What changed in this filing

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Item 1. Business

2022-02-28 compared with 2021-03-17 · 261 added, 228 removed, 693 unchanged (41% of the section changed)

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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, and expect to report initial data from this trial in the second half of 2021.

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.

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

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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.

In 2020, the American Cancer Society, or ACS, estimated there would be approximately 276,000 new cases of female breast cancer and over 42,000 deaths from metastatic breast cancer in the United States.

In 2021, the American Cancer Society, or ACS, estimated there were approximately 282,000 new cases of female breast cancer and over 43,600 deaths from metastatic breast cancer in the United States.

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

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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.

As summarized in the 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.

In addition, we believe that combining OP-1250 with HER2 targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2, as up to 50% of patients with metastatic HER2+ breast cancer develop CNS disease, and the majority of patients with HER2+ breast cancer also express ER.

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

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

Olema 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 1 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.

The expansion phase will enroll patients at the RP2D in order to explore preliminary efficacy in selected patient populations.

The first cohort of the expansion phase consists of women and men with recurrent, locally advanced or metastatic breast cancer whose disease has progressed on prior endocrine therapy.

A second cohort is exploratory and will enroll individuals with metastatic breast cancer who have brain metastases.

Enrollment in the Phase 1 dose-escalation phase of our Phase 1/2 clinical trial continues on track and we expect to report initial data from the Phase 1 portion of the trial in the second half of 2021.

Preliminary PK data from the first dose cohort is consistent with nonclinical modeling of our Phase 1 starting dose.

We expect to report initial data from the Phase 1 portion of the trial in the second half of 2021.

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 PI3Kα, which have been shown to lead to improvements in both progression-free and overall survival.

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 PI3Kα inhibitor.

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;

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 CDK 4/6 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:

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.

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.

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.

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

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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 expect to report initial data from this trial in the second half of 2021.

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

We also plan to study OP-1250 in selected breast cancer populations, including pre-menopausal women and patients with mutations in the estrogen-binding domain of ESR1, the gene that encodes the ER.

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.

● 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 PI3Kα, 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 PI3Kα.

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 PI3Kα inhibitor.

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 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.

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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.

In addition, combining OP-1250 with HER2 targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2, as up to 50% of patients with metastatic HER2+ breast cancer develop CNS disease, and the majority of patients with HER2+ breast cancer also express ER.

In 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.

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

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

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

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

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

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

Our Opportunity

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

In 2020, the ACS estimates there will be approximately 276,000 new cases of female breast cancer and over 42,000 deaths in the United States, making it the second-leading cause of cancer death in women.

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.

Approximately 2,500 men are also diagnosed with breast cancer each year in the United States.

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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.

The percentage breakdown of all breast cancers by subtype are shown in the Figure 1.

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

Types of breast cancer

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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 PI3Kα inhibitor, was approved in 2019

Alpelisib, a PI3K a inhibitor, was approved in 2019

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

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OP-1250 was designed by our scientific team based both on a detailed structural understanding of the ER and on known alterations to this structure induced by fulvestrant and other ER ligands.

We have demonstrated in nonclinical studies that OP-1250 functions both as a CERAN, inactivating both AF1 and AF2

transcriptional activation functions, and a SERD, promoting degradation of the ER.

In several xenograft models, OP-1250, both as a monotherapy and in combination with CDK4/6 inhibitors demonstrated robust tumor shrinkage, including a breast cancer brain metastasis model.

Preliminary PK data from the first dose cohort is consistent with nonclinical modeling of our Phase 1 starting dose.

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).

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.

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)

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%).

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.

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.

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.

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.

PR, partial response;

SD, stable disease;

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.

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.

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.

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

We believe that combining OP-1250 with HER2 targeted agents may represent an opportunity to improve upon recent advancements in the treatment of CNS disease in patients that express both ER and HER2.

We 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.

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.

Nonclinical data

Potent anti-proliferative activity

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

In a cell proliferation assay using CAMA-1 cells, a human breast cancer line that is partially resistant to tamoxifen, administration of OP-1250 led to concentration-dependent anti- proliferative activity with a half maximal inhibitory concentration, or IC50, of 3.1 nM.

The IC50 is the concentration of OP-1250 resulting in inhibiting estrogen-stimulated proliferation by 50%.

We observed a similar potency in this cell line for fulvestrant.

Endoxifen, a key active metabolite of tamoxifen, had a weaker potency in this assay, requiring a concentration of 24.3 nM to achieve an IC50.

OP-1250 inhibits the proliferation of CAMA-1 cells

In vitro cell proliferation experiment measuring DNA content after 8-day treatment of CAMA-1 breast cancer cells with ligands in the presence of 100 pM 17β- estradiol, or E2.

Shown in the left side dose response graph of Figure 7 are mean values normalized to vehicle, or +E2, along with error bars representing the standard error of the mean, or SEM, from triplicate wells.

Residual response to estrogen due to incomplete antagonism is the amount of proliferation remaining at saturating drug concentration relative to the proliferation seen in the absence of estrogen.

Shown in the right side table of Figure 7 is mean percent residual proliferative response to estrogen calculated over multiple experiments after normalizing to +E2 (100%) and -E2 (0%) for endoxifen and some SERDs with incomplete antagonism, ARN-810, AZD9496, RAD1901, and the CERANS OP-1250 and fulvestrant.

Complete ER antagonism

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

A nonclinical model often used to assess the residual agonistic effect of ER antagonists is the ovariectomized mouse uterine weight model.

In this model, removal of the ovaries eliminates the primary source of estrogen in the mouse and limits the development of uterine tissue.

As shown in this head-to-head comparison study, dosing of these mice with estrogen leads to an increase in the weight of uterine tissue.

Administration of tamoxifen in the absence of estrogen also results in an increase in uterine weight, illustrating that tamoxifen possesses some agonistic activity on ER in certain biological contexts.

Furthermore, tamoxifen is unable to block the effect of estrogen in this model.

Neither OP-1250 nor fulvestrant led to an increase in uterine weight in the absence of estrogen and both suppressed the stimulatory activity of estrogen, illustrating that OP-1250 and fulvestrant are CERANs.

OP-1250 and fulvestrant, both CERANs, lacked any ER agonistic activity and

completely blocked ER activation by estrogen in an ovariectomized mouse uterine weight

head-to-head comparison model

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.

As shown in Figure 13 below, OP-1250 and other CERANs lack agonistic estrogen like effects and completely block the effects of estrogen.

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

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

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

do not fully inhibit estrogen-stimulated AF-1 activity

SERD activity

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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 and several non-CERAN SERDs (specifically, RAD1901, ARN-810, AZD9496) to degrade ER across seven different cell lines.

As shown in Figure 9, after treatment of these cell lines for four hours, there was a dramatic difference in the effect on ER destabilization.

Endoxifen, the active metabolite of tamoxifen, had virtually no effect and RAD1901, ARN-810 and AZD9496 degraded the ER to some degree in several of the cell lines.

In contrast, fulvestrant and OP-1250 profoundly degraded the ER in each one of the cell lines, and the level of ER degradation for the cell lines treated with OP-1250 was consistent with that of fulvestrant.

OP-1250 degrades ER similarly to fulvestrant in seven tested cell lines.

ERα protein levels were measured by western blot following treatment with indicated compound in a panel of six ER+ breast cancer cell lines (CAMA-1, BT-474, MCF-7, T47D, SUM44, HCC1500) and one ER+ endometrial cancer cell line.

ERα protein levels by culturing breast cancer cell lines with 316 nM ligand in E2-depleted media for 4 hours.

Protein lysates were immunoblotted with an antibody to ERα.

Shown are mean ERα protein levels normalized to vehicle, and SEM from triplicate wells.

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.

As shown in Figure 14, after treatment of these cell lines for four hours, OP-1250 and other CERANs strongly degraded the estrogen receptor in all five ER+ cell lines, while non-CERANS demonstrated variable and inconsistent ER degradation.

Of note, Estradiol, or E2, the

prototypical agonist of ER a , degraded ER a in all five ER+ cell lines.

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

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.

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

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

Potent anti-proliferative activity

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

As shown in Figure 15 below, in a cell proliferation assay using CAMA-1 cells, a human breast cancer line, OP-1250 and other CERANs inhibited estrogen-driven proliferation to a greater degree than non-CERANs.

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

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

Cell number was approximated using a DNA-binding dye.

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

Potent antagonist activity on both wild-type and mutant ER

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

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

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

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

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

In vitro alkaline phosphatase, or AP, activity mediated by Y537S and D538G mutant ERα in an endometrial cell line.

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

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

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

Orally available, once daily dose

In animal studies, OP-1250 has demonstrated high oral availability with favorable exposure in four model species:

mouse, rat, dog, and cynomolgus monkey;

with a half-life supportive of once daily dosing in humans.

Repeat daily dosing in these studies demonstrated that at steady-state the plasma levels of OP-1250 were relatively constant through the entire 24-hour period with little peak to trough variation.

We believe that oral dosing of OP-1250 has the potential to achieve much higher drug levels as compared to fulvestrant administration which requires two intramuscular injections every four weeks.

The profile of OP-1250 is consistent with daily oral dosing in humans and we believe that we will be able to achieve targeted drug exposure levels with a once daily dose.

Steady state drug levels of OP-1250 following once daily dosing showed high

plasma levels throughout the entire day

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

After multi-day dosing, plasma levels were measured over the 24 hours following the last dose.

Plasma levels were high, reached steady state, and showed allometric scaling.

Potent tumor shrinkage in nonclinical models

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

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

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

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.

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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 8 over the course of the study.

Right 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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HCI-013 PDX model with Y537S ER in NOD/SCID mice.

Drug accumulation in tumors

We observed that OP-1250 was consistently more effective in shrinking tumors in xenograft models than fulvestrant, despite the roughly equal potency of OP-1250 and fulvestrant in cell culture assays in which the drug is added directly to the cells.

Detailed analyses of the tissue distribution of these two molecules identified that OP- 1250 became concentrated in tumors many-fold greater as compared to plasma.

By contrast, the tumor-to-plasma ratio for fulvestrant was 2 to 3.

Levels of OP-1250 were many-fold higher in tumors compared to those in plasma

(assuming density

Tumor to Plasma

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

Plasma levels were measured by high performance liquid chromatography, or HPLC.

Tumors were removed surgically, weighed, macerated, and extracted to determine the concentration of OP-1250.

Brain penetration

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

Combined with the ability to achieve higher drug levels with OP-1250, due to its improved PK properties, than fulvestrant, we found that we could obtain brain exposure to concentrations of OP-1250 that were greater than 30 times that of fulvestrant.

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

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

OP-1250 demonstrated robust CNS penetration in the mouse brain

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

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

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

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

The mice were then treated with one of the following:

3 mg/kg OP-1250;

vehicle control;

vehicle control with ovariectomy;

5 mg/mouse fulvestrant;

60 mg/kg tamoxifen;

10 mg/kg OP-1250;

75 mg/kg ribociclib, a CDK4/6 inhibitor known to cross the blood brain barrier;

a combination of 3 mg/kg OP-1250 and 75 mg/kg ribociclib;

or vehicle control.

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

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

Monotherapy with 3 mg/kg OP-1250, or 75 mg/kg ribociclib, had small effects on survival, but the combination of both compounds increased survival five-fold from 15 to 80 days compared to vehicle control.

In further contrast, mice treated with 10 mg/kg OP-1250 did not reach median survival at 100 days.

No detectable tumors were found in six of the seven then surviving mice after 80 days, and six of eight mice were still alive after 100 days.

Treatment was stopped at 100 days and the survival of the mice was followed.

In this high dose, OP-1250 group median survival was reached at 125 days, despite suspension of therapy at day 100.

At the conclusion of the experiment at day 160, two of the three surviving mice had no detectable brain tumor and the third had

a slowly growing tumor.

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

Treatment with 10 mg/kg OP-1250 led to long-term survival in a xenograft model

of breast cancer brain metastases

The figure above highlights an experiment in an intracranial breast cancer brain metastases xenograft study.

Endpoints were tumor volume and survival.

Shown is a Kaplan-Meier plot showing the percentage of surviving mice in each group over time.

Tick marks indicate censored data reflecting that mice were enrolled on different days.

Dashed red line shows cessation of treatment in OP-1250 10 mg/kg group.

Treatment with 10 mg/kg OP-1250 led to tumor shrinkage in a xenograft model

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

All tumors responded to OP-1250 treatment.

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

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

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

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

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

of breast cancer brain metastases

ST941 PDX material was stereotactically implanted directly into the brains of nude mice.

Tumor volumes were followed and confirmed via MRI prior to inclusion in study.

Drugs were administered for up to 100 days and tumor growth was followed via MRI.

Daily oral administration of OP-1250 slowed tumor growth in the ST941 brain metastases model at 3 mg/kg, and shrunk tumors at 10 mg/kg.

Ribociclib (ribo) at 75 mg/kg also slowed tumor growth but to a lesser degree than did OP-1250 at 3 mg/kg.

The combination of 3 mg/kg OP-1250 and 75 mg/kg ribociclib substantially slowed tumor growth, to a much greater degree than 3 mg/kg OP-1250 or 75 mg/kg alone, but did not shrink tumors as OP-1250 as 10 mg/kg OP-1250 did.

Combinations with other breast cancer therapies

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

We observed that OP-1250 in combination with three different CDK4/6 inhibitors resulted in increased inhibition of MCF-7 cell proliferation as did OP-1250 in combination with the PI3Kα inhibitor alpelisib in T47D cells.

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

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

The combination of OP-1250 and PI3Kα inhibitors resulted in potent

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

anti-proliferative activity in T47D cells

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

ER+/HER2+ breast cancer

In addition to the favorable efficacy profile of OP-1250 in the Phase 1a dose-escalation portion of the ongoing Phase 1/2 clinical 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Summary of nonclinical properties

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

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

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

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

Clinical development plan for OP-1250 and additional clinical opportunities

In August 2020, we initiated enrollment in our Phase 1/2 open label, multi-center clinical trial of OP-1250, OP- 1250-001, in patients, both women and men, with recurrent, locally advanced or metastatic ER+/HER2- breast

The Phase 1 portion of this trial consists of monotherapy dose-escalation cohorts of three to six patients receiving oral daily doses of OP-1250.

The primary objectives of this portion of the trial are to assess safety, tolerability, PK, pharmacodynamics and the determination of the MTD and/or the RP2D.

We expect to report initial data from the Phase 1 portion of this trial in the second half of 2021.

After determining the MTD or RP2D for OP-1250 as monotherapy, we expect to initiate enrollment in the Phase 2 dose expansion portion of the trial to assess preliminary anti-tumor efficacy of OP-1250 as assessed by response rate and other clinical endpoints including safety, tolerability and PK.

One cohort will enroll metastatic breast cancer patients whose disease has progressed following at least one anti-estrogen therapy in the advanced setting.

A second cohort is exploratory and will enroll metastatic breast cancer patients diagnosed with brain metastases.

Patients will be treated until progression of disease or unacceptable toxicity.

Additionally, ESR1 status and relevant mutations will be evaluated from cell free DNA at various time points throughout the trial in order to assess outcomes in patients with both wild-type and mutant genes.

Preliminary PK data from the first dose cohort is consistent with nonclinical modeling of our Phase 1 starting dose.

We currently anticipate enrolling up to 94 patients in the OP-1250-001 trial.

We expect such trial to generate safety, PK, response and other data in patients with and without ESR1 mutations, and data in patients that are both pre- and post-menopausal.

The design of the trial allows the potential to expand our cohorts to include additional patient subsets as the trial design and data help to identify those patients most likely to benefit.

A robust monotherapy response rate along with a clinically meaningful duration of response would enable us to move directly to a randomized pivotal trial evaluating OP-1250 versus fulvestrant in either an unselected population, a selected subset (patients with ESR1 mutations) or both.

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

After the RP2D is identified in the current OP-1250-001 trial, OP-1250 will be evaluated in combination with both a CDK4/6 inhibitor, and a PI3Kα inhibitor in patients with a PIK3CA mutation.

Each combination will be evaluated in an abbreviated dose escalation starting one to two dose levels below the RP2D of OP-1250 identified in the Phase 1 portion of the trial followed by a small expansion cohort to further evaluate the safety of each of the two combinations.

Assuming that each combination is well tolerated, and that the monotherapy efficacy data from the Phase 1/2 trial is robust, we could move each combination into registration directed pivotal trials.

Historically, treatment for pre-menopausal women with ER+ breast cancer was limited to tamoxifen given the dual source of estrogen in women with functioning ovaries.

Today, some clinicians will treat pre-menopausal women with luteinizing hormone-releasing hormone, or LHRH, agonists to suppress ovarian function in combination with drugs such as AIs or fulvestrant.

Given OP-1250’s potency, and our data in nonclinical models of pre- menopausal animals, we intend to further study OP-1250 in pre-menopausal women without the use of LHRH agonists once preliminary data from the OP-1250-001 trial is obtained.

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

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.

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.

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.

Clinical Trial Collaboration and Supply Agreement with Novartis

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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.

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

be responsible for the conduct of the clinical trials 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.

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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

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

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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.

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.

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

Such an international application, often

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

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

For most jurisdictions, national phase applications claiming priority to a PCT application must be filed within 30 to 32 months of the PCT’s earliest priority date.

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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 February 17, 2021, we own two issued patents in the United States and one granted patent in Japan relating to OP-1250.

Granted claims encompass the OP-1250 compound, pharmaceutical compositions that include OP-1250, and, in some jurisdictions, certain methods of using OP-1250, including in treatment which may involve combination therapy;

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.

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

Neither of the U.S.

patents was awarded any PTA and it is uncertain whether any PTE will be available, and if so, how much.

A related U.S.

application remains pending, and applications are also pending in various ex-U.S.

jurisdictions, including certain major market countries such as Australia, Canada, China, Europe and Japan.

Two additional applications are pending, relating to certain dosing regimens or treatment of particular cancers or patient populations.

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.

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.

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For information regarding risks related to intellectual property, see the section titled “Risk Factors—Risks Related to Our Intellectual Property.”

We have also applied to register the “Olema,” “Olema Oncology,” and “Olema Therapeutics” trademarks with the USPTO.

We have also applied to register the “Olema,” “Olema Oncology,” “Olema Oncology and design,” and “Olema Therapeutics” trademarks with the USPTO.

We do not currently own any U.S.

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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 RG6171 being developed by Roche Holding AG/Genentech, Inc., fulvestrant, marketed as Faslodex® by AstraZeneca PLC, or any generic equivalents of Faslodex® that may be developed, AZD9833 being developed by AstraZeneca PLC, SAR439859 being developed by Sanofi S.A.

and LY3484356 being developed by Eli Lilly and Co.;

companies that develop or produce SERD or non-CERAN SERD therapies, such as 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.

and H3B-6545 being developed by H3 Biomedicines, a subsidiary of Eisai Co., Ltd.

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.

Government Regulation and Product Approval

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

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

minimized and are reasonable in relation to anticipated benefits.

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

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

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

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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) and teaching hospitals, certain ownership and investment interests held by these healthcare providers and their immediate family members.

Beginning in 2022, applicable manufacturers also will be required to report such information regarding its payments and other transfers of value to physician assistants, nurse practitioners, clinical nurse specialists, anesthesiologist assistants, certified registered nurse anesthetists and certified nurse midwives during the previous year.

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

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.

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

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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.

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 identifiable living individual).

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.

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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, pursuant to the transitional arrangements agreed between the United Kingdom and the European Union, we will have to 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.

Pursuant to the Trade and Cooperation Agreement, which went into effect on January 1, 2021, the United Kingdom and European Union agreed to a specified period during which the United Kingdom will be treated like a European Union member state in relation to transfers of personal data to the United Kingdom for four months from January 1, 2021.

This period may be extended by two further months.

Unless the European Commission makes an ‘adequacy finding’ in respect of the United Kingdom before the expiration of such specified period, the United Kingdom will become an ‘inadequate third country’ under the GDPR and transfers of data from the EEA to the United Kingdom will require an ‘transfer mechanism,’ such as the standard contractual clauses.

Furthermore, following the expiration of the specified period, there will be increasing scope for divergence in application, interpretation and enforcement of the data protection law as between the United Kingdom and EEA.

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.

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

Certain aspects of cross-border data transfers under the GDPR are uncertain as the result of legal proceedings in the European Union, including a recent decision by the Court of Justice for the European Union that invalidated the EU-U.S.

Privacy Shield and, to some extent, called into question the efficacy and legality of using standard contract clauses.

This may increase the complexity of transferring personal data across borders.

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.

Recent legal developments in the European Union have created complexity and uncertainty regarding transfers of personal data from the EEA to the United States.

On July 16, 2020, the Court of Justice of the European Union, or CJEU, invalidated the EU-US Privacy Shield Framework, or Privacy Shield, under which personal data could be transferred from the EEA to US

entities who had self-certified under the Privacy Shield scheme.

While the CJEU upheld the adequacy, subject to certain conditions, of the standard contractual clauses (a standard form of contract approved by the European Commission as an adequate personal data transfer mechanism), future regulatory guidance could result in changes to the use of standard contractual clauses.

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.

Further, the vote in the United Kingdom in favor of exiting the European Union, referred to as Brexit, has complicated data protection regulation in the United Kingdom.

In particular, as of January 1,2021, the GDPR has been converted into United Kingdom law and the United Kingdom is now a “third country” under the GDPR.

In addition, 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.

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.

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.

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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.

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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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.

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.

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 “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.”

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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Department of Defense purchases for its TRICARE program via a rebate system.

Participation under the VHCA also requires submission of pricing data and calculation of discounts and rebates pursuant to complex statutory formulas, as well as the entry into government procurement contracts governed

by the Federal Acquisition Regulations.

If our products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.

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

Other member states allow companies to fix their own prices for medicines, but monitor and control company profits.

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

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

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.

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

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

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

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

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

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

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;

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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 December 14, 2018, a U.S.

District Court Judge in the Northern District of Texas ruled that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.

Additionally, on December 18, 2019, the U.S.

Court of Appeals for the 5th Circuit ruled that that the individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the ACA are invalid as well.

Supreme Court is currently reviewing this case, but it is unknown when a decision will be reached.

Although the U.S.

Supreme Court has not yet ruled on the constitutionality of the ACA, 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 instructs 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.

It is unclear how the U.S.

Supreme Court ruling, other such litigation and the healthcare reform measures of the Biden administration will impact the ACA and our business.

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.

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

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

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

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

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 3% in the final fiscal year of this sequester.

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

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 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.

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 also released a final rule, effective November 30, 2020, implementing a portion of the importation executive order providing guidance for states to build and submit importation plans for drugs from Canada.

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 pending review by the Biden administration until March 22, 2021.

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 28, 2020, the United States District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule.

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.

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.

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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, a clinical trial application, or CTA, must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively.

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.

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

The European Union’s regulatory environment for clinical trials is being harmonized as part of the Clinical Trial Regulation, which is expected to take effect in late 2021, there will be a centralized application procedure where one national authority takes the lead in reviewing the application and the other national authorities have only a limited involvement .

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.

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.

the European Economic Area.

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

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

● The Centralized marketing authorization, which is issued by the European Commission through the Centralized Procedure, based on the scientific opinion of the 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 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 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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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.

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

country to country.

In all major territories, 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.

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Employees and Human Capital

As of March 1, 2021, we had 37 employees, 36 of whom were full-time, consisting of clinical, research, operations, regulatory, finance and business development personnel.

As of January 31, 2022, we had 74 employees, 73 of whom were full time, consisting of clinical, research, operations, regulatory, finance and business development personnel.

25 of our employees hold Ph.D.

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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 over the past year and become a public company, we have focused on diversity, inclusion and belonging both at the Board level, where we appointed two global biotech female leaders to our Board in 2020, and for all employees.

As we have grown significantly since our initial public offering in November 2020, we have focused on diversity, inclusion and belonging both at the 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.

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

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

As we further expand our human capital processes and focus in 2021, we strive to create a positive employee experience by fostering an inclusive and equitable culture.

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.

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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 .

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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.

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.

The SEC maintains an internet site that contains reports, proxy and information statements and other information regarding issuers that file electronically with the SEC at www.sec.gov.

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.

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