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Item 1. Business

2023-03-09 compared with 2022-02-28 · 323 added, 294 removed, 660 unchanged (48% of the section changed)

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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 tumor shrinkage in several xenograft models, including a breast cancer brain metastasis model.

In August 2020, we initiated an ongoing Phase 1/2 dose escalation and expansion trial 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 1 dose escalation portion of this trial in November 2021, which provide proof-of-concept for OP-1250 as a monotherapy treatment for ER+/HER2- breast cancer.

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.

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.

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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 women’s cancer.

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.

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

Approximately 75% of all breast cancers are ER+, and approximately 65% are ER+/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 HR+/HER2-, highlighting the central role of the ER in driving a large majority of breast cancer.

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

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

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

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

All key breast cancer populations will experience strong sales growth.

We expect sales in the HR+/HER2- population to rise from $11.3 billion in 2020 to $30.6 billion in 2030.

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

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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.

In 1977, the first endocrine therapeutic, the anti-estrogen tamoxifen, was approved by the U.S.

Food and Drug Administration, or FDA, for the treatment of breast cancer.

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

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

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

Additionally, most patients with metastatic breast cancer have been shown to ultimately develop resistance to AIs.

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

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.

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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.

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

Consequently, SERDs are not necessarily CERANs.

Notably, estrogen itself leads to ER degradation.

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

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

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

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.

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● 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 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 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 nonclinical differences, we believe that OP-1250 has the potential to demonstrate clinical outcomes superior to fulvestrant.

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 pharmacokinetic, or PK, properties, and higher plasma and tumor drug concentrations.

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

OP-1250 has the potential to address a critical unmet need as 10-15% of ER+ breast cancer patients develop brain metastases for which there are currently limited treatment options.

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.

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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 Pipeline

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

Phase 1a consists 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 pharmacokinetics with oral bioavailability and dose-proportional exposures supporting once daily dosing;

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.

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 completed the Phase 1a dose escalation portion of our trial and we are currently conducting Phase 1b dose expansion at two dose levels (60 mg and 120 mg daily), which will help inform the selection of the Recommended Phase 2 Dose, or RP2D, to advance into Phase 2 efficacy evaluation.

Phase 2 efficacy evaluation is expected to initiate in the first half of 2022 with approximately 80 patients enrolled across three cohorts:

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).

In addition, we plan to explore the potential clinical benefit of OP-1250 in combination with other approved agents for breast cancer, such as inhibitors of CDK4/6 and phosphatidylinositol 3-kinase alpha, or PI3K a , which have been shown to lead to improvements in both progression-free and overall survival.

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 trial, as well as supplying their drugs.

In November 2020, we entered into a non-exclusive clinical trial agreement with Pfizer Inc., or Pfizer, 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 trial for the combined therapy and Pfizer is responsible for supplying IBRANCE® (palbociclib) to us at no cost to us.

In December 2021, we initiated a Phase 1b clinical trial of OP-1250 in combination with palbociclib.

Additional combination studies with CDK4/6 and PI3K a inhibitors are planned in 2022.

In addition, we plan to initiate a Phase 1b clinical trial of OP-1250 in combination with HER2+ inhibitors in patients with ER+/HER2+ breast cancer and CNS metastasis in 2022.

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.

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

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● 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 trial in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer whose disease has progressed on endocrine therapy.

We reported initial data from this trial in November 2021.

After examining safety and PK as well as determining the RP2D, we intend to advance OP-1250 into Phase 2 efficacy evaluation, and to study OP-1250 in patients with earlier stage disease.

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 treatment options.

We plan to explore the potential clinical benefit of OP-1250 in combination with other approved agents for breast cancer, such as inhibitors of CDK4/6 and PI3K a , which have been shown to lead to improvements in both progression-free and overall survival.

At low concentrations in nonclinical models, OP-1250 worked in combination with inhibitors of CDK4/6 and PI3K a .

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

In November 2020, we entered into a non-exclusive agreement with Pfizer to evaluate OP-1250 in combination with IBRANCE®, a selective CDK4/6 inhibitor.

In December 2021, we initiated a Phase 1b clinical trial of OP-1250 in combination with palbociclib.

Additional combination studies with CDK4/6 and PI3K a inhibitors are expected to initiate in 2022.

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.

We believe OP-1250’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.

● Exploring additional clinical opportunities for OP-1250, 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.

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

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

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

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● 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 a clinical collaboration with Novartis and intend to continue evaluating opportunities to work with partners that meaningfully enhance our capabilities with respect to the development and commercialization of OP-1250.

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.

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Epidemiology and classification of breast cancer

Breast cancer is the second-most common cancer worldwide, with nearly 2 million new diagnoses per year.

In 2021, the ACS estimate there were approximately 282,000 new cases of female breast cancer and over 43,600 deaths in the United States, making it the second-leading cause of cancer death in women.

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.

Approximately 2,700 men are also diagnosed with breast cancer each year in the United States.

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Tumors that express HER2 are denoted HER2+, and tumors that do not express ER, PR or HER2 are classified as triple negative breast cancer.

Approximately 75% of all breast cancers are ER+, and approximately 65% are ER+/HER2-, highlighting the central role of ER signaling in driving a large majority of breast cancer.

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.

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

Alpelisib, a PI3K a inhibitor, was approved in 2019

in combination with fulvestrant for the treatment of HR+/HER2- breast cancers that have mutations in PIK3CA.

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

Figure 3 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.

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

About 10-15% of women with metastatic breast cancer develop brain metastases.

About 10% to 15% of women with metastatic breast cancer develop brain metastases.

Brain metastases present a significant challenge to systemic therapy, and the primary treatment for CNS metastases is typically surgical resection, radiation, or a combination of both.

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Partial agonists, such as tamoxifen, are unable to completely block ER activation

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

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

However, most patients with metastatic breast cancer have been shown to ultimately develop resistance to these therapies.

Similar to tamoxifen, resistance to AIs, such as anastrozole, exemestane or letrozole, can develop by multiple mechanisms, including activation of the AF1 pathway and development of mutations.

Mutations in ESR1 that confer estrogen-independent ER activity arise in 30-40% of patients receiving AI treatment.

Mutations in ESR1 that confer estrogen-independent ER activity arise in up to 50% of patients receiving treatment with an AI in combination with a CDK4/6 inhibitor in the first-line metastatic setting.

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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Previous work by one of our co-founders identified specific interactions between fulvestrant-bound ER and N-CoR and that the strength of these interactions correlated with the ability of fulvestrant-bound ER to inactivate gene transcription through the transcription factor activating domain, AF1.

CERANs block AF1 and AF2 activity inhibiting cell proliferation

Complete antagonists turn off AF2 and recruit N-CoR to inactivate AF1

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

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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.

In several xenograft models, OP-1250, both as a monotherapy and in combination with CDK4/6 inhibitors, demonstrated robust tumor

shrinkage, including in a breast cancer brain metastasis model.

In November 2021, we presented interim Phase 1a dose escalation data from our ongoing Phase 1/2 clinical trial of OP-1250 as a monotherapy treatment in ER+/HER2- breast cancer.

The Phase 1b dose expansion stage of the clinical trial is ongoing at two dose levels (60 mg and 120 mg daily) and is expected to enroll 15 patients in each cohort.

Phase 2 efficacy evaluation is expected to initiate in the first half of 2022 with approximately 80 patients enrolled across three cohorts:

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

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

We plan to initiate additional combination studies with CDK4/6 and PI3K a inhibitors, along with a Phase 1b clinical trial of OP-1250 in combination with HER2+ inhibitors in patients with ER+/HER2+ breast cancer and CNS metastasis in 2022.

A pivotal study for OP-1250 as a monotherapy in the metastatic setting is expected to initiate in 2023.

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.

Phase 1a dose-escalation initial data

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

Pharmacokinetics, 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 trial (NCT04505826).

Phase 1/2 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).

As shown in Figure 8 below, this was a heavily pretreated population:

95% of patients were previously treated with a cyclin-dependent kinase (CDK) 4/6 inhibitor (9 patients, or 22%, received 2 or more prior CDK4/6 inhibitor regimens), 68% of patients received prior fulvestrant, and 42% received prior chemotherapy in the advanced setting.

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 (ctDNA) was assessed, ESR1 mutations were detected in 49% at baseline.

OP-1250 Phase 1 Study Population Received Extensive Prior Therapy

Pharmacokinetic 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.

As shown in Figure 9 below, at doses 60 mg and above, OP-1250 achieved exposures exceeding the predicted thresholds for maximal anti-tumor efficacy based on preclinical models.

OP-1250 Mean Plasma Concentration-Time Profiles (C2D1)

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 as assessed by study investigator were nausea (49%), fatigue (34%), vomiting (22%) and headache (17%).

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, 3 patients had grade 4 neutropenia attributed to study drug by the investigator.

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 pharmacokinetics, favorable tolerability, and initial evidence of anti-tumor activity.

Treatment-Related Adverse Events

treatment-related adverse event as assessed by study investigator.

Efficacy Profile

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

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 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 set forth in the Figures 11 and 12 below, 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.

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.

Four response-eligible patients had target lesion reductions of greater than 30%.

Across all doses, the ORR was 8% (2/24) and the CBR was 29% (7/24).

For the dose levels within the RP2D range, the ORR was 17% (2/12) and the CBR was 46% (6/13).

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.

Best Response of Target Lesion in Patients with Measurable Disease

*Patient’s response unconfirmed due to progression with a new non-target lesion at follow-up visit.

Efficacy-evaluable patients include those with measurable disease at baseline and at least one post-baseline scan.

Data cut-off:

November 1, 2021.

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.

Almost all patients (96%) received prior treatment with a CDK4/6 inhibitor, and 65% 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;

Treatment Duration (weeks) and Response by Dose in All Patients (N=41) as of Nov.

*Four patients in the 300 mg cohort dose reduced, three to 120 mg and one to 60 mg with most occurring at the beginning of cycle 2.

These patients are included in RP2D CBR calculation set forth above.

PR, partial response.

PD, progressive disease;

AI, aromatase inhibitor;

CDK4/6i, cyclin-dependent kinases inhibitor.

Data cut-off:

November 1, 2021.

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

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

Based on data from the Phase 1a dose-escalation portion of our Phase 1/2 clinical trial, we are advancing OP-1250’s clinical development program with a number of anticipated program milestones.

The Phase 1b dose expansion portion of our Phase 1/2 clinical trial is ongoing at two dose levels (60 mg and 120 mg daily) and is expected to enroll 15 patients in each cohort.

Findings from this stage will help inform selection of the RP2D.

After determining the RP2D for OP-1250, we expect to initiate the Phase 2 efficacy evaluation in the first half of 2022 with approximately 80 patients enrolled across three cohorts:

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

Designs of the Phase 1/2 OP-1250-001 trial and Phase 1b OP-1250-002 for OP-1250

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

We expect to initiate additional combination studies with CDK4/6 and PI3K a inhibitors in 2022.

Each of the combination trials will be evaluated in an abbreviated dose escalation followed by a small expansion cohort to further evaluate the safety of each of the two combinations.

We expect to initiate a pivotal study for OP-1250 in the metastatic setting in 2023.

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.

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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 expect to initiate a Phase 1b clinical trial of OP-1250 in combination with HER2+ inhibitors in patients with ER+/HER2+ breast cancer and CNS metastasis, in 2022.

We are conducting a series of pharmacology studies for OP-1250, including drug-drug interaction, or DDI, fed/fast and bioequivalence to a tablet formulation, and expect to complete these studies in 2022.

We believe that the conversion from capsule to tablet formulation of OP-1250 may help lower the incidence of upper gastrointestinal adverse events we observed in the Phase 1a portion of our clinical trial.

We expect to transition to tablet administration prior to initiation of a pivotal study in 2023.

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.

While our initial trials 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.

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

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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 is an estrogen-responsive gene in ECC-1 cells driven by AF1 action.

The in vitro alkaline phosphatase, or AP, model is a method of determining complete ER antagonism.

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.

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

In a 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.

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.

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.

CERANs reliably degrade ER a in multipl e cell lines while non-CERANs have a variable degradation profile.

Immunoblot of ER a across multiple ER+ cell lines.

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.

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

At daily oral doses of 3 mg/kg and above, treatment with OP-1250 led to tumor

shrinkage in all treated mice in an HCI-013EI patient-derived xenograft model

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).

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

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

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.

OP-1250 led to tumor shrinkage in multiple breast cancer xenograft models in

mice including HCC1500, which contain wild-type ER, and ST941 and HCI-013, which

contain the Y537S mutation in ER

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).

Left panel of Figure 18 shows tumor size of each tumor measured with calipers at termination.

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

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;

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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

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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 trial 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.

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.

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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 trial of OP-1250 in patients with metastatic ER+ breast cancer.

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

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.

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 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 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 trials for the combined therapies.

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).

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.

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

Either party may terminate the Novartis Agreement for the uncured material breach or insolvency of the other party, if it reasonably deems it necessary in order to protect the safety, health or welfare of subjects enrolled in the clinical trials 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.

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

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

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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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 trial for the combined therapies and Pfizer is responsible for supplying IBRANCE® to us at no cost to us.

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.

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

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.

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 trials 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.

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.

The Pfizer 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.

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.

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.

The Pfizer Agreement does not grant any right of first negotiation to participate in future clinical studies, and each of the parties retains all rights and ability to evaluate their respective compounds.

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.

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.

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

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

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

The term of the Aurigene Agreement will continue until the expiration of the last-to-expire of all payment obligations with respect to all licensed products thereunder, unless terminated earlier in accordance with the terms of the Aurigene Agreement.

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

Intellectual Property

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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 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.

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 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.

As of January 31, 2022 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 OP-1250, including granted claims that encompass the OP-1250 compound, pharmaceutical compositions that include OP-1250, and certain methods of using OP-1250, including in treatment which may involve combination therapy.

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

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

Additional applications are pending, including ones that relate to dosing regimens and treatment of particular cancers and patient populations, and have 20-year terms that expire as late as 2042.

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.

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 European Medicines Agency, or 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.

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.

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We intend to continue evaluating opportunities to work with partners that enhance our capabilities with respect to the development and commercialization of OP-1250.

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.

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.

Manufacturing

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

These competitors, if successful in clinical development, may achieve regulatory approval and market adoption in

advance of our product candidates, constraining our ability to gain significant market share for such product candidates.

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

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 may compete with OP-1250 if approved, including:

certain CERAN therapies, such as giredestrant (GDC-9545) being developed by Roche Holding AG/Genentech, Inc., fulvestrant, marketed as Faslodex® by AstraZeneca PLC, or any generic equivalents of Faslodex® that are marketed or in development, camizestrant (AZD9833) being developed by AstraZeneca PLC, amcenestrant (SAR439859) being developed by Sanofi S.A.

and imlunestrant (LY3484356) being developed by Eli Lilly and Co., ZN-c5 being developed by Zentalis Pharmaceuticals, Inc., elacestrant being developed by Radius Health, Inc., ARV-471 being developed by Arvinas, Inc., rintodestrant (G1T48) being developed by G1 Therapeutics, Inc.

H3B-6545 being developed by H3 Biomedicines, a subsidiary of Eisai Co., Ltd, D-0502 being developed by InvestisBio Co., Ltd, and lasofoxifene being developed by Sermonix Pharmaceutials.

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;

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

giredestrant (GDC-9545), being developed by Roche Holding AG/Genentech, Inc.;

camizestrant (AZD9833), being developed by AstraZeneca PLC;

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

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

and lasofoxifene, being developed by Sermonix Pharmaceuticals.

Government Regulation and Product Approval

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

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

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

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

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

In certain instances, FDA may mandate the performance of Phase 4 trials.

In certain instances, the FDA may mandate the performance of Phase 4 trials.

In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

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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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Additionally, before approving an NDA, the FDA may inspect one or more clinical sites to assure compliance with GCP requirements.

After the FDA evaluates the application, manufacturing process and

manufacturing facilities, it may issue an approval letter or a Complete Response Letter.

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.

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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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A REMS could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

Orphan drug designation

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product.

Orphan designation must be requested before submitting an NDA.

After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the

FDA may not approve any other applications to market the same drug or biological product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities.

The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.

Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

Orphan exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval of the same drug as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease.

If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.

Orphan drug status in the European Union has similar but not identical benefits in that jurisdiction.

Expedited development and review programs

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Fast track designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

A sponsor may seek FDA designation of a drug candidate as a “breakthrough therapy” if the drug is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early

in clinical development.

The designation includes intensive FDA interaction and guidance.

If a drug is designated as breakthrough therapy, FDA will expedite the development and review of such drug.

Breakthrough therapy designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance.

The breakthrough therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.

If a product is designated as breakthrough therapy, the FDA will work to expedite the development and review of such drug.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

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Post-approval requirements

direct- to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Any drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements, which include, among others, standards for direct- to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.

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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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Although we currently do not have any products on the market, we are and, upon approval and commercialization, will be subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which we conduct our business.

In the United States, such laws include, without limitation, state and federal anti-kickback, fraud and abuse, false claims, privacy and security, price reporting, and provider transparency laws and regulations.

In the United States, such laws include, without limitation, state and federal fraud and abuse (such as anti-kickback and false claims), privacy and security, price reporting, and provider transparency laws and regulations.

The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering or arranging for the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs.

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Our practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor.

Additionally, the intent standard under the Anti-Kickback Statute and the criminal healthcare fraud statutes (discussed below) was amended by the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010, together with subsequent amendments and regulations, collectively, the ACA, to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Additionally, the intent standard under the Anti-Kickback Statute and certain criminal healthcare fraud statutes (discussed below) was amended by the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010, together with subsequent amendments and regulations, collectively, the ACA, to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, the ACA codified case law that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act (discussed below).

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As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S.

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

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

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

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

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 healthcare providers 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.

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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.

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.

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

For example, in Europe we are subject to Regulation (EU) 2016/679, the General Data Protection Regulation, or GDPR, in relation to our collection, control, processing and other use of personal data (i.e.

data relating to an identified or identifiable living individual).

In order to distribute products commercially, we must comply with state laws that require the registration of manufacturers and wholesale distributors of pharmaceutical products in a state, including, in certain states, manufacturers and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state.

Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.

Several states have enacted legislation requiring pharmaceutical companies to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, track and report gifts, compensation and other remuneration made to physicians and other healthcare providers, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.

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.

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

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

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

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

The GDPR is directly applicable in each European Union Member State, however, it provides that European Union Member States may introduce further conditions, including limitations which could limit our ability to collect, use and share personal data (including health and medical information), or could cause our compliance costs to increase, ultimately having an adverse impact on our business.

The GDPR imposes onerous accountability obligations requiring data controllers and processors to maintain a record of their data processing and implement policies as part of its mandated privacy governance framework.

It also requires data controllers to be transparent and disclose to data subjects (in a concise, intelligible and easily accessible form) how their personal information is to be used, imposes limitations on retention of personal data;

defines pseudonymized (i.e., key-coded) data;

introduces mandatory data breach notification requirements;

and sets higher standards for data controllers to demonstrate that they have obtained valid consent for certain data processing activities.

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

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

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

Further, following the withdrawal of the United Kingdom from the European Union on January 31, 2020, , we must comply with the GDPR and separately the GDPR as implemented in the United Kingdom, each regime having the ability to fine up to the greater of €20 million/ £17 million or 4% of global turnover.

In addition, as of January 1, 2021, the United Kingdom Information Commissioner’s Office is not able to be our ‘lead supervisory authority’ in respect of any ‘cross border processing’ for the purposes of the GDPR.

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

In addition, the GDPR includes restrictions on cross-border data transfers.

The European Commission, however, released a set of “Standard Contractual Clauses” in June 2021 that are designed to be a valid mechanism by which entities can transfer personal data out of the EEA to jurisdictions that the European Commission has not found to provide an adequate level of protection.

Currently, these Standard Contractual Clauses are a valid mechanism to transfer personal data outside of the EEA.

The Standard Contractual Clauses, however, require parties that rely upon that legal mechanism to comply with additional obligations, such as conducting transfer impact assessments to determine whether additional security measures are necessary to protect the at-issue personal data.

Moreover, due to potential legal challenges, there exists some uncertainty regarding whether the Standard Contractual Clauses will remain a valid mechanism for transfers of personal data out of the EEA.

The GDPR will increase our responsibility and liability in relation to personal data that we process where such processing is subject to the GDPR, and we may be required to put in place additional mechanisms to ensure compliance with the GDPR, including as implemented by individual countries.

We are also subject to European Union rules with respect to cross-border transfers of personal data out of the European Union and EEA.

As supervisory authorities issue further guidance on personal data export mechanisms, including circumstances where the standard contractual clauses cannot be used, and/or start taking enforcement action, we could suffer additional costs, complaints and/or regulatory investigations or fines, and/or if we are otherwise unable to transfer personal data between and among countries and regions in which we operate, it could affect the manner in which we provide our services, the geographical location or segregation of our relevant systems and operations, and could adversely affect our financial results.

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

The CCPA requires

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

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

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

In general, if our efforts to comply with the GDPR or other applicable European Union laws and regulations are not successful, it could adversely affect our business in the European Union.

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.

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

Although there are currently various mechanisms that may be used to transfer personal data from the EEA and UK to the United States in compliance with law, such as the EEA and UK’s standard contractual clauses, these mechanisms are subject to legal challenges, and there is no assurance that we can satisfy or rely on these measures to lawfully transfer personal data to the United States.

If there is no lawful manner for us to transfer personal data from the EEA, the UK or other jurisdictions to the United States, or if the requirements for a legally-compliant transfer are too onerous, we could face significant adverse consequences, including the interruption or degradation of our operations, the need to relocate part of or all of our business or data processing activities to other jurisdictions at significant expense, increased exposure to regulatory actions, substantial fines and penalties, the inability to transfer data and work with partners, vendors and other third parties, and injunctions against our processing or transferring of personal data necessary to operate our business.

Additionally, companies that transfer personal data out of the EEA and UK to other jurisdictions, particularly to the United States, are subject to increased scrutiny from regulators, individual litigants, and activist groups.

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

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

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

The CCPA provides for civil penalties for violations, as well as a private right of action for certain data breaches that result in the loss of personal information.

This private right of action may increase the likelihood of, and risks associated with, data breach litigation.

The CCPA became effective on January 1, 2020, and (a) allows enforcement by the California Attorney General, with fines set at $2,500 per violation (i.e., per person) or $7,500 per intentional violation and (b) authorizes private lawsuits to recover statutory damages for certain data breaches.

The CCPA (a) allows enforcement by the California Attorney General, with fines set at $2,500 per violation (i.e., per person) or $7,500 per intentional violation and (b) authorizes private lawsuits to recover statutory damages for certain data breaches.

In addition, laws in all 50 U.S.

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

Additionally, California voters approved a new privacy law, the California Privacy Rights Act, or CPRA, in the November 3, 2020 election.

Effective starting on January 1, 2023, the CPRA will significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information.

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

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

New legislation proposed or enacted in various other states will continue to shape the data privacy environment nationally.

For example, Virginia passed the Consumer Data Protection Act, and Colorado passed the Colorado Privacy Act.

For example, Virginia, Colorado, Utah, and Connecticut have all enacted broad privacy legislation.

Certain state laws may be more stringent or broader in scope, or offer greater individual rights, with respect to confidential, sensitive and personal information than federal, international or other state laws, and such laws may differ from each other, which may complicate compliance efforts.

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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.

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

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

For information regarding risks related to these

compliance requirements, see the section titled “Risk Factors—Risks Related to Regulatory Approval and Other Legal Compliance Matters.”

Pharmaceutical coverage, pricing and reimbursement

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

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

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.

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.

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

Among the ACA’s provisions of importance to the pharmaceutical industry, in addition to those otherwise described above, are the following:

● an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents apportioned among these entities according to their market share in some government healthcare programs;

● an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively, and a cap on the total rebate amount for innovator drugs at 100% of the Average Manufacturer Price, or AMP;

● a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point- of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

● extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

● expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals, including individuals with income at or below 133% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability;

● expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;

● a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

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

For example, the Tax Cuts and Jobs Act, or the Tax Act was enacted, which includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On June 17, 2021, the U.S.

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

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

Thus, the ACA will remain in effect in its current form.

Prior to the U.S.

Supreme Court ruling, on January 28, 2021, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through May 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

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

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

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

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

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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.

However, COVID-19 relief legislation suspended the 2% Medicare sequester from May 1, 2020 through March 31, 2022.

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.

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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.

In addition, Congress is considering additional health reform measures.

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.

The Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

For example, on July 24, 2020 and September 13, 2020, President Trump announced several executive orders related to prescription drug pricing that attempt to implement several of the Administration’s proposals.

The FDA concurrently released a final rule and guidance, implementing a portion of the importation executive order providing pathways for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed until January 1, 2023.

On November 20, 2020, CMS issued an interim final

rule implementing President Trump’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

On December 27, 2021, CMS published a final rule that rescinds the Most Favored Nation model interim final rule.

things, bring more transparency to product pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

At the federal level, in July 2021, the Biden administration released an executive order that included multiple provisions aimed at prescription drugs.

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

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

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

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

These provisions 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.

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.

We anticipate that these new laws will result in additional downward pressure on coverage and the price that we receive for any approved product, and could seriously harm our business.

Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payors.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our products (if approved).

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

For example, it is possible that additional governmental action is taken in response to the COVID-19 pandemic.

Foreign Corrupt Practices Act

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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 European Medicine Agency's, or 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.

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

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

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

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

the European Economic Area.

The 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.

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

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

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

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

The Centralized Procedure is mandatory for certain types of products, such as (i) biotechnology medicinal products such as genetic engineering, (ii) orphan medicinal products, (iii) medicinal products containing a new active substance indicated for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune and viral diseases and (iv) advanced-therapy medicines, such as gene therapy, somatic cell therapy or tissue-engineered medicines.

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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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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.

25 of our employees hold Ph.D.

Thirty-two of our employees hold Ph.D.

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

We consider our relationship with our employees to be good.

Olema’s 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, including with the appointment of Naseem Zojwalla, M.D., as our Chief Medical Officer in January 2022.

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.

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

Olema faces significant competition for biotechnology talent from both established and early-stage biotechnology companies.

Further, we are headquartered in the San Francisco Bay Area, a global biotechnology hub with many employment choices.

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

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

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

As of January 31, 2023, 54% of our employee population is male, and 46% is female.

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

We are committed to the health, safety, and well-being of our employees, with a particular focus on COVID-19 related protections and precautions for our workforce.

This commitment is reflected in our ability to attract and retain the best and we have a robust employment package that promotes well-being across all aspects of our employees’ lives, including healthcare, paid time-off, retirement savings with a company match through a 401(k) plan, our equity incentive plans, and our employee stock purchase plan.

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

From time to time, including during the first quarter of 2022, we may offer additional stock-based compensation awards to our employees to continue to motivate employees and assist with retention, particularly at times when our stock price, or the stock price of biotechnology companies generally, is volatile.

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

Legal Proceedings

From time to time, we may become involved in legal proceedings or be subject to claims arising in the ordinary course of our business.

We are not currently a party to any material legal proceedings.

Regardless of outcome, such proceedings or claims can have an adverse impact on us because of defense and settlement costs, diversion of resources and other factors, and there can be no assurances that favorable outcomes will be obtained.

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

We believe we have a robust employment package that promotes well-being across all aspects of our employees’ lives, including healthcare, paid time-off, retirement savings with a company match through a 401(k) plan, our equity incentive plans, and our employee stock purchase plan.

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

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

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

Corporate Information

We were incorporated in Delaware on August 7, 2006 under the legal name of CombiThera, Inc.

and on March 25, 2009 were renamed Olema Pharmaceuticals, Inc.

We were incorporated in Delaware on August 7, 2006 under the legal name of CombiThera, Inc., and, on March 25, 2009, were renamed Olema Pharmaceuticals, Inc.

Available Information

Our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and amendments to reports filed pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, are filed with the SEC.

Our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and amendments to reports filed pursuant to Sections 13(a) and 15(d) of the Exchange Act, are filed with the SEC.

Such reports and other information filed by us with the SEC are available free of charge on the Investors section of our website, www.olema.com, when such reports are available on the SEC’s website.

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The information contained on the websites referenced in this Annual Report on Form 10-K is not incorporated by reference into this filing.

Further, our references to website URLs are intended to be inactive textual references only.

Further, any references to website URLs are intended to be inactive textual references only.

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