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 CTG
Cell Viability Cell 200000200000 (Luminescent Output)
100000100000
0 Vehicle ORIC-101 Dex DHT DHT + DHT + DHT + Enza Enza + Enza +
Dex Dex + ORIC-101
GR activation by glucocorticoid treatment (e.g. dexamethasone) drives enzalutamide resistance in vitro;
ORIC-101 resensitizes these prostate cancer cells to enzalutamide
Source: ORIC data. Note: BMC5 organoid model. Dex: dexamethasone, DHT: dihydrotestosterone, Enza: enzalutamide.
15 Recently Completed Phase 1a Study Supports Broad Clinical Development Strategy for ORIC-101
Phase 1a: Single Agent PK, PD, and Safety Phase 1b: Multiple Indications and Combinations (Complete)
Start Data 2Q19 • Initial Safety / PK (4Q19) Phase 1b • RP2D (1Q20) Solid tumors • Initial Translational / ORIC-101 + Abraxane Efficacy (1H20)
3Q19 • Initial Safety / PK (1H20) Phase 1a Phase 1a Phase 1b NHV Multiple • Initial Translational / NHV Single Prostate cancer Ascending Dose / Efficacy (2H20) Ascending Dose ORIC-101 + AR modulator Formulation
4Q19 • Initial Safety / PK (1H20) Phase 1b • Initial Translational / Solid tumors Efficacy (2H20) ORIC-101 + PD-1 / PD-L1
Note: NHV: normal healthy volunteer.
16 ORIC-101 Demonstrated a Favorable Safety and Tolerability Profile in Phase 1a
200 mg (n=6) 350 mg (n=6) Treatment-Emergent AEs All doses (n=56) Grade 1 Grade >2 Grade 1 Grade >2 Nausea 7 ─ ─ 3 ─ Diarrhea 3 ─ ─ 1 ─ Abdominal pain 2 ─ ─ 1 ─ Dysgeusia 2 ─ ─ 2 ─ Dyspepsia 2 ─ ─ 2 ─ Fatigue 2 ─ ─ 2 ─ Back pain 1 ─ ─ ─ ─ Catheter site swelling 1 ─ ─ ─ ─ Decreased appetite 1 ─ ─ 1 ─ Dry eye 1 ─ ─ ─ ─ Gastroesophageal reflux disease 1 ─ ─ 1 ─ Headache 1 ─ ─ ─ ─ Hot flush 1 ─ ─ 1 ─ Insomnia 1 ─ ─ ─ ─ Musculoskeletal chest pain 1 1 ─ ─ ─ Pain in extremity 1 ─ ─ ─ ─ Proctalgia 1 ─ ─ 1 ─ Somnolence 1 ─ ─ 1 ─ Vomiting 1 1 ─ ─ ─
All adverse events observed across phase 1a studies were limited to grade 1; higher rate of GI events at 350 mg attributed, at least in part, to pill burden of the early clinical formulation (7 capsules)
Source: ORIC data.
17 Exposure of ORIC-101 from the Phase 1a Multiple-Ascending Dose Study Supports Once-Daily Dosing
1 ORIC-101 350 mg (Day 10) ORIC-101 200 mg (Day 10) M) µ
0.1 Target exposure
0.01 Unbound Plasma Concentration ( Half Life (t1/2) = 14-15 hours
0.001 0 5 10 15 20 25 Time (hr)
Steady-state Cmax and AUC increased in a dose dependent manner
Source: ORIC data.
18 Mean Plasma Cortisol Levels Increased with ORIC-101 GR Inhibition in the Phase 1a Multiple-Ascending Dose Study
Mean Plasma Cortisol (ORIC-101 200 mg Cohort) Mean Plasma Cortisol (ORIC-101 350 mg Cohort)
300 300
250 250
200 200
150 150
100 100 Mean Plasma Cortisol(ng/mL) Mean Plasma Cortisol(ng/mL) 50 50
0 0 Day 1 Day 2 Day 4 Day 8 Day 10 Day 14 Day 1 Day 2 Day 4 Day 8 Day 10 Day 14
ORIC-101 Daily Dosing ORIC-101 Daily Dosing
Mean waking plasma cortisol concentrations increased over time with once-daily ORIC-101 (44% increase on day 8 in 200 mg cohort and 78% increase on day 10 in 350 mg cohort); plasma cortisol concentrations decreased after ORIC-101 was discontinued
Source: ORIC data.
19 ORIC-101 Was Associated with Downregulation of Key Pharmacodynamic Biomarkers of GR Activity in the Phase 1a Multiple-Ascending Dose Study
FKBP5 Expression DDIT4 Expression
0.020 0.020 200 mg 200 mg
0.015 0.015
0.010 0.010
0.005 0.005 Relative mRNA Levels Relative mRNA Levels
0.000 0.000
Day 1 Day 1 Day 8 Day 8 Day 1 Day 1 Day 8 Day 8 0hr 12hr 0hr 12hr Day0hr 10 12hrDay 10 0hr 12hr 0hr 12hr Day0hr 10 12hrDay 10 (0hr) (0hr) (0hr) (0hr) (0hr) (0hr) (12hr) (12hr) (12hr) (12hr) (12hr) (12hr) Day 1 Day 8 Day 10 Day 1 Day 8 Day 10 0.030 0.030 350 mg 350 mg
0.020 0.020
0.010 0.010 Relative mRNA Levels Relative mRNA Levels
0.000 0.000
Day 1 Day 1 Day 8 Day 8 0hrd1-0hr 12hr 0hrd8-0hr 12hr 0hr 12hr 0hr 12hr 0hr 12hr Day0hr 10 12hrDay 10 d1-12hr d8-12hr d10-0hr (0hr) (0hr) (0hr) d10-12hr (12hr) (12hr) (12hr) Day 1 Day 8 Day 10 Day 1 Day 8 Day 10 Rapid and sustained functional GR inhibition were demonstrated in PBMCs of healthy volunteers with once-daily ORIC-101
Source: ORIC data. Note: ORIC-101 was dosed once daily for 10 days. PBMC: peripheral blood mononuclear cell, FKBP5: FK506 binding protein, DDIT4: DNA-damage-inducible transcript 4 protein.
20 ORIC Will Broadly Explore PD Activity and Predictive Biomarkers to Determine Patient Selection and Confirm Target Engagement in Phase 1b
1.251.25 • PD biomarker modulation will be measured to assess target engagement FKBP5 FKBP5 1.001.00 G IL Z G IL Z
and pathway modulation similar to phase 1a 0.75 0.75 • Cortisol levels in plasma 0.500.50 0.250.25 • GR target genes in PBMCs (e.g. FKBP5, DDIT4, GILZ) 0.000.00 m Dexl) to RNA (Rel Expression
Relative mRNA Expression Dex Dex + Dex + Dex +
ORIC37nM-101 ORIC-101 ORIC-101 111nM 333nM
Dex 30nM (37nM) (111nM) (333nM) Dex30nM + ORIC-101
GR IHC • Proprietary CLIA IHC test developed by ORIC will be used for patient Low Medium High stratification
Cell Line • Proprietary GR gene activation signature developed by ORIC will be used for patient stratification and monitoring PD modulation • Developed using NGS and NanoString technologies Genes
Note: CLIA: clinical laboratory improvement amendments, NGS: next-generation sequencing. GR “off” GR “on”
21 Phase 1b Study of ORIC-101 in Combination with Abraxane in Patients with Solid Tumors Initiated in 2Q19
Phase 1b: Dose Identification (n = 3-6 per dose level) Phase 1b: Dose Expansion
Dose Level 4 Cohort 1+ ORIC-101: 480 mg QD D1-21 + ORIC-101: RP2D QD D1-21 + 2 Nab-paclitaxel: 100 mg/m D1/8/15 Nab-paclitaxel: 100 mg/m2 D1/8/15
Dose Level 3 Indications Under Consideration: ORIC-101: 400 mg QD D1-21 + TNBC, pancreatic, ovarian and endometrial Nab-paclitaxel: 100 mg/m2 D1/8/15
Dose Level 2 ORIC-101: 320 mg QD D1-21 + Nab-paclitaxel: 100 mg/m2 D1/8/15
Dose Level 1 ORIC-101: 240 mg QD D1-21 + Initial ORIC-101 dose expected to be active based on phase 1a data Nab-paclitaxel: 100 mg/m2 D1/8/15
• Dose identification: Standard schedule of Abraxane (nab-paclitaxel) with escalating doses of ORIC-101 in patients with solid tumors • Enrollment not limited by GR status • Dose expansion: Patients with certain solid tumors based upon baseline GR status • Data will be generated from collection of archival tumor tissue, pre and on-treatment biopsies, and PBMCs
Initial combination safety data expected in 4Q19 followed by preliminary efficacy / translational data in 1H20
Note: 28-day cycles.
22 Phase 1b Study of ORIC-101 in Combination with an AR Modulator in Patients with Castration-Resistant Prostate Cancer Progressing on an AR Modulator
Phase 1b: Dose Identification (n = 3-6 per dose level) Phase 1b: Dose Expansion
Dose Level 3 Cohort 1+ ORIC-101: 480 mg QD + AR modulator ORIC-101: RP2D QD + AR modulator
Dose Level 3 ORIC-101: 400 mg QD + AR modulator
Dose Level 1 Initial ORIC-101 dose expected to be active based on phase 1a data ORIC-101: 320 mg QD + AR modulator
• Patients with chemotherapy-naïve metastatic CRPC with evidence of disease progression while on treatment with an AR modulator • Exclude patients who progress within 3 months of starting AR modulator treatment to exclude primary refractory patients • Dose identification: Continued standard dose of an AR modulator with escalating doses of ORIC-101 • Enrollment not limited by GR status • Dose expansion: Additional patients treated with ORIC-101 at RP2D in combination with an AR modulator • Assess safety, PK, PD and initial evidence for clinical activity (PSA decline, imaging, CTC conversion)
Initial combination safety data expected in 1H20 followed by preliminary efficacy / translational data in 2H20
Note: AR modulators under consideration include enzalutamide and apalutamide.
23 ORIC-101 Commencing Three Phase 1b Studies in 2019 Across Multiple Indications In Combination with Various Treatment Regimens
2019 2020 2021
Phase 1b Solid tumors + Abraxane
Initial PK / Initial Efficacy / Safety Data Translational Data
Phase 1b Prostate cancer + AR modulator ORIC-101
Initial PK / Initial Efficacy / Safety Data Translational Data
Phase 1b Solid tumors + PD-1 / PD-L1
Initial PK / Initial Efficacy / Safety Data Translational Data
24 Pipeline
25 Pipeline of Assets in Addition to ORIC-101 Focused on Resistance in Oncology
Exploratory / Lead ID / Preclinical / Phase 1 Pipeline Status Hit ID Optimization IND Enabling
Phase 1a Complete ORIC-101 (GR Antagonist) Phase 1b Initiated 2Q19 • Phase 1b initiated in 2Q19
CD73 Potential best-in-class oral small molecule • Candidate selection in 2H19 targeting the adenosine pathway
Target 3 Potential first-in-class candidate targeting an oncogenic driver • and mechanism of resistance in squamous cancers Antibody discovery initiated
Additional programs generated from research platform and in-licensing
26 CD73, a Broadly Expressed Ecto-nucleotidase in the Adenosine Pathway, Has Been Linked to Therapy Resistance
• CD73 coordinately converts AMP to adenosine Tumor cell death increases extracellular ATP • Overexpressed across cancer types driving local elevation of adenosine
• Expression correlated with poor prognosis
• Mediates immunosuppression and chemoresistance via adenosine production
• Upregulated in response to PD-1 / PD-L1 and CTLA-4 inhibition cAMP synthesis Immunosuppression Chemoresistance
Therapeutic Hypothesis • CD73 inhibition may enhance activity of chemotherapy and immunotherapy • Small molecule approach may differentiate in safety profile, dosing regimen and tumor penetration
Note: Adapted from Allard et al. Curr Opin Pharmacol (2016) and Lebon et al. Nature (2011).
27 Several Value-Inflection Points Across the ORIC Portfolio Expected Over the Coming Years
2018 2019 2020 2021
Phase 1b Solid tumors + Abraxane
Initial PK / Initial Efficacy / Safety Data Translational Data
Phase 1b Prostate cancer + AR modulator ORIC-101 Initial PK / Initial Efficacy / Safety Data Translational Data
Phase 1b Solid tumors + PD-1 / PD-L1
Initial PK / Initial Efficacy / Safety Data Translational Data
Lead Optimization IND Enabling CD73 Clinical Candidate IND Filing
Biology Lead Generation Cell Line / Scale Up / IND Enabling Target 3 IND Filing
28 ORIC Vision: Become a Leading Oncology Company at the Forefront of Overcoming Resistance in Cancer
20152015 – 20182018 20192015 – 20182020 20212015 – 20182023 20152024+ – 2018
Advance lead GR program from • Progress ORIC-101 through • Conduct ORIC-101 registrational • Commercialize ORIC-101 concept to clinic multiple clinical studies studies • Progress second program Build pipeline of resistance • Advance second program into • Expand clinical and preclinical through registrational studies targets clinical development pipeline
• Phase 1b: ORIC-101 + Abraxane in solid tumors • Study start: 2Q19 • Preliminary efficacy / translational data: 1H20 • Phase 1b: ORIC-101 + AR modulator in castration-resistant prostate cancer Upcoming Milestones • Study start: 3Q19 and • Preliminary efficacy / translational data: 2H20 Clinical Updates • Phase 1b: ORIC-101 + PD-1 / PD-L1 in solid tumors • Study start: 4Q19 • Preliminary efficacy / translational data: 2H20 • CD73 candidate selection: 2H19
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