Olema Pharmaceuticals(OLMA) - 2025 Q2 - Quarterly Results

Corporate Overview This section provides an introductory overview of the company's identity and foundational information Legal Disclaimer This section outlines legal disclaimers for forward-looking statements, product status, and data interpretation - The presentation contains forward-looking statements regarding research, clinical development, commercial launch, financial sufficiency, and regulatory approvals, which are subject to risks and uncertainties[3] - Product candidates discussed are under clinical study and not yet approved by the U.S. FDA, with no claims made regarding their safety or effectiveness[4] - Cross-trial comparisons against third-party data are presented with inherent risks due to differences in study design and should be interpreted with caution[4] Strategic Focus & Market Opportunity This section details the company's strategic focus and significant market opportunities in metastatic breast cancer Transforming the Treatment Paradigm Olema Pharmaceuticals is dedicated to revolutionizing the treatment landscape for metastatic breast cancer (MBC) by advancing two key programs: palazestrant for first-line (1L) and second/third-line (2/3L) MBC, and OP-3136, a potential best-in-class KAT6 inhibitor - Olema is focused on transforming the metastatic breast cancer treatment paradigm[5] - Advancing palazestrant with blockbuster potential in 1L MBC with ribociclib and 2/3L MBC as a monotherapy[7] - Progressing OP-3136, a potent and potential best-in-class KAT6 inhibitor[7] ER+/HER2- Global Metastatic Breast Cancer Market The global ER+/HER2- metastatic breast cancer market represents a significant opportunity, estimated at over $20 billion, with the majority of all breast cancers falling into this subtype. Both 1L and 2/3L settings offer substantial market potential - The ER+/HER2- global metastatic breast cancer market presents a $20 billion+ opportunity[8] ER+/HER2- MBC Market Opportunity (2025 Estimates) | Category | Patients (Global) | Duration of Therapy | Global Market Potential (USD) | | :------------------- | :------------------ | :------------------ | :---------------------- | | 1L ER+/HER2- MBC | ~100K+ | ~6-36+ months | $10 billion+ | | 2/3L ER+/HER2- MBC | ~150K+ | ~2-12+ months | $5 billion+ | | Total Global Market | | | ~$20 billion+ | - 70% of all breast cancers are ER+/HER2-[8] Palazestrant Program This section details the Palazestrant program, focusing on its development as a potential best-in-class therapy for MBC Palazestrant Overview & Best-in-Class Potential Palazestrant is positioned as a potential best-in-class, backbone endocrine therapy for metastatic breast cancer, designed to offer complete ER antagonism, activity in both ESR1 wild-type and mutant tumors, good tolerability, and an optimal oral PK profile - Palazestrant has the potential to become a best-in-class, backbone endocrine therapy for metastatic breast cancer[9] - Key properties include complete ER antagonism, activity in ESR1 wild-type and mutant tumors, good tolerability, combinability at full doses, and optimal oral PK profile[10] - Designed to help patients feel better, longer[10] Palazestrant Mechanism of Action & Properties Palazestrant is a differentiated oral Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD) that completely inactivates the ER by targeting both AF1 and AF2, unlike SERM/SERDs which only partially inactivate ER. This complete antagonism is crucial for shutting off all ER signaling and delivering superior therapeutic exposure - Palazestrant is a Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD), currently in Phase 3 for monotherapy and combination[27] - It completely inactivates the ER (AF1 and AF2) by recruiting N-CoR, preventing transcription of proliferation genes, unlike SERM/SERDs which only partially inactivate ER (AF2 only)[29] - Palazestrant is a potent ER degrader and uniquely meets optimal drug-plasma exposure, demonstrating potential activity in ESR1 wild-type and mutant tumors[31] Palazestrant in Combination with Ribociclib in 1L ER+/HER2- MBC Palazestrant, in combination with ribociclib, is being developed for 1L ER+/HER2- MBC, aiming for significant improvement in PFS and OS. Initial Phase 1b/2 data show promising efficacy and a safety profile consistent with ribociclib + ET, with a pivotal Phase 3 OPERA-02 trial initiating in Q3 2025 Key Properties & Market Potential (1L MBC) This section highlights palazestrant's unique properties, efficacy potential, and anticipated global market entry in 1L MBC - Palazestrant is the only investigational drug combining with ribociclib in 1L MBC, which is quickly becoming the CDK4/6i of choice[13][14] - Potential for significant improvement in PFS and OS, with activity in ESR1 wild-type and mutant tumors[13] - Anticipated potential global market opportunity by 2028-2029[13] Upcoming Milestones (1L Combo) This section outlines key upcoming milestones for palazestrant and ribociclib in 1L MBC, including trial initiation, data, and launch - Initiate pivotal Phase 3 OPERA-02 trial in Q3 2025[33] - Present mature Phase 1b/2 palazestrant + ribociclib data at ESMO 2025[33] - Anticipated announcement of top-line results from OPERA-02 in 2028, with potential FDA approval and U.S. launch in 2029[33] Phase 1b/2 Study Design & Demographics This section details the design and patient demographics of the Phase 1b/2 study for palazestrant with ribociclib in MBC - Phase 1b/2 study evaluated palazestrant (90 mg / 120 mg) in combination with ribociclib (600 mg) in ER+/HER2- advanced or metastatic breast cancer patients[35] - Key eligibility included up to 2 prior endocrine therapies ± CDK4/6i and up to 1 prior chemotherapy line[35] Phase 1b/2 Study Demographics (N=62) | Characteristic | Value | | :---------------------------------- | :---- | | Median age (years) | 61 | | Female sex | 100% | | Measurable disease at baseline | 68% | | Visceral disease | 58% | | Prior CDK4/6 inhibitor | 74% | | ESR1 mutations at baseline (ctDNA) | 28% | Phase 1b/2 Safety Profile This section presents the safety profile of palazestrant with ribociclib from the Phase 1b/2 study, highlighting tolerability and adverse events - The combination was well tolerated with no DLTs, and the safety profile was consistent with ribociclib + ET[37][38] - No dose modifications were required for palazestrant, and no patients discontinued palazestrant alone due to TEAEs[14][38] Common TEAEs (≥25%) in Palazestrant + Ribociclib (n=62) | TEAEs (All grades) | Palazestrant + Ribociclib (n=62) (%) | | :----------------- | :------------------------------- | | Neutropenia | 82% (Grade 3: 45%, Grade 4: 10%) | | Nausea | 79% (Grade 3: 3%) | | Fatigue | 60% (Grade 3: 3%) | | Diarrhea | 50% (Grade 3: 3%) | | Anemia | 44% (Grade 3: 2%) | | WBC decrease | 42% (Grade 3: 16%, Grade 4: 2%) | Phase 1b/2 Efficacy Data This section presents efficacy data from the Phase 1b/2 study, including median PFS and competitive benchmarks Median PFS (mPFS) in Phase 1b/2 Study (Data Cutoff: Feb 18, 2025) | Patient Group | Median PFS (months) | | :------------------------------------------ | :------------------ | | All Patients (120 mg palazestrant + ribociclib, n=56) | 13.8 | | Patients with Prior CDK4/6i + ET (n=40) | 13.1 | - The median PFS of 13.1 months in prior CDK4/6i patients compares favorably to competitive benchmarks like MAINTAIN (ET + Ribociclib: 12.0 months, ET + Placebo: 5.3 months) and other SERDs[41][42] - 6-month PFS Rate was 74% for all patients and 68% for patients with prior CDK4/6i + ET[40] OPERA-02 Phase 3 Pivotal Trial Design This section details the design of the OPERA-02 Phase 3 pivotal trial for palazestrant with ribociclib in 1L ER+/HER2- MBC - OPERA-02 is a ~1,000-patient Phase 3 pivotal trial evaluating palazestrant (90 mg) in combination with ribociclib (600 mg) versus letrozole (2.5 mg) + ribociclib (600 mg) in 1L ER+/HER2- MBC[45][46] - Primary endpoint is PFS (Investigator), with key secondary endpoint OS. Trial initiation is in 2025 in collaboration with Novartis[46] - Eligibility includes ER+/HER2- MBC, any menopausal status, no prior systemic therapy or CDK4/6 inhibitor for MBC[46] Strategic Rationale: TAGRISSO Case Study This section provides the strategic rationale for OPERA-02, drawing parallels with the TAGRISSO case study for resistance suppression in MBC - The FLAURA trial for TAGRISSO demonstrated that suppressing common resistance mechanisms (EGFR T790M mutation) led to significant PFS improvement and label expansion into 1L[47][48] - Comparable EGFR mutation rates after 1L TKI to ESR1 mutation rates after 1L CDK4/6i + AI (~40-50%) suggest a similar strategic opportunity for OPERA-02[47] - OPERA-02 is designed to demonstrate greater PFS by suppressing the most common resistance mutation (ESR1) in 1L endocrine sensitive MBC patients, mirroring TAGRISSO's success[48] Palazestrant Monotherapy in 2/3L ER+/HER2- MBC Palazestrant monotherapy offers a first market entry opportunity in 2/3L ER+/HER2- MBC by 2027, aiming to be a best-in-class single agent. Phase 1/2 data show compelling efficacy in ESR1 mutant and wild-type tumors with a well-tolerated safety profile, supporting the ongoing pivotal Phase 3 OPERA-01 trial Key Properties & Market Entry (2/3L Mono) This section highlights palazestrant monotherapy's key properties and anticipated market entry in 2/3L MBC as a best-in-class agent - Palazestrant monotherapy in 2/3L ER+/HER2- MBC offers the first opportunity for market entry in 2027[15][17] - Potential to become the best-in-class single agent endocrine therapy, improving upon current standard of care[15] - Favorable pharmacokinetic properties include high oral bioavailability, dose-proportional exposure, and a long half-life supporting once-daily dosing[18] Upcoming Milestones (2/3L Mono) This section outlines key upcoming milestones for palazestrant monotherapy in 2/3L MBC, including trial accrual, results, and launch - Advance patient accrual in pivotal Phase 3 OPERA-01 trial in 2025[51] - Announce top-line results from OPERA-01 in H2 2026[51] - Anticipated submission of New Drug Application (NDA) and potential FDA approval and U.S. commercial launch in 2027[51] Phase 1/2 Study Design This section details the design of the Phase 1/2 study for palazestrant monotherapy in advanced MBC, including objectives - Phase 1/2 study evaluated palazestrant as a monotherapy in patients with advanced or metastatic ER+/HER2- breast cancer[52][53] - Key eligibility criteria included 1-4 prior endocrine therapies for metastatic disease and up to 1 line of prior chemotherapy[53] - Primary objectives were pharmacokinetics, safety, and tolerability at RP2D, with secondary objectives including efficacy (ORR, CBR, DOR)[53] Phase 1/2 Safety Profile This section presents the safety profile of palazestrant monotherapy from the Phase 1/2 study, highlighting tolerability and adverse events - Palazestrant was well-tolerated, with most treatment-emergent adverse events (TEAEs) being Grade 1/2[55] Common TEAEs (≥15%) in Palazestrant 120 mg (n=83) | TEAEs (All grades) | Palazestrant 120 mg (n=83) (%) | | :----------------- | :------------------------- | | Nausea | 65% (Grade 3: 3%) | | Vomiting | 30% (Grade 3: 1%) | | Fatigue | 27% (Grade 3: 3%) | | Neutropenia | 25% (Grade 3: 3%, Grade 4: 6%) | | Headache | 20% | | Constipation | 18% | | AST increased | 16% (Grade 3: 1%) | - Grade 4 neutropenia events were observed in 6 patients, managed with dose interruption/reduction or discontinuation, with recovery[55] Phase 1/2 Efficacy Data This section presents efficacy data from the Phase 1/2 study, including median PFS in ESR1 mutant and wild-type tumors, showing best-in-class potential Median PFS (mPFS) in Phase 1/2 Study (Data Cutoff: July 7, 2023) | Patient Group (2/3L ±CT) | Median PFS (months) | | :----------------------- | :------------------ | | ESR1 Mutant (n=23) | 7.3 | | ESR1 Wild-Type (n=21) | 5.5 | - Palazestrant shows best-in-class potential, being the only CERAN/SERD with potential for approval in both ESR1 mutant and wild-type tumors[58] - The mPFS of 7.3 months in ESR1 mutant patients and 5.5 months in ESR1 wild-type patients compares favorably to other SERDs in CDK4/6i-experienced patients[57][59] OPERA-01 Phase 3 Monotherapy Trial Design This section details the design of the OPERA-01 Phase 3 monotherapy trial, aiming for superior efficacy in ESR1 mutant and wild-type tumors - OPERA-01 is a Phase 3 monotherapy trial designed to show superior efficacy in ESR1 mutant and ESR1 wild-type tumors[60][61] - The trial includes a dose selection part (Palazestrant 120 mg vs 90 mg) and a dose assessment part (Palazestrant vs. SOC Endocrine Therapy) with ~510 patients[61] - Primary endpoint is PFS (BIRC) in ESR1 mutant and ESR1 mut-nd, with top-line results expected in H2 2026[61] Commercial Launch Planning (2/3L Mono) This section outlines commercial launch planning for palazestrant monotherapy in 2/3L MBC, including market potential and preparations - Planning for commercial launch of palazestrant as a monotherapy in 2/3L ER+/HER2- MBC is anticipated in 2027[62] - The annual U.S. incidence is estimated at ~40,000 patients, with a U.S. market potential of ~$3-5 billion in the 2/3L setting[62] - Preparatory work includes establishing manufacturing supply and distribution, and building a targeted field force of ~75–100 reps to cover U.S. breast oncologists[62] OP-3136 Program This section introduces the OP-3136 program, highlighting its development as a novel KAT6 inhibitor for breast cancer and solid tumors OP-3136 Overview & Value Potential OP-3136, Olema's potent and selective KAT6A/B inhibitor, represents an exciting new target in breast cancer with the potential to generate further value and meaningfully impact the MBC treatment landscape. Preclinical data show synergistic activity with palazestrant and CDK4/6 inhibitors, with a Phase 1 study currently enrolling - OP-3136 has the potential to generate further value and meaningfully impact the MBC treatment landscape[19] - KAT6 is an exciting new target in breast cancer, with promising preclinical data in breast cancer and other solid tumors[20] - OP-3136 is potent and selective against KAT6A/B, synergizes with palazestrant in preclinical models, and has a potential global market opportunity of $5 billion+[20] OP-3136 at a Glance OP-3136 is a KAT6A/B inhibitor currently in Phase 1 development, with an initial development indication for 2/3L ER+/HER2- MBC. Initial monotherapy and combination data from the Phase 1 study are anticipated in 2026 - Mechanism of Action: KAT6A/B inhibitor[65] - Stage of Development: Phase 1, with initial development indication for 2/3L ER+/HER2- MBC[65] - Upcoming Milestone: Initial monotherapy and combination data from the Phase 1 study expected in 2026[64] Mechanism of Action & Target Validation OP-3136 targets KAT6, an exciting and validated target in ER+/HER2- MBC. KAT6 acetylates chromatin, enabling transcription and proliferation, and OP-3136 prevents this by blocking histone acetylation. Clinical proof of concept for KAT6 inhibitors has been demonstrated by Pfizer, validating KAT6 as an active new target and highlighting the potential for synergistic combination therapies - OP-3136 is a potent and selective KAT6A/B inhibitor, orally bioavailable with high free drug exposure, and synergizes with palazestrant and CDK4/6 inhibitors in preclinical models[66] - KAT6 acetylates chromatin, enabling transcription and proliferation; OP-3136 inhibits KAT6, stopping histone acetylation and blocking transcription of proliferation-associated genes[68] - KAT6 is a clinically validated target, with overexpression correlated with worse clinical outcomes in ER+ breast cancer. Pfizer's first-in-human data for a KAT6 inhibitor validates it as an active new target and shows synergistic activity with ET[69][72] Preclinical Data & Selectivity OP-3136 demonstrates high potency and superior selectivity for KAT6A/B over other essential KAT family members (KAT5 and KAT8) compared to PF-8144, suggesting a potential safety advantage. Preclinical studies also show strong synergistic anti-tumor activity when combined with palazestrant, leading to significant tumor regression Biochemical Potency (IC50 nM) and Selectivity | Target | OP-3136 | PF-8144 | | :----- | :------ | :------ | | KAT6A | 9 | 7 | | KAT6B | 1 | 1 | | KAT7 | 108 | 88 | | KAT5 | 6792 | 1288 | | KAT8 | 4490 | 1372 | - OP-3136 showed >500-fold selectivity over KAT5 and KAT8, which may confer a safety advantage over alternative products like PF-8144[74] - OP-3136 demonstrated synergistic activity in combination with palazestrant in preclinical breast cancer models, resulting in strong tumor regression and improved anti-tumor efficacy compared to PF-8144 combinations[75][77] Phase 1 Study Design The OP-3136 Phase 1 study, with IND cleared by FDA, is currently recruiting patients. It includes dose escalation for monotherapy and combination, followed by dose expansion cohorts for OP-3136 with fulvestrant, palazestrant, and a triple combination with palazestrant + ribociclib - The IND for OP-3136 has been cleared by the FDA, and the Phase 1 study is actively recruiting patients[78][79] - The study design includes dose escalation (monotherapy and combination) and dose expansion cohorts for OP-3136 + Fulvestrant, OP-3136 + Palazestrant, and OP-3136 + Palazestrant + Ribociclib[79] - Key eligibility criteria include ER+/HER2- MBC (or MCRPC or MNSCLC for Part 1A) and at least one prior line with CDK4/6i + ET for combination cohorts[79] Overall Pipeline & Strategic Milestones This section provides an overview of the company's pipeline and outlines key strategic milestones for advancing programs and generating value Pipeline Overview Olema is rapidly advancing its pipeline of novel therapies, including Palazestrant (CERAN/SERD) for ER+/HER2- metastatic breast cancer and OP-3136 (KAT6 Inhibitor) for breast cancer and other solid tumors, targeting significant global market opportunities - Olema is rapidly advancing its pipeline of novel therapies through the clinic[22] Olema Pipeline and Market Opportunities | Product Candidate | Mechanism/Target | Indication | Stage | Potential Global Market Opportunity* (USD) | | :---------------- | :--------------- | :--------- | :---- | :--------------------------------- | | Palazestrant | CERAN/SERD | ER+/HER2- metastatic breast cancer | Planned pivotal Phase 3 trial evaluating palazestrant combination with ribociclib in 1L MBC; Ongoing pivotal Phase 3 trial evaluating palazestrant as a monotherapy in 2/3L MBC | $10 billion+ (1L), $5 billion+ (2/3L) | | OP-3136 | KAT6 Inhibitor | Breast cancer and other solid tumors | Ongoing Phase 1 study evaluating OP-3136 monotherapy and combination in advanced or metastatic: ER+/HER2- breast cancer, Castrate-resistant prostate cancer, Non-small cell lung cancer | $5 billion+ | Value-Generating Catalysts & Corporate Priorities Olema has a clear roadmap of value-generating catalysts through 2030, focusing on advancing global registrational studies, achieving product approvals and launches for Palazestrant in both 2/3L and 1L MBC, and progressing the OP-3136 program with initial clinical data. These milestones are aimed at transforming the MBC treatment paradigm and generating significant shareholder value - Olema aims to transform the metastatic breast cancer treatment paradigm and generate significant shareholder value by 2030[80] - Key milestones include executing global registrational studies (2025), product approval and launch for Palazestrant in 2/3L MBC (2027), pivotal OPERA-02 readout in 1L MBC (2028), OP-3136 clinical data and OPERA-01 readout in 2/3L MBC (2026), and label expansion in 1L MBC (2029)[23][81] - Palazestrant is highly differentiated with activity in ESR1 mutant and wild-type tumors, with OPERA-01 and OPERA-02 trials on track. OP-3136 is an exciting new target, synergizes with Palazestrant, and its Phase 1 study is enrolling with initial data expected in 2026[82] Conclusion This section concludes with the company's commitment to advancing therapeutic solutions for breast cancer and beyond - Olema Pharmaceuticals is committed to advancing medicines for breast cancer and beyond[83]