Overcoming Resistance In Cancer Jefferies Healthcare Conference June 6th, 2019 ORIC Pharmaceuticals: Dedicated to Overcoming Resistance in Cancer Lead program targeting primary resistance Additional pipeline candidates focused pathway for multiple cancers on key resistance mechanisms • Potent and selective glucocorticoid receptor antagonist • Potential best-in-class and first-in-class programs targeting entering multiple phase 1b studies in 2019 resistance to multiple therapeutic classes Internal drug discovery capabilities Leadership team with significant support further pipeline expansion oncology experience • Expertise in nuclear hormone receptors and in identifying • Distinguished founders, investors and management with novel targets involved in therapy resistance proven track records of success 1 Founders and Investors with Significant Oncology Experience Distinguished Founders and Scientific Advisors Charles Sawyers, MD Scott Lowe, PhD Rich Heyman, PhD Richard Scheller, PhD Founder, SAB Founder, Consultant Founder, BOD Chair BOD Member, SAB • MSKCC and HHMI Investigator • MSKCC and HHMI Investigator • CEO/founder Aragon • CSO and Head of Therapeutics • Key role in discovery and • Chair, Cancer Biology & Genetics (sold to Johnson & Johnson) 23andMe development of Gleevec, Sprycel, and Cancer Research • CEO/founder Seragon • Previously CSO Genentech Xtandi and Erleada • Expert in tumor networks, and (sold to Roche) • National Academy of Sciences • National Academy of Sciences molecular determinants of • Board member at Gritstone, • Institute of Medicine treatment response Vividion, Metacrine Over $120 Million Raised in Series A/B/C Kravis Investment Partners 2 Executive Team with Expertise in Building Leading Oncology Companies Jacob Chacko, MD • Previously CFO of Ignyta (acquired by Roche), raised over $500mm in capital Chief Executive Officer • TPG Capital (completed $10bn of aggregate acquisitions) and McKinsey • Board member of Turning Point Therapeutics and 4D Molecular Therapeutics; previously Bonti, RentPath, EnvisionRx, Par Pharma, IMS, Quintiles Pratik Multani, MD • Previously CMO of Ignyta, led development and regulatory for entrectinib & other clinical assets Chief Medical Officer • CMO of Fate Therapeutics; development leadership at Salmedix, Kanisa and Kalypsys • Contributed to development of Rituxan and Zevalin at Idec; earlier at Dana Farber and Mass General Matt Panuwat • Previously SVP of BD at Prothena, established R&D collaboration with Celgene for up to $2.2bn Chief Business Officer • Head of BD at Medivation (acquired by Pfizer), led M&A including the acquisition of talazoparib • Global Healthcare Investment Banking at Merrill Lynch Edna Chow Maneval, PhD • Previously SVP of CD at Ignyta; clinical lead for entrectinib, led transition team through global filings SVP Clinical Development • VP of CD at Seragon and Aragon, clinical lead for apalutamide • Led pivotal phase 3 study in RCC for Sutent at Pfizer 3 ORIC Strategy Focuses on Resistance to Multiple Treatment Modalities Immune Chemotherapy Therapy Targeted Hormone Therapy Therapy 4 Pipeline of Assets Focused on Resistance in Oncology Potential to Overcome Resistance to: Exploratory / Lead ID / Preclinical / Chemo- Immune Hormone Targeted Phase 1 Hit ID Optimization IND Enabling therapy therapy therapy therapy Phase 1a Complete ORIC-101 (GR Antagonist) Phase 1b Initiated 2Q19 CD73 Potential best-in-class oral small molecule targeting the adenosine pathway Target 3 Potential first-in-class candidate targeting an oncogenic driver and mechanism of resistance in squamous cancers Additional programs generated from research platform and in-licensing 5 Glucocorticoid Receptor (GR) Overview 6 Glucocorticoids Act Via the Glucocorticoid Receptor and Regulate Multiple Physiological Processes Glucocorticoids 1 1. Glucocorticoids regulate metabolism, cell growth, inflammation, apoptosis α Cytoplasm GR 2 and differentiation HSPs 2. Glucocorticoids signal through the glucocorticoid receptor (GR), a nuclear receptor expressed across a variety of tissues 3 3. Upon ligand binding, GR translocates Transcription GREs to nucleus & triggers transcription of a spectrum of genes Transcription Regulation Nucleus Source: Azher et al. J Cell Physiol (2016) and Clark et al. Curr Top Med Chem (2008). Note: HSP: heat shock protein, GRE: glucocorticoid response element. 7 GR is Overexpressed in Many Solid Tumors and Associated with Therapy Resistance Tumors with High GR Expression Associated GR Overexpressed in Many Solid Tumors (1) with Worse Clinical Outcomes (Chemotherapy Treated ER─ Breast Cancer Patients) (2) 100 100% 1.0 90 0.8 GR Low 80% 75 0.6 Free Survival - 60% 0.4 40-50 40-50 Relapse 0.2 GR High 40% P = < 0.01 30 0.0 20-30 % GR Positive Tumors (IHC) % Tumors GR Positive 0 2 4 6 8 10 20% Years 6 • Elevated GR expression also correlated with poor prognosis in: (3) 0% • Endometrial cancer Colon CRPC TNBC Ovarian Pancreatic NSCLC Renal Melanoma • CRPC treated with enzalutamide (4) Note: IHC: immunohistochemistry, CRPC: castration-resistant prostate cancer, TNBC: triple negative breast cancer, NSCLC: non-small cell lung cancer, ER: estrogen receptor. (1) Arora et al. Cell (2013), Block et al. Canc Man Res (2017) and ORIC data. (2) Pan et al. Clin Cancer Res (2011). (3) Tangen et al. Gynecol Oncol (2017). (4) Arora et al. Cell (2013). 8 GR Expression is Associated with Clinical Resistance to Enzalutamide in the Treatment of Prostate Cancer Elevated GR Expression Seen in Tumors of Patients Elevated GR Expression Associated with a Limited PSA Responding Poorly to Enzalutamide Treatment Response in Enzalutamide-Treated Patients All 3 patients with high GR expression at baseline had a poor clinical response to enzalutamide Initial observations from Sawyers’ lab established a correlation between increased GR expression and poor clinical response to enzalutamide, and raised the possibility that AR inhibition may induce GR expression in some patients Source: Arora et al. Cell (2013). Note: Patients who continued to benefit from enzalutamide therapy for greater than 6 months were defined as good responders, whereas those in whom therapy was discontinued earlier than 6 months due to a lack of clinical benefit were classified as poor responders. *: p = < 0.05, **: p = < 0.01. 9 In Addition to Direct Action on Tumor, GR May Also Modulate Therapy Response by Acting on the Immune System GR Acts as a Pro-Survival GR Inhibits Immune Function Mechanism in Tumors in the Tumor Microenvironment Glucocorticoids Immune Suppression Treg MDSCz ↓ Apoptosis (Tumor Progression) Th2 ↓ Adhesion CD8+ ↓ Inflammation ↑ ↑ “Stemness” Tregs + Tumor ↑ MDSCs Metabolic changes Microenvironment ↓ CD8+ T cells Pro-Survival Mechanisms Glucocorticoids • Counteracting GR is expected to block the transcriptional • Counteracting GR is expected to stimulate the immune program driving tumor cell survival and therapy escape system and overcome resistance to therapy Note: Treg: T regulatory cell, MDSC: myeloid-derived suppressor cell. 10 ORIC-101 Overview 11 ORIC-101 is a Potent and Selective GR Antagonist that was Specifically Designed for Development in Oncology Mifepristone Relacorilant ORIC-101 (steroidal) (non-steroidal) (steroidal) ORIC Medicinal ORIC-101 Differentiation Chemistry GR antagonism 2.9 16 vs. Mifepristone IC [nM] 7.3 50 • No AR agonism • Reduced CYP inhibition AR agonism 25 >2500 >2500 IC50 [nM] ORIC-101 Differentiation vs. Relacorilant PR antagonism • Reduced CYP inhibition 0.4 >2500 22 IC50 [nM] Better than ORIC-101 Inhibitor of Inhibitor of Drug-Drug Inhibitor of Comparable to ORIC-101 CYP2C8, CYP2C9 and CYP2C8, CYP2C9 and Interaction CYP3A4 CYP3A4 CYP3A4 Improved Worse than ORIC-101 Profile ORIC-101 is a potent and selective GR antagonist without CYP liabilities of other molecules (CYP2C8 plays a critical role in metabolism of taxanes and enzalutamide) Source: ORIC data. Note: GR: glucocorticoid receptor, AR: androgen receptor, PR: progesterone receptor. GR antagonism, AR antagonism and PR antagonism measured by luciferase assay. 12 ORIC-101 Overcomes GR-Driven Chemotherapy Resistance Across a Wide Range of Human Cancer Cell Lines ORIC-101 + GR Ligand + GR Ligand + Vehicle Chemo Chemo Chemo Ovarian Cancer GR Positive TNBC GR Positive NSCLC GR Positive Green = tumor cell colony Ovarian Cancer GR Negative % = Percentage of plate covered with tumor cell colonies Source: Jahchan et al. AACR NCI EORTC Poster (2017) and additional ORIC data. Note: Chemotherapeutic agent is gemcitabine for ovarian cancer and paclitaxel for TNBC and NSCLC. GR ligand is dexamethasone. 13 ORIC-101 Overcomes GR-Driven Resistance to Chemotherapy in TNBC Xenograft Models 2000 ) Cortisol (control) 3 1500 1000 Mean Tumor Volume (mm 500 Cortisol + paclitaxel Cortisol + paclitaxel + ORIC-101 0 0 10 20 30 40 50 60 Days after Treatment Comparable activity demonstrated in xenograft models of ovarian cancer, other TNBC and in combination with other classes of chemotherapy Source: ORIC data. Note: HCC-1806 xenograft model. Paclitaxel dosed 15 mg/kg, Q3Dx5, IP. ORIC-101 dosed 150 mg/kg, QD, PO. Cortisol added to drinking water throughout study. Cortisol supplementation required for xenograft models to activate human GR since primary glucocorticoid utilized by rodents is corticosterone. Cortisol levels intended to simulate physiological corticosteroid levels in humans. 14 ORIC-101 Reverses Enzalutamide Resistance in an In Vitro Prostate Cancer Model Androgen-Dependent Organoid (AR+, GR+) 500000500000 400000400000 300000300000