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Rucaparib (CO-338) April, 2015 Rucaparib: Summary • Rucaparib is an oral, small molecule poly ADP-ribose polymerase (PARP) inhibitor that is a potent inhibitor of PARP-1 and PARP-2 • Rucaparib is being developed for the treatment of patients with cancers predisposed to PARP inhibitor sensitivity • Our initial focus is on tumors with defective DNA repair function (BRCA1/2 mutations and BRCA-like genomic alterations) in ovarian cancer • Promising activity seen in ovarian cancer at RP2/3D of 600mg BID – 70% ORR (RECIST & CA-125) in patients with BRCA1/2 mutated tumors 1 – 48% ORR (RECIST & CA-125) in patients with a HRD / BRCA-like signature1 • Rucaparib is well tolerated – no discontinuations due to adverse events (AEs) – ARIEL2 • Several global Phase 2/3 trials: – Study CO-338-010 – Phase 2 ovarian cancer, platinum sensitive, BRCA1/2 mutated, treatment setting – ARIEL2 – Phase 2 ovarian cancer, treatment setting – ARIEL3 – Phase 3 ovarian cancer, platinum sensitive, maintenance setting • Additional information: http://www.clovisoncology.com/products-companiondiagnostics/rucaparib/ 2 1Swisher, SGO 2015 Rucaparib: a potent PARP-1 and PARP-2 inhibitor • Rucaparib (CO-338; formerly known as AG-014447 and PF-01367338) • Potent inhibitor of PARP-1 (inhibition constant (Ki) 1.4 nM) and PARP-2 (0.17 nM) • As a single agent, rucaparib is cytotoxic to cells with a breast cancer gene 1 (BRCA1) mutation, BRCA2 mutation, or epigenetically silenced BRCA1, consistent with the concept of synthetic lethality R u c a p a r i b c y t o t o x ic i t y in a n is o g e n i c o v a r ia n c e ll lin e p a i r Rucaparib 90 80 (m e a n S E M ) % v ia b ilit y r e la t iv e t o c o n t r o l 100 70 1 5 - fo ld in c r e a s e 60 in s e n s itiv ity in B R C A 1 50 m u ta n t c e ll lin e 40 30 20 B R C A 1 w ild -ty p e 10 B R C A 1 m u ta n t 0 1 100 10000 [R u c a p a r ib ] lo g 1 0 nM 3 Company data 3 Rucaparib efficacy in BRCA-mutated xenograft models • Rucaparib has anti-tumor efficacy in BRCA-mutated cell line or patientderived xenograft (PDX) models – Significant responses observed in ovarian, breast and pancreatic models • Dose (150 mg/kg BID PO) used in murine xenograft studies is below AUC24 exposure of human RP2/3D R u c a p a r ib e f f i c a c y i n M D A - M B - 4 3 6 R u c a p a r ib e f f ic a c y in H B C x 1 7 (B R C A 2 m u ta n t) x e n o g ra ft m o d e l (B R C A 2 m u ta n t) T N B C P D X M o d e l 2000 1200 T u m o r v o lu m e 800 3 600 400 3 (M e a n m m S E M ) R u c a p a r ib 1 5 0 m g /k g B ID 1000 (m m ) SEM M e a n tu m o r v o lu m e V e h ic le 1500 1000 V e h ic le R u c a p a r ib 1 5 0 m g /k g B ID 500 200 0 0 5 10 15 20 25 30 35 40 45 * * 0 0 10 20 30 D a y s p o s t- tr e a tm e n t D a y s p o s t- tre a tm e n t D o s i n g p e r io d D o s in g p e r io d 4 Company data 40 50 Additional genes beyond BRCA1/2 involved in homologous recombination and repair can confer rucaparib sensitivity • Employed siRNA knockdown of homologous recombination repair (HRR) genes as a model of deleterious mutation in 4 ovarian cell lines • Knockdown of 48% of HRR genes induces sensitivity to rucaparib – Cell line context effects observed within 4 ovarian lines examined Rucaparib IC50 Fold Change After siRNA Knockdown in OVCAR-3 Cell Line Controls High sensitivity Intermediate sensitivity Low sensitivity 55 IC50=half maximal inhibitory concentration. NT4 = transfection control Swisher, ENA 2014 Rucaparib clinical development • CO-338-010 is a Phase 1/2, open-label, study of monotherapy oral rucaparib treatment for patients with solid tumors who progressed on prior treatment (Phase 1 portion) and patients with platinum-sensitive, relapsed ovarian cancer associated with a deleterious BRCA mutation (Phase 2 portion) • CO-338-017 (ARIEL2) is a Phase 2 single-arm, study of monotherapy oral rucaparib for treatment of relapsed, high-grade ovarian cancer • CO-338-014 (ARIEL3) is a Phase 3, randomized, double-blind study of monotherapy oral rucaparib versus placebo as switch maintenance treatment in patients with platinum-sensitive, relapsed, high-grade ovarian cancer who achieved a response to platinum-based chemotherapy • RUBY: A single arm, open-label, Phase 2 study to assess the efficacy of rucaparib in metastatic breast cancer patients with a BRCA-like genomic signature • CO-338-023 (RUCAPANC) is a Phase 2, single-arm, open-label study of monotherapy oral rucaparib as treatment for patients with previously treated locally advanced or metastatic pancreatic ductal adenocarcinoma and a known deleterious BRCA mutation 6 Collaboration with Foundation Medicine to Develop Companion Diagnostic to determine BRCA mutations and a BRCA-like genomic signature • Rucaparib is being developed in parallel with a companion diagnostic (CoDx) program • Collaboration with Foundation Medicine (FM) for CoDx development and commercialization • Clovis and FM are developing a homologous recombination deficiency (HRD) signature that will identify patients most likely to respond to rucaparib – HRD signature encompasses BRCA1/2 mutations and determination of BRCA-like alterations by comprehensive genomic profiling – HRD signature identifies patients with a defect in homologous recombination independent of BRCA1/2 mutation – HRD signature prospectively applied to ARIEL2 Part 2 and ARIEL3 studies • HRD signature in ovarian cancer is the initial focus – Expansion of HRD signature in additional cancer indications currently on-going 7 HRD causes genome-wide loss of heterozygosity (LOH) that can be measured by comprehensive genomic profiling based on NGS BRCAmut Hypothesis 1: Ovarian cancer patients with high genomic LOH suggesting BRCA-like signature will respond to PARPi BRCAwt Hypothesis 2: Ovarian cancer patients BRCAwt Chromosome No. mut=mutation; NGS=next-generation sequencing; wt=wild type. 8 Swisher, SGO 2015 who are “biomarker negative” (ie, with low genomic LOH) will not respond to PARPi Diagnostic development: cutoff defined for BRCA-like signature, being tested and refined TCGA and AOCS Overall Survival Data Used to Develop LOH Cutoff to Identify High-Grade Ovarian Cancer Patient Tumors with BRCA-like Signature 100 0.25 0.20 0.15 0.10 High genomic LOH (n=97) Low genomic LOH (n=212) 80 Optimal LOH cutoff Overall Survival (% probability) Log-rank P Value (high vs low LOH groups) 0.30 60 Log-rank: P=0.0047 Hazard ratio=0.62 40 Independent predictor from BRCAmut status 20 0.05 0 0 Genomic LOH Cutoff Median overall survival: 56.4 vs 38.2 months 0 25 50 75 100 125 Overall Survival (months) Prospective testing of prespecified cutoff in ARIEL2 and ARIEL3 The Cancer Genome Atlas (TCGA) Research Network. Nature. 2011;474:609-615; Wang ZC et al; Australian Ovarian Cancer Study (AOCS). Clin Cancer Res. 2012;18:5806-5815. 9 Swisher, ENA 2014 Rucaparib has a favorable pharmacokinetic profile in patients with low variability geomean variability in range difference: geomean variability in range difference: Plasma Cmin at steady state (µM) Plasma Cmin at steady state (µM) 21 21 2x 2x 4x 4x 5x 5x 2x 1x 2x 1x • High fat breakfast did not cause clinically meaningful changes of rucaparib PK 18 18 15 15 • Time to maximum concentration: 2.5 - 4 hours 12 12 9 6 3 0 • Plasma half-life of 17 hours with steady state achieved by Day 8 9 6 • Patients treated with ≥360 mg BID achieved desirable trough levels 3 0 • Dose proportional PK observed up to 600 mg BID 240 360 480 600 840 240 360 tablet 480 600 840 tablet BID (mg) Rucaparib Rucaparib BID (mg) 10 Company data • Carboplatin co-administration did not alter rucaparib exposure in a clinically meaningful manner ARIEL2 goal: Assess rucaparib sensitivity in prospectively defined sub-groups of ovarian cancer Endpoints: Key Eligibility • High-grade serous or endometrioid ovarian cancer • ≥1 prior platinum chemotherapy (PART 1) • ≥3 prior platinum chemotherapy (PART 2) • Measurable disease 600 mg BID rucaparib continuously until progression by RECIST N ~ 480 • Adequate tumor tissue • No prior PARPi CA-125=cancer antigen 125 test; ORR=overall response rate; PFS=progression-free survival; RECIST=Response Evaluation Criteria In Solid Tumors. 11 11 • PFS (RECIST) in: – BRCA mutation – BRCA-like – Biomarker negative • ORR (RECIST & CA-125) • Safety • Pharmacokinetics Rucaparib is well tolerated – no discontinuations due to adverse events (AEs) – ARIEL2 data Treatment-Related AEs in ≥15% of Patients (N=121*) Nausea Fatigue ALT/AST Increased Dysgeusia Constipation Anemia/Low Hgb Decreased Appetite Vomiting Diarrhea Grade 1 Grade 2 Grade 3 Grade 4 0 20 40 60 80 100 Worst Grade (NCI-CTCAE v4), % * Data as of 02 Feb 2015 in patients enrolled by 15 Oct 2014 AE=adverse event; ALT=alanine transaminase; AST=aspartate transaminase; Hgb=hemoglobin; NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. 12 Swisher, SGO 2015 In ARIEL2, rucaparib has demonstrated robust clinical activity in BRCA mutant, platinum-sensitive ovarian cancer patients – 70% ORR (RECIST & CA-125) – 14/23 (61%) of patients continuing on treatment (+) as of Feb 2015 • Responses observed in germline and somatic BRCAmut tumors Best Response in Target Lesions Change from Baseline (%) • Robust clinical activity observed in BRCAmut patients (n=23) – 65% ORR (RECIST) 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 Somatic BRCA mutation Indeterminate Germline BRCA mutation + + + + + + + + + + + + + + +=ongoing. 13 Swisher, SGO 2015 In ARIEL2 differential rucaparib activity seen in patients with/without BRCA-like signature • Clinical activity observed in patients with BRCA-like signature (n=25) – 40% ORR (RECIST) – 48% ORR (RECIST & CA-125) – 9/25 (36%) of patients continuing on treatment (+) as of Feb 2015 Few responses observed in BRCAwt patients without BRCA-like signature (n=13) – 8% ORR (RECIST) – 8% ORR (RECIST & CA-125) – 1/13 (8%) of patients continuing on treatment (+) as of Feb 2015 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 Change from Baseline (%) • Best Response in Target Lesions BRCAwt BRCA-like + + + + + + + + + 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 Biomarker negative + +=ongoing. 14 Swisher, SGO 2015 ARIEL Program Prospectively Validates Clinical Utility of the HRD Test ARIEL2 Part 1 Pre-specified HRD test • Efficacy (PFS) in pre-specified HRD subgroups • Optimize definition of rucaparib-sensitive patients ARIEL2 Part 2 • Treatment setting • Efficacy (ORR) in prospectively defined HRD subgroups ARIEL3 • Maintenance setting • Efficacy (PFS) in prospectively defined HRD subgroups 15 Lock down HRD test Test all ARIEL2 Part 2 tumor samples, classify HRD status Final Analysis Test all ARIEL3 tumor samples, classify HRD status Final Analysis Rucaparib: Differentiation and areas of interest • Rucaparib has a unique efficacy profile and biomarker strategy: – 70% ORR (RECIST & CA-125) in OC patients with BRCA1/2 mutated tumors1 – 48% ORR (RECIST & CA-125) in OC patients with BRCA-like tumors1 – Companion diagnostic developed for determining BRCA-like genomic signature in addition to BRCA mutations; prospectively applying this analysis in ARIEL2 Part 2 and ARIEL3 studies • Clovis is interested in expanding rucaparib monotherapy efficacy studies and predictive HRD / BRCA-like signature development in additional cancer indications beyond ovarian including breast, prostate, gastroesophageal, endometrial and lung cancer • Clovis is interested in performing drug combination studies with rucaparib including targeted therapies (e.g. CDKi, PI3Ki, HSP90i, HDACi, CHKi), immunotherapeutics (e.g. PD-1, PD-L1 mAb), anti-angiogenics (small and large molecule) and radiotherapy 16 1Swisher, SGO 2015