven by estrogen.

Nonclinical data

Complete ER antagonism

A key distinguishing feature of CERANs is that they completely lack any agonistic estrogen-like effects, and completely block the effects of estrogen.

In a nonclinical model, we evaluated OP-1250 and other compounds with publicly-disclosed chemical structures that have been or are in clinical development for ER+ breast cancer to compare their ability to block breast cancer proliferation and degrade estrogen receptors.

Alkaline phosphatase, or AP, is an estrogen-responsive gene in ECC-1 cells driven by AF1 action.

The in vitro AP model is a method of determining complete ER antagonism.

As shown in Figure 20 below, OP-1250 and other CERANs lack agonistic estrogen like effects and completely block the effects of estrogen.

In the absence of estrogen, OP-1250 and other CERANs completely inactivated AF1 and did not stimulate AF1-dependent AP activity.

In the presence of estrogen, OP-1250 and other CERANS demonstrated complete antagonism while non-CERANs were unable to fully inhibit estrogen-stimulated AF-1 activity.

CERANs do not activate AF1 in the absence of estrogen, and partial and strong agonists

do not fully inhibit estrogen-stimulated AF-1 activity

SERD activity

SERDs are ER ligands that lead to partial degradation of the ER.

This degradation takes place within four hours after exposure of cells to the SERD, indicating that it comes from destabilization of the ER protein.

nonclinical analysis, we have tested the ability of OP-1250, fulvestrant, other CERANs and several non-CERAN SERDs to degrade ER across five different cell lines.

As shown in Figure 21, after treatment of these cell lines for four hours, OP-1250 and other CERANs strongly degraded the estrogen receptor in all five ER+ cell lines, while non-CERANS demonstrated variable and inconsistent ER degradation.

Of note, Estradiol, or E2, the prototypical agonist of ER a , degraded ER a in all five ER+ cell lines.

In all cases, none of the compounds achieved full ER degradation, further supporting our belief that complete ER antagonism is independent from degradation and key to inactivating any remaining ER receptor.

CERAN/SERDs and SERM/SERDs are strong degraders of ER α across multiple cell lines

Immunoblot of ERa across multiple ER+ cell lines.

Cells were incubated with 300nM compounds for 4h in estrogen-depleted media.

Shown here are the densitometry results of the immunoblot showing ER ⍺ protein levels relative to vehicle-treated cells after normalizing ER ⍺ to actin.

Potent anti-proliferative activity

In nonclinical studies, we found that OP-1250 was a potent inhibitor of proliferation in multiple breast cancer cell lines.

As shown in Figure 22 below, in a cell proliferation assay using CAMA-1 cells, a human breast cancer line, OP-1250 and other CERANs inhibited estrogen-driven proliferation to a greater degree than non-CERANs.

OP-1250 and CERANs more completely block estrogen-driven breast cancer proliferation than non-CERANs

Proliferation of CAMA-1 breast cancer cells treated with antiestrogens for 6-8 days in the presence of 100pM E2 in E2-depleted media.

Cell number was approximated using a DNA-binding dye.

Shown are mean values normalized to E2 from 3 independent experiments.

Potent antagonist activity on both wild-type and mutant ER

Treatment of breast cancers with AI therapy has been shown to lead to the development of resistance mutations in the ESR1 gene.

These mutations are acquired during treatment and are found in less than 2% of untreated early- stage breast tumors but in 30-40% of metastatic tumors after treatment with AIs.

More than 80% of mutations are found at three locations corresponding to amino acid residues 380, 537 and 538.

These mutations result in resistance to many estrogen therapies.

We assessed the ability of estrogen compounds to inhibit ER-dependent transcription in cell lines containing ER alleles with mutations that have been found in patients.

We used alkaline phosphatase, which is encoded by a gene activated by the ER primarily through the AF1 transcriptional activation function and has an enzymatic activity that can be readily measured in cells, as a surrogate for ER driven target gene transcription.

We tested two clinical stage SERD compounds:

ARN-810, also known as GDC-0810, a discontinued compound previously in Phase 2 clinical development by Genentech;

and AZD9496, an AstraZeneca compound that has presented Phase 1 data.

compounds were unable to fully inhibit the activity of the mutant ER.

At the highest concentrations tested of approximately 1 μM, these compounds were unable to fully inhibit the alkaline phosphatase activity stimulated by the D538G mutation and had no activity in cells containing the Y537S mutation.

In contrast, both OP-1250 and fulvestrant were able to fully inhibit the alkaline phosphatase activity in cells containing these mutations.

These observations suggest that tumors that become resistant to other estrogen therapies may remain sensitive to OP-1250.

Both OP-1250 and fulvestrant inhibit the activity of the ER containing mutations

that commonly arise in breast cancer patients treated with other antiestrogen therapies

AP activity mediated by Y537S and D538G mutant ER a in an endometrial cell line.

AP activity was assayed by treating transiently transfected Ishikawa cells with ligands in E2-depleted media for 3 days.

Absorbance was read after incubation with a chromogenic substrate for AP.

Shown are mean values normalized to vehicle, along with SEM from triplicate wells.

The line labeled “endogenous” represents the mean AP activity of cells transfected with an empty vector, indicating the AP activity of the endogenous receptor.

ARN-810, also known as GDC-0810, has been discontinued by Genentech.

Potent tumor shrinkage in nonclinical models

OP-1250 shrank or eliminated tumors in a wide variety of xenograft models including in an ovariectomized mouse breast cancer model designed to mimic the endocrine environment of post-menopausal women using HCI- 013EI, an estrogen-independent patient-derived xenograft model containing a Y537S mutation.

In this model, tumor growth occurred even in the absence of estrogen production due to the constitutive or always-on activity of the Y537S mutant ER protein.

At daily oral doses of 3 mg/kg and higher, dosing with OP-1250 led to tumor reductions in all treated mice.

In contrast, fulvestrant led to a detectable reduction in only two of the seven treated mice.

OP-1250 has demonstrated robust tumor shrinkage in both ESR1 wild-type and mutant xenograft models

Change in tumor volume of HCI013EI patient-derived tumors, carrying the Y537S mutation in the ER and adapted to grow without estrogen, implanted in the mammary fat pad of non-obese diabetic, or NOD/SCID ovariectomized mice.

Mice were treated with oral OP-1250 at the dose indicated, or with subcutaneous fulvestrant (Faslodex preparation).

Bottom panel shows tumor size of each tumor measured with calipers at termination.

Top panel shows mean tumor size of each treatment group of 8 over the course of the study.

Change in tumor volume of various human xenograft tumors implanted in the mammary fat pad of ovary intact immunodeficient mice supplemented with estrogen releasing pellets and treated with the indicated dose of oral OP-1250, oral OP-1250 plus oral palbociclib, or subcutaneous fulvestrant (Faslodex preparation).

Bottom panel of Figure 24 shows tumor size of each tumor measured with calipers at termination.

Top panel shows mean tumor size of each treatment group of eight over the course of the study.

HCC1500, wild type ER cell line implanted in NSG mice;

ST941 patient derived xenograft, or PDX, model with Y537S ER in JAX nude mice;

HCI013 PDX model with Y537S ER in NOD/SCID mice.

Daily oral dosing with OP-1250 led to tumor shrinkage in multiple xenograft models in mice with intact ovaries.

These models included the HCC1500 cell line, which have wild-type ER and the ST941 and HCI-013 patient- derived xenograft models, both of which contain ERs that have the Y537S mutation.

Similar to what was seen in the ovariectomized mouse model, OP-1250 demonstrated more potent antitumor activity than fulvestrant, which failed to consistently shrink tumors in any of these models.

Brain penetration

There remains an unmet medical need in the treatment of patients with metastatic ER+/HER2- breast cancer that has spread to the brain.

The challenges in treating brain metastasis are multifactorial and likely include the presence of resistance mutations and the inability to achieve efficacious levels of effective drugs in brain tissue.

In mice, we found that OP-1250 reached drug levels in the brain as high as 50% greater than in plasma.

Combined with the ability to achieve higher drug levels with OP-1250, due to its improved PK properties, than

fulvestrant, we found that we could obtain brain exposure to concentrations of OP-1250 that were greater than 30 times that of fulvestrant.

OP-1250 demonstrated robust CNS penetration in the mouse brain

Concentration

Concentration (ng/mL)

Brain to Plasma Ratio

OP-1250 was dosed daily orally by gavage in the mouse.

Plasma levels were measured by HPLC.

Cranial tissue samples removed surgically, weighed, macerated, and extracted to determine the concentration of OP-1250.

OP-1250 was effective in an intracranial xenograft brain metastasis model, in which ST941 tumor cells expressing mutant ESR1-Y537S receptors were implanted directly into the brain by stereotactic surgery.

Tumors were stimulated with estrogen and allowed to grow for two or three weeks and their presence in the brain confirmed by MRI.

The mice were then treated with one of the following:

vehicle control;

vehicle control with ovariectomy;

5 mg/mouse fulvestrant;

60 mg/kg tamoxifen;

10 mg/kg OP-1250;

or 10 mg/kg OP-1250 in combination with 75 mg/kg ribociclib, a CDK4/6 inhibitor known to cross the blood brain barrier.

Mice were treated once daily for up to 100 days and followed for tumor size with MRI and survival.

As shown in the figures below, OP-1250 shrank tumors in a preclinical intracranial xenograft metastatic tumor model expressing mutant estrogen receptor ESR1-Y537S.

All tumors responded to OP-1250 treatment.

At 100 days, tumors in mice treated with 10 mg/kg OP-1250 or the combination of 10 mg/kg OP-1250 and 75 mg/kg ribociclib remained small or undetectable while tumors in mice treated with fulvestrant and tamoxifen had started to grow.

Further, treatment with OP-1250 alone or in combination with ribociclib prevented death in all animals at day 120 while the vast majority of untreated animals died by day 25.

We believe that the ability of OP-1250 to eradicate brain metastasis in mice demonstrates that OP-1250 may have the potential to advance the treatment of patients with breast cancer with brain metastases.

Treatment with 10 mg/kg OP-1250 was superior to tamoxifen, fulvestrant and ovariectomy in shrinking mutant ESR1-Y537S tumors in an intracranial model of ER+ breast cancer brain metastasis

Treatment with OP-1250 led to long-term survival in a xenograft model

of breast cancer brain metastases

Combinations with other breast cancer therapies

As in most other solid tumors, effective antitumor activity often requires the use of combination therapy.

In the case of ER+ breast cancer, for example, activation of the CDK4/6 pathway is associated with resistance to fulvestrant and CDK4/6 inhibitors are routinely used in combination with fulvestrant.

We observed that OP-1250 in combination with three different CDK4/6 inhibitors resulted in increased inhibition of MCF-7 cell proliferation as did OP-1250 in combination with the PI3K a inhibitor alpelisib in T47D cells.

The combination of OP-1250 and CDK4/6 inhibitors resulted in potent

anti-proliferative activity in MCF-7 cells

In vitro cell proliferation experiment measuring DNA content after 7-day treatment of MCF-7 breast cancer cells with ligands in the presence of 100 pM E2.

Shown are mean values normalized to vehicle (+E2), along with SEM from triplicate wells.

The combination of OP-1250 and PI3K a inhibitors resulted in potent

anti-proliferative activity in T47D cells

In vitro cell proliferation experiment measuring DNA content after 6-day treatment of T47D breast cancer cells with ligands in the presence of 100 pM E2.

Shown are increasing concentrations of alpelisib with three different concentrations of OP-1250, mean values normalized to vehicle (+E2), and SEM from triplicate wells.

ER+/HER2+ breast cancer

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

The HER2 oncogene is overexpressed in approximately 25% of breast cancer tumors, about half of which also express ER, and HER2+ tumors have a high rate of brain metastasis.

In three ER+/HER2+ cell lines, treatment with OP-1250 reversed the increase in cellular growth induced by treatment with E2 and combined effectively at some dose ranges with the HER2 inhibitor tucatinib.

OP-1250 inhibits estrogen receptor-driven proliferation in ER+/HER2+ breast cancer cell lines

Proliferation assays of three ER+/HER2+ cell lines treated for 7 days with OP-1250, tucatinib, or the equimolar combination in stripped serum media supplemented with 500 pM estradiol.

All cell lines demonstrate reduction in proliferation with OP-1250 treatment and efficacy of combined compound treatment.

OP-1250 also reduced growth of ER+/HER2+ cell lines or patient-derived xenograft models in mouse xenograft studies.

Cells were implanted either subcutaneously or in the mammary fat pad and allowed to establish a tumor prior to dosing with OP-1250 and/or HER2 inhibitors tucatinib and trastuzumab.

OP-1250 treatment demonstrated reduced tumor growth in combination with both individual HER2 inhibitors and dual HER2 therapy using both tucatinib and trastuzumab.

The addition of OP-1250 to HER2 inhibitors Tucatinib and Trastuzumab enhances tumor growth inhibition in ER+/HER2+ cell line or patient-derived xenograft models

Xenograft studies of ER+/HER2+ cell line or patient-derived xenograft (PDX) treated with OP-1250 and HER2 inhibitors.

Left, tumor volume of BT-474 cell line implanted into the mammary fat pad of NSG mice.

Right, tumor growth of CTG-3266 PDX model implanted subcutaneously into nude mice.

OP-1250 treatment inhibited growth in both models in combination with HER2 inhibitors.

Animals were dosed orally with OP-1250 and tucatinib, and by intraperitoneal injection with trastuzumab at the doses listed.

Summary of nonclinical properties

We have demonstrated in nonclinical studies that OP-1250 functions both as a CERAN and a SERD, but is distinguished from fulvestrant in several noteworthy ways, including:

● OP-1250 has favorable biodistribution properties leading to higher drug concentrations in the plasma and tumor than those achieved with fulvestrant, as shown in a head-to-head mouse xenograft study;

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

We believe OP-1250 has the potential to improve clinical outcomes for patients with metastatic breast cancer, initially for patients who have previously received endocrine therapy, as well as those who are treatment naïve in the metastatic setting.

Additionally, given the differentiated product profile, we believe that OP-1250 has the potential to advance into the adjuvant setting for early-stage ER+ breast cancer.

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.

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.

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.

KAT6 inhibition downregulates genes involved in estrogen receptor signaling and other signaling pathways.

Schematic of KAT6 biology and impact of OP-3136 inhibition

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.

The collaboration is focused on the evaluation of the safety, tolerability and efficacy of OP-1250 in combination with Novartis’ proprietary CDK4/6 inhibitor KISQALI® (ribociclib) and/or Novartis’ proprietary phosphatidylinositol 3-kinase inhibitor PIQRAY® (alpelisib), or collectively the Novartis Study Drugs, as part of our planned Phase 1b clinical study of OP-1250 in patients with metastatic ER+ breast cancer.

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

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.

1 (the “Novartis Amendment”) to Amended and Restated Clinical Collaboration and Supply Agreement with Novartis (as amended, the “Novartis Agreement”).

The collaboration is focused on the evaluation of the safety, tolerability and efficacy of palazestrant in combination with Novartis’ proprietary CDK4/6 inhibitor KISQALI® (ribociclib) and/or Novartis’ proprietary phosphatidylinositol 3-kinase inhibitor PIQRAY® (alpelisib), or collectively the Novartis Study Drugs, as part of our planned Phase 1b clinical study of palazestrant in patients with metastatic ER+ breast cancer.

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

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

As part of the collaboration, the parties granted to each other a non-exclusive, royalty- free license under certain of the parties’ respective background patent rights and other technology to use the parties’ respective study drugs in research and development, solely to the extent reasonably needed for the other party’s activities in the collaboration.

All inventions and data developed in the performance of the clinical studies for the combined therapies (other than those specific to each component study drug), will be jointly owned by the parties.

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

All inventions and data 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.

We are responsible for manufacturing, packaging and labeling palazestrant, and for packaging and labeling all drugs used in the clinical studies for the combined therapies (other than the Novartis Study Drugs).

Novartis is responsible for manufacturing and delivering to us the Novartis Study Drugs in such quantities as reasonably needed for the clinical studies for the combined therapies.

In accordance with an agreed budget, Novartis will reimburse us for a majority of the direct outside costs, but no more than an amount in the low single digit millions of U.S.

In accordance with an agreed budget, Novartis is reimbursing us for a portion of the direct outside costs, but no more than an amount in the low single digit millions of U.S.

dollars, that we incur related to conducting the activities under the agreed development plan in conducting the clinical trials for the combined therapies.

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 OP-1250.

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.

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.

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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 OP-1250 in combination with Pfizer’s proprietary CDK4/6 inhibitor IBRANCE® (palbociclib) in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer in a clinical trial.

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

All inventions and data developed in the performance of the clinical trials for the combined therapies (other than those specific to each component study drug), will be jointly owned by the parties.

We are responsible for manufacturing, packaging and labeling OP-1250, and for packaging and labeling all drugs used in the clinical trials for the combined therapies (other than IBRANCE® (palbociclib)).

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.

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.

As part of the collaboration, the parties granted to each other a non-exclusive, royalty- free license under certain of the parties’ respective patent rights in the combination of IBRANCE® and palazestrant 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.

All inventions and data developed in the performance of the clinical trials for the combined therapies (other than those specific to each component study drug), are jointly owned by the parties.

We are responsible for manufacturing, packaging and labeling palazestrant, and for packaging and labeling all drugs used in the clinical trials for the combined therapies (other than IBRANCE® (palbociclib)).

Pfizer is responsible for manufacturing and delivering to us IBRANCE® (palbociclib) in such quantities as reasonably needed for the clinical studies for the combined therapies.

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

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 IBRANCE® (palbociclib) or OP-1250.

Either party may terminate the Pfizer 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 IBRANCE® (palbociclib) or palazestrant.

In addition, either party may terminate the Pfizer Agreement if certain disputes between the parties are not resolved after following the applicable dispute resolution procedures or if either party determines to discontinue clinical development for medical, scientific, legal or other reasons.

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License Agreement with Aurigene

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

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.

Financial terms of the Aurigene Agreement include a $8.0 million upfront payment from us for rights to a pre-existing Aurigene program and potential future milestone payments of up to $60.0 million in clinical development and regulatory milestones, and up to $370.0 million in commercial milestones.

Aurigene is also eligible to receive mid-single-digit to low double-digit royalties on product sales, if any.

Aurigene is also eligible to receive mid-single-digit to low double-digit royalties as percentages of product sales, if any.

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

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Intellectual Property

Our success depends, in part, on our ability to obtain, maintain and protect our intellectual property and other proprietary rights for OP-1250 and any future product candidates and other discoveries, inventions, trade secrets and know-how that are critical to our business operations.

Our success depends, in part, on our ability to obtain, maintain and protect our intellectual property and other proprietary rights for palazestrant, OP-3136 and any future product candidates and other discoveries, inventions, trade secrets and know-how that are critical to our business operations.

Our success also depends in part on our ability to operate without infringing, misappropriating or otherwise violating the intellectual property and proprietary rights of others, and in part, on our ability to prevent others from infringing, misappropriating or otherwise violating our intellectual property and proprietary rights.

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Changes in the patent laws and rules, either by legislation, judicial decisions, or regulatory interpretation in other countries may diminish our ability to protect our inventions and enforce our intellectual property rights, and more generally could affect the value of our intellectual property.

in part on our success in obtaining, defending and enforcing patent claims that cover our technology, inventions, and improvements.

In particular, our ability to stop third parties from making, using, selling, offering to sell, importing or otherwise commercializing any of our patented inventions, either directly or indirectly, will depend in part on our success in obtaining, defending and enforcing patent claims that cover our technology, inventions, and improvements.

Regardless of the coverage we seek under our existing patent applications, there is always a risk that an alteration to the product or process may provide sufficient basis for a competitor to avoid infringement claims.

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The term of a patent, and the protection it affords, is therefore limited and once the patent term of our issued patents has expired, we may face competition.

Because of the extensive time required for clinical development and regulatory review of the drugs we develop, it is possible that, before OP-1250 or any future product candidates we may develop can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent.

Because of the extensive time required for clinical development and regulatory review of the drugs we develop, it is possible that, before palazestrant, OP-3136 or any future product candidates we may develop can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent.

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, 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.

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

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Moreover, even if we comply with all deadlines and requirements, we may not be able to issue patents in relevant jurisdictions, and furthermore cannot predict whether any patents that might issue will provide us with any competitive advantage.

We have granted patents and pending applications relating to OP-1250, including granted claims that encompass the OP-1250 compound, pharmaceutical compositions that include OP-1250, and certain methods of using OP-1250, including in treatment which may involve combination therapy.

We have granted patents and pending applications relating to palazestrant, including granted claims that encompass the palazestrant compound, pharmaceutical compositions that include palazestrant, and certain methods of using palazestrant, including in treatment which may involve combination therapy.

The 20-year term for these patents expires in 2036.

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Additional applications are pending, including ones that relate to dosing regimens and treatment of particular cancers and patient populations, and, if granted, will have 20-year terms that expire between 2040 and 2043.

Certain patents related to OP-1250 may be eligible for PTE in certain jurisdictions, including the United States and Europe, upon approval of a commercial use of the corresponding product by a regulatory agency in the jurisdiction where the patent was granted.

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.

The 20-year term for the pending patent application related to OP-3136 expires in 2044.

In the United States, it is uncertain whether any PTE will be available, and if so, how much.

Certain patents related to palazestrant or OP-3136 (once granted) may be eligible for PTE in certain jurisdictions, including the United States and Europe, upon approval of a commercial use of the corresponding product by a regulatory agency in the jurisdiction where the patent was granted.

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

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

Furthermore, as OP-1250 has not previously been approved in the United States for any indication, OP-1250 may be eligible for five years of NCE exclusivity upon its first approval.

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.

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.

With respect to our owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any current patents or any patents that may be granted to us in the future will be commercially useful in protecting OP-1250 or any future product candidates and the methods used to manufacture them.

Moreover, any issued patents and those that may issue in the future may not guarantee us the right to practice our technology in relation to the commercialization of OP-1250 or any future product candidates.

Any patents and those that may issue in the future may be challenged, narrowed, circumvented or invalidated, which could limit our ability to stop competitors from marketing related product candidates or limit the length of the term of patent protection that we may have for OP-1250 or any future product candidates.

With respect to our owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any current patents or any patents that may be granted to us in the future will be commercially useful in protecting palazestrant, OP-3136 or any future product candidates and the methods used to manufacture them.

Moreover, any issued patents and those that may be issued in the future may not guarantee us the right to practice our technology in relation to the commercialization of palazestrant, OP-3136 or any future product candidates.

In addition, the rights granted under any issued patents may not provide us with complete protection or competitive advantages against competitors with similar products to ours.

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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 OP-1250.

We 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 OP-1250 for nonclinical and clinical testing, as well as for commercial manufacture if OP-1250 receives marketing approval.

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 maintain agreements with our manufacturers that include confidentiality and intellectual property provisions to protect our proprietary rights related to OP-1250.

We have engaged CMOs to manufacture and package OP-1250 for nonclinical and clinical use.

Additional CMOs are used to label and distribute OP-1250 for clinical use.

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.

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

We obtain our supplies from these CMOs on a purchase order basis and do not have long-term supply arrangements in place.

Although we do not currently have contractual arrangements in place for redundant supply for OP-1250, it is our goal to identify and contract with at least two manufacturers for active pharmaceutical ingredient and two manufacturers for drug product.

More broadly, for OP-1250 and any other product candidates we may develop, we intend to identify and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services prior to seeking regulatory approval.

Although we do not currently have contractual arrangements in place for redundant supply for palazestrant, it is our goal to identify and contract with at least two manufacturers for active pharmaceutical ingredient and two manufacturers for drug product.

More broadly, for palazestrant and any other product candidates we may develop, we intend to identify and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services prior to seeking regulatory approval.

The biotechnology and pharmaceutical industries are characterized by rapid technological advancement, significant competition and an emphasis on intellectual property.

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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.

There are several currently marketed drugs and product candidates currently in development for the treatment of ER+ breast cancer that target the estrogen receptor that may compete with OP-1250:

including fulvestrant, marketed as Faslodex® by AstraZeneca PLC and or any generic equivalents of Faslodex® that are marketed or in development;

There are several currently marketed drugs and product candidates currently in development for the treatment of ER+ breast cancer that target the estrogen receptor that may compete with palazestrant including:

fulvestrant, marketed as Faslodex® by AstraZeneca PLC and or any generic equivalents of Faslodex that are marketed or in development;

elacestrant, marketed as ORSERDU TM by Stemline Therapeutics Inc.;

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imlunestrant (LY3484356), being developed by Eli Lilly and Co.;

ARV-471, being developed by Arvinas, Inc.;

vepdegestrant (ARV‑471), being developed by Arvinas, Inc.

in partnership with Pfizer, Inc.;

and lasofoxifene, being developed by Sermonix Pharmaceuticals.

There are a number of KAT6 inhibitor product candidates in development that may compete with OP-3136 including PF-07248144, which is being developed by Pfizer.

Government Regulation and Product Approval

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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.

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.

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Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

This group provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial.

This group assesses whether or not a trial may move forward at designated check points based on access to certain data from the ongoing trial.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

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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.

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.

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.

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational drug product to the satisfaction of the FDA.

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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.

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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.

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.

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.

Even if such data and information is submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.

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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.

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.

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

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.

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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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.

Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) annually report information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, certain ownership and investment interests held by these physicians and their immediate family members.

Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) annually report information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, and certain ownership and investment interests held by these physicians and their immediate family members.

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.

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.

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 “quitam” 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 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.

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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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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 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, or 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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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.

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.

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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 2031.

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.

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.

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.

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.

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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 will take effect progressively starting in fiscal year 2023, although they may be subject to legal challenges.

In addition, the Biden administration released an additional executive order on October 14, 2022, directing HHS to report on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

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.

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.

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.

Other states have also submitted SIP proposals that are pending review by the FDA.

Any such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs.

In addition, it is possible that there will be further legislation or regulation that could harm our business, financial condition, and results of operations.

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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.

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.

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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.

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.

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Orphan drug designation is only available if there is no other satisfactory method approved in the European Union of diagnosing, preventing or treating the condition, or if such a method exists, the proposed orphan drug will be of significant benefit to patients.

Orphan drug designation provides opportunities for free protocol assistance, fee reductions for access to the centralized regulatory procedures and ten years of market

exclusivity following drug approval, which can be extended to 12 years if trials are conducted in accordance with an agreed-upon pediatric investigational plan.

Orphan drug designation provides opportunities for free protocol assistance, fee reductions for access to the centralized regulatory procedures and ten years of market exclusivity following drug approval, which can be extended to 12 years if trials are conducted in accordance with an agreed-upon pediatric investigational plan.

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.

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Employees and Human Capital

As of January 31, 2023, we had 86 employees, 83 of whom were full time, consisting of clinical, research, operations, regulatory, finance and business development personnel.

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.

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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 Board level, where we appointed three global biotech female leaders to our Board, and for all employees.

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.

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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, with a particular focus on COVID-19 related protections and precautions for our workforce.

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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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