Bristol-Myers Squibb. HCV Full Development Portfolio Overview. Richard Bertz Int Workshop CP HIV Meeting Amsterdam, Netherlands 24 April 2013

Transcription

1 Bristol-Myers Squibb HCV Full Development Portfolio Overview Richard Bertz Int Workshop CP HIV Meeting Amsterdam, Netherlands 24 April

2 BMS Agents in Clinical Development: DAAs and INF Lambda Lambda IFN Type III pegylated interferon Expression of receptor is more limited than Alfa, should lead to improved tolerability and safety NS3 Inhibitor Inhibits activity of NS3 protease Prevents processing of HCV proteins required for replication BMS: Asunaprevir (ASV) NS5B Inhibitor Inhibits NS5B RNA replicase Prevents replication of viral genome BMS (-325) NS5A Inhibitor Inhibits activity of NS5A, a multifunction protein essential for viral replication Prevents viral replication BMS: Daclatasvir (DCV) Shaw-Stiffel T. Reference to Hepatitis C Infection. 2004; Tibotec. HCV Discovery Available at: Accessed December 1, 2009.

3 Daclatasvir: Clinical Pharmacology Summary NS5A inhibitor with picomolar potency and pan-genotypic HCV antiviral in vitro T-half hours supports QD dosing;~ 99% protein bound Dose proportional PK in range of 1 to 100 mg No effect on cardiac conduction at supratherapeutic dose (3x 60mg) Intrinsic Factors: No effect of hepatic impairment on unbound concentrations Plasma PK similar by gender, race or ethnicity, minimal effect of BW DDI : Substrate for CYP3A4 and P-gp; manageable DDI with HIV co-meds ATV/RTV : decrease dose by half & EFV: increase dose by 50% No clinically relevant effect of gastric acid modifiers No clinically relevant effect of DCV on CYP3A4 probe midazolam No effect on oral contraceptives Moderate inhibitor of OATP1B and P-gp 3

4 Daclatasvir Phase 3 Dose Selection Based on the integrated exposure-response, safety and efficacy data from Phase 2 (3 to 60 mg QD dose) the 60 mg daily dose was selected for Phase 3 studies Comparable Safety and Efficacy at 20 and 60 mg QD DCV doses tested in Phase 2B A 60 mg dose may provide additional benefit in difficult-to-treat patients, while compensating for reduced exposures due to food, ph modifiers and CYP3A4 inducers A single 60 mg tablet QD used in Phase 3 without regard to meals 4

5 Asunaprevir: Clinical Pharmacology Summary Potent NS3 protease inhibitor with in vitro activity against HCV GT 1, 4, 5 and 6 High CL/F despite terminal T-HALF ~20 h ; > 99% protein bound Time dependent PK (autoinduction) Low plasma concentrations/high liver concentrations (>20 fold in animals) TQT study ongoing; no conduction effects noted in animal studies Intrinsic Factors: Moderate and severe liver impairment increase plasma exposures by 10 & 32 fold Difference in Asian plasma AUC (1.5-2 x increase) ; no diff based on gender or BW Older subjects (> 60) appear to have higher (~30%) exposure DDI data: Sensitive OATP1B1/2B1 substrate; single dose rifampin increased AUC ~15 fold Moderate CYP2D6 inhibitor; weak CYP3A4 inducer; weak OATB1B1 inhibitor No meaningful effect on CYP1A2, 2C9 or 2C19 in vivo Clinically significant effect of potent CYP3A4 inhibitors (>5 x increase plasma AUC) No clinically significant PK interaction when ASV and DCV co-administered 5

6 Asunaprevir: Phase 3 Dose Selection Study AI (200 mg BID, 600 mg QD and 600 mg BID ASV tablet), served as the Phase 2a/b dose ranging study Exposure-response (anti-viral response) and exposure-safety (probability of ALT elevation) assessment conducted prior to transition from the 2a to 2b portion of AI Improved safety profile at 200 mg BID tablet with similar anti-viral response relative to higher doses 200 mg BID dose was selected for the Phase 2b portion and all other ongoing studies 100 mg BID of a lipid-based soft gel capsule was selected as the Phase 3 dose for ASV based on the results of a relative BA study (AI447024) 100 mg BID softgel capsule (given with or without meals) produces similar AUC to 200 mg BID Phase 2 tablet formulation that has been demonstrated to be safe and efficacious Phase 3 Dose Softgel capsule at 100 mg BID without regard to food in Phase 3 6

7 AI447011: Daclatasvir + Asunaprevir (Dual/Quad) Sentinel Cohort Study Design: PR Null Responders Group A (n = 11) DCV 60 mg QD + ASV 600 mg BID Follow-up (up to 48 weeks post-treatment) Group B (n = 10) DCV 60 mg QD + ASV 600 mg BID + alfa/rbv Follow-up (up to 48 weeks post-treatment) 24 weeks Lok A, et al. Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. N Engl J Med ; 366;3: alfa/rbv: peginterferon alfa-2a 180 µg SC once weekly; RBV mg daily according to body weight

8 AI447011: DCV + ASV + Alfa/RBV (DCV/ASV Quad) HCV RNA by Patient: Group B Sentinel DCV + ASV + alfa/rbv Follow-up 7 HCV RNA (log 10 IU/mL) Week 24 PT4 PT12 PT24 LLOQ LLO D PT, post-treatment. 10/10 patients undetectable by week 6 of therapy with no viral breakthrough 10/10 patients achieved SVR 12 and 9/10 achieved SVR 24-1 patient <LLOQ at week 24 post-treatment undetectable on retesting 1 and 3 months later alfa/rbv: pegifnα-2a / Ribavirin

9 AI447011: DCV+ ASV (DCV/ASV Dual) HCV RNA by Patient: Group A DCV + ASV Follow-up 7 HCV RNA (log 10 IU/mL) Week 24 PT4 PT12 PT24 LLOQ LLOD PT, post-treatment. Six patients (all GT 1a) experienced viral breakthrough on therapy One patient with EOTR experienced viral relapse at 4 weeks post-treatment 2/2 GT 1b patients and 2/9 GT1a patients achieved SVR24

10 AI447017: BMKK Study in Japanese Subjects Phase 2a Sentinel Cohort (DCV/ASV Dual): PR Null-Responders & Ineligible/Intolerants Null responders (N = 21) DCV 60 mg QD + ASV 200 mg BID* Follow-up x 24 weeks Ineligible/intolerant (N = 22) DCV 60 mg QD + ASV 200 mg BID Follow-up x 24 weeks Week 4 (RVR) Week 12 (cevr) Week 24 (EOTR) Post-treatment Week 12 (SVR 12 ) Post-treatment Week 24 (SVR 24 ) *ASV initially 600 mg BID in sentinel cohort of 10 null responders, reduced to 200 mg BID during treatment Non-cirrhotic Japanese adults with HCV genotype 1 infection, HCV RNA 10 5 IU/mL Null responders: < 2 log 10 HCV RNA decline after 12 weeks of peg-alfa/rbv Ineligible/intolerant: previously intolerant to peg-alfa/rbv OR peg-alfa/rbv medically unsuitable Sentinel cohort of 10 null responders reported previously (SVR 24 90%); 1 results combined here with data for additional null responders Primary efficacy endpoint: SVR 12 cevr, complete early virologic response; EOTR, end of treatment response; ervr, extended rapid virologic response; RVR, rapid virologic response; SVR sustained virologic response 1 Chayama K, et al. Hepatology 2012; 55: Suzuki F, et al. EASL Oral 2344.

11 AI (DCV/ASV Dual): Virologic Endpoints - All Patients HCV RNA undetectable (% of patients) Week 4 RVR Week 12 cevr End of treatment a a End of treatment = Week 24 or last on-treatment visit for patients who discontinued early Intention to treat (missing = failure) analysis RVR, rapid virologic response; cevr, complete early virologic response; SVR, sustained virologic response Lower limit of quantitation for HCV RNA determinations = 15 IU/mL /43 39/43 38/43 33/43 33/43 35/43 SVR 4 SVR 12 SVR 24 Suzuki F, et al. EASL Oral 2344.

12 AI447017: On-Treatment AEs (Any Grade) and Grade 3 or 4 Laboratory Abnormalities Event, n (%) Null Responders (N = 21) Ineligible/Intolerant (N = 22) Headache 8 (38) 6 (27) Nasopharyngitis 6 (29) 8 (36) ALT increase 6 (29) 6 (27) Diarrhea a 9 (43) 2 (9) AST increase 6 (29) 4 (18) Pyrexia 3 (14) 5 (23) Eosinophilia 1 (5) 4 (18) Abdominal discomfort 3 (14) 2 (9) Malaise 2 (10) 3 (14) Constipation 2 (10) 3 (14) Back pain 3 (14) 1 (5) Decreased appetite 0 3 (14) ALT 2 (10) 2 (9) AST 1 (5) 2 (9) Lymphocytes 2 (10) 1 (5) Phosphorus 1 (5) 1 (5) Bilirubin, total 1 (5) 0 Leukocytes 1 (5) 0 Adverse Events Occurring in 3 Patients in Either Group Grade 3 or 4 Lab Abnormalities a All reports of diarrhea were grade 1 and did not result in discontinuation ALT, alanine aminotransferase; AST, aspartate aminotransferase Suzuki F, et al. EASL Oral 2344.

13 BMS : Clinical Pharmacology Potent NS5B non-nucleoside polymerase inhibitor with In vitro activity against HCV GT 1, 3, 4, 5 and 6 T-HALF 7-9 h, BID dosing HCV-infected have ~2x plasma AUC vs healthy subjects Active metabolite approximately 25% of parent in plasma Auto induction of metabolism (CYP3A4) No cardiac conduction defects noted preclinically No clinically relevant effect on PK of ASV/DCV/-325 in combination 13

14 Phase 2a Open-Label Study (AI ) Primary endpoint: SVR 12 Group 1 Part 1 Group 2 Group 3 Part 2 Group 4 Study Week DCV + ASV + BMS mg DCV + ASV + BMS mg 12-week follow-up DCV + ASV + BMS mg DCV + ASV + BMS mg 12-week follow-up 12-week follow-up 12-week follow-up Additional follow-up to SVR 48 Patients: treatment-naïve, non-cirrhotic, HCV GT 1 stratified by subtype 1a/1b Treatment: DCV 60 mg QD + ASV 200 mg BID + BMS either 75 mg BID (Part 1) or 150 mg BID (Part 2) HCV RNA endpoints: per FDA guidance, HCV RNA < LLOQ TD = target detected but below the assay lower limit of quantitation (LLOQ; 25 IU/mL); LLOQ TND = below LLOQ and target not detected (previously referenced as HCV RNA undetectable or < LOD; 10 IU/mL for this study) Primary endpoint: HCV RNA < LLOQ 12 weeks posttreatment (SVR 12 ) Modified intent-to-treat analysis: missing, breakthrough, or relapse = failure Interim analysis: Part 1 results reported through posttreatment week 4 (Group 1; SVR 4 ) or posttreatment week 12 (Group 2; SVR 12 ); Part 2 enrolled and ongoing, results not yet available Everson GT, et al. AASLD Oral LB-3

15 HCV RNA Outcomes by HCV Genotype 1 Subtype Modified Intention-to-Treat Analysis GT 1a GT 1b Patients achieving endpoint (%) a % < LLOQ TD or TND N = EOT b PT4 (SVR 4 ) EOT b PT4 (SVR 4 ) 24-week (Group 1) HCV RNA < LLOQ TD or TND Missing data 12-week (Group 2) HCV RNA < LLOQ TD or TND Missing data a Includes 1 patient with HCV RNA 118 IU/mL at last on-treatment visit but < LLOQ TND 2 and 4 weeks posttreatment (SVR 4 ). b EOT, end of treatment; includes patients who discontinued prior to the protocol-defined last treatment visit. < LLOQ TD or TND, HCV RNA below assay lower limit of quantitation (25 IU/mL) and target detected (LLOQ TD ) or target not detected (LLOQ TND ; HCV RNA < LOD 10 IU/mL, previously reported as HCV RNA undetectable); PT, posttreatment. Everson GT, et al. AASLD Oral LB-3

16 Safety, Adverse Events, and Laboratory Abnormalities On Treatment Number of Patients (%) 24-Wk Treatment Group 1, N = Wk Treatment Group 2, N = 16 Total N = 32 Serious AEs a 0 1 (6) 1 (3) AEs leading to discontinuation Grade 3 4 AE b 0 1 (6) 1 (3) Grade 3 4 laboratory abnormalities c 0 1 (6) 1 (3) AE in > 10% of patients in combined treatment groups Headache 4 (25) 6 (38) 10 (31) Diarrhea 2 (13) 6 (38) 8 (25) Asthenia 2 (13) 3 (19) 5 (16) a Renal calculus, considered by the investigator to be unrelated to study therapy. b Grade 3 headache, resolved after 7 days with continued study treatment. c Lymphopenia at a single study visit concomitant with influenza; there were no grade 3-4 bilirubin or transaminase elevations. Everson GT, et al. AASLD Oral LB-3

17 Potential Impact of Lambda Receptor Distribution IFNα receptors widely distributed throughout body Potential for more IFN-associated abnormalities: Neutropenia Thrombocyopenia Flu-Like Symptoms Musculoskeletal Symptoms Lambda receptors not widely distributed throughout body Potential for less IFN-associated abnormalities: Neutropenia Thrombocyopenia Flu-Like Symptoms Musculoskeletal Symptoms 17

18 EMERGE GT1,4: AEs (Any Grade) Occurring in 20% of Patients in Any Treatment Group Preferred term 120 µg (N = 98) Lambda 180 µg (N = 102) 240 µg (N = 104) Alfa 180 µg (N = 103) AE (any grade), % Fatigue Headache Myalgia Pyrexia Nausea Pruritus Insomnia Rash Chills Arthralgia > 2-fold difference in frequency, Lambda 180 µg vs alfa 180 µg. Muir AJ, et al. AASLD Oral

19 EMERGE: Changes in Hematologic Parameters Over Time and Hematology-Associated PegIFN and RBV Dose Reductions 150 EOT Hgb (g/l) (mean) 130 Lambda 120 µg Lambda 180 µg Lambda 240 µg Alfa 180 µg 110 Neutrophils (GI/L) (mean) Platelets (GI/L) (mean) LLN LLN LLN weeks % Hgb low < 9 g/dl OR 4.5 g/dl Lambda 180 µg (N = 102) Alfa 180 µg (N = 103) RBV reduction (Hgb-associated) Neutrophils low < 750/mm Platelets low < 50,000/mm PegIFN reduction (hematologic abnormality) Muir AJ, et al. AASLD Oral

20 EMERGE GT1,4: Treatment-Emergent Liver-Related Laboratory Abnormalities Lambda Alfa Lab toxicity High ALT and/or AST levels, % Total bilirubin high, % Severity PegIFN dose reductions due to liver-related lab abnormality, % 120 µg (N = 98) 180 µg (N = 102) 240 µg (N = 104) 180 µg (N = 103) > ULN > 10 ULN ULN > 5.0 ULN PegIFN discontinuations due to liver-related lab abnormality, % a a All cases of hyperbilirubinemia resolved following discontinuation of study drug without sequelae. Muir AJ, et al. AASLD Oral

21 BMS HCV Full Development Program Summary Comprehensive development program with lead NS5A inhibitor daclatasvir being extensively studied as a key component of DAA-based treatment regimens: First all-daa, Dual oral combination of DCV +ASV in GT1b patients with both a global and Japan-specific development program [in Phase 3] First highly-effective Quad regimen of DCV + ASV + alfa/rbv in GT1 Null Responders [in Phase 3] Triple DAA alfa-interferon-, ribavirin- and ritonavir-sparing regimen combining DCV + ASV + NS5B non-nucleoside BMS [in Phase 2B] Interferon Lambda being studied as a differentiated alternative to Interferon Alfa [in Phase 3]