Safety and Efficacy of Daclatasvir - PowerPoint Presentation

1. Safety and Efficacy of Daclatasvir Plus Sofosbuvir With or Without Ribavirin for the Treatment of Chronic HCV Genotype 3 Infection: Interim Results of a Multicenter European Compassionate Use ProgramWelzel TM,1 Petersen J,2 Ferenci P,3 Gschwantler M,4 Herzer K,5 Cornberg M,6 Schott E,7 Berg T,8 Spengler U,9 Weiland O,10 van der Valk M,11 Geier A,12 Rockstroh JK,9 Peck-Radosavljevic M,3 Zhao Y,13 Jimenez-Exposito MJ,14 Zeuzem S11Universitätsklinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany; 2IFI Institut für Interdisziplinäre Medizin, Hamburg, Germany; 3Medizinische Universität Wien, Vienna, Austria; 4Wilhelminenspital, Vienna, Austria; 5Universitätsklinikum Essen (AöR), Essen, Germany; 6Medizinische Hochschule Hannover, Hannover, Germany; 7Charité Universitätmedizin Berlin, Berlin, Germany; 8Universitätsklinikum Leipzig, Leipzig, Germany; 9Universitätsklinikum Bonn, Bonn, Germany; 10Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; 11Academic Medical Center, Amsterdam, Netherlands; 12Universitätsklinikum Würzburg, Würzburg, Germany; 13Bristol-Myers Squibb, Hopewell, NJ, USA; 14Bristol-Myers Squibb, Princeton, NJ, USA The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015Mercury-Nr: 1392DE15NP07880-03Date of preparation: Nov-2015

2. 2BackgroundTreatment of HCV genotype (GT) 3-infected patients is a challenge, with urgent need of effective antiviral therapies1The pan-genotypic, 12-week, all-oral, RBV-free regimen of DCV and SOF achieved 96% SVR12 rates in GT 3-infected noncirrhotic patients (ALLY-3)2Optimized treatment for GT 3-infected patients with advanced liver disease remains a medical need Here we report interim findings on the combination of DCV + SOF  RBV in HCV GT 3-infected patients with advanced liver disease enrolled in the European DCV compassionate use program (CUP; AI444-237)3RBV, ribavirin; DCV, daclatasvir (NS5A inhibitor); SOF, sofosbuvir, (NS5B inhibitor); DAA, direct-acting antiviral.Pol S, et al. Liver Intl 2014;34:(18–23); 2. Nelson D, et al. Hepatology; 2015;61(4):1127–1135; 3. EU CUP, AI444-237; ClinicalTrials.gov identifier NCT02097966.

3. European DCV Compassionate Use Program Inclusion criteriaAge ≥ 18 years with no treatment options High risk of hepatic decompensation or death within 12 months if left untreatedOr urgent need of viral clearance(extrahepatic manifestations/comorbidities)Exclusion criteriaCreatinine clearance ≤ 30 mL/minPregnancy or not using contraceptionPrimary objective: To provide access to DCV to patients with life-threatening chronic HCV infection who have no other treatment options3Week 24#Week 36Day 1DCV (60 mg)* + SOF (400 mg) ± RBV#Follow-UpSVR12‡Primary endpointAdditional Optional Follow-UpWeek 48Week 72SVR24#Addition of RBV and shorter duration of treatment at the discretion of the physician *Dose adjusted for concomitant ARVs‡HCV RNA < LLOQ, TD or TND at post treatment Week 12 (next value carried backward approach)

4. 4All Treated GT 3-Infected Patients N = 102Efficacy PopulationN = 82Excluded from this interim analysis, N = 20aDid not reach posttreatment Week 12, n = 7 Missing data (not caused by death or treatment discontinuation due to AE), n = 13Safety PopulationN = 102Populations and Statistical Analysis(Interim Analysis)Primary Efficacy Analysis (mITT): Patients with missing data who died, discontinued treatment due to AEs, or had virologic breakthrough/relapse before posttreatment Week 12 were classified as failures Safety Analysis: Clinical (AEs, serious AEs, AEs leading to discontinuation, and deaths) and laboratory abnormalitiesa All patients had HCV RNA < LLOQ, TD or TND, at EOT (Week 24) or at the last available assessment.All Treated PatientsN = 485

5. 5Demographics and Baseline CharacteristicsParameterDCV + SOFN = 62DCV + SOF + RBVN = 40All PatientsN = 102Age, median (range) yr54.5(33–75)55(31–62)55(31–75)Male, n (%)41(66)28(70)69(68)White, n (%)56 (90)34(85)90(88)HCV RNA log10 IU/mL, median (range)a 5.4(0–6.9)6.0(0–7.1)5.6(0–7.1)HCV RNA ≥ 2,000,000 IU/mL, n (%)a 8(13)13(33)21(21)Cirrhosis, n (%)b51(82)36(90)87(85)Child-Pugh class, n (%)a,cA23(45)18(50)41(47)B18(35)16(44)34(39)C9(18)2(6)11(13)MELD score median (range)a10.0(6–20)11.0(6–22)10.0(6–22)MELD score > 15, n (%)a,c6(12)3(8)9(10)ALT, median (range) IU/La52(15–372)59(19–211)56(15–372)Total bilirubin, median (range) mmol/L21(5–99)26(7–74)22(5–99)Albumin, median (range) g/La35(18–50)34(22–50)34(18–50)Platelet count, median (range) × 109/La86(23–378)75(32–273)75(23–378)Prior HCV therapy, n (%)34(55)26(65)60(59)Liver transplant recipient, n (%)4(6)4(10)8(8)HIV coinfection, n (%)a9(15)6(15)15(15)HBV coinfection, n (%)a4(6)1(3)5(5)a Excludes patients with missing data; b Cirrhosis diagnosed by liver biopsy (Metavir > F3, Ishak > 4, or the equivalent), n=9; FibroScan (> 14.6 kPa), n=48; or FIB-4 score (> 3.25), n=30. Cirrhosis status indeterminate/not reported, n=8: DCV + SOF, n=5; DCV + SOF + RBV, n=3;c Percentages based on cirrhotic patients.

6. Primary Efficacy Analysis – SVR12 (mITT)6Not Achieving SVR127411Breakthrough101Relapse336Discontinuation (AE)011Deatha303424971822933DCV + SOFDCV + SOF + RBVAll PatientsBreakthrough: confirmed on-treatment HCV RNA ≥ 1 log10 IU/mL over nadir, or ≥ LLOQ if previously < LLOQ, TD or TND; Relapse: confirmed HCV RNA ≥ LLOQ during any posttreatment visit following HCV RNA < LLOQ, TD or TND, at end-of-treatment;a Includes 1 patient who died during follow-up period; HCV RNA < LLOQ at post-treatment Week 10. HCV RNA < LLOQ, TD or TND% ± 95% CI

7. SVR12 (mITT) in Patients With Cirrhosis7DCV + SOFDCV + SOF + RBVHCV RNA < LLOQ, TD or TND, %37422529191912151214162068Child-Pugh ClassMELD Score Categoryb11132245221517891717a Excludes 4 patients with indeterminate cirrhosis status (1 DCV+SOF; 3 DCV+SOF+RBV); all achieved SVR12; cirrhosis was absent in 5 patients (4 DCV+SOF; 1 DCV+SOF+RBV); all except 1 (DCV+SOF) achieved SVR12;b Excludes 1 cirrhotic patient with missing baseline MELD data; patient discontinued therapy at Week 4 due to AE (non-SVR12).

8. 8SVR12 (mITT) by SubgroupDCV + SOFDCV + SOF + RBVHCV RNA < LLOQ, TD or TND, %35421820771112334419211212232817215655HCV RNA, IU/mLaPrior HCV therapyDuration of treatmentb675736422426a Excludes 1 patient with missing data at baseline (relapse).b Duration of therapy estimated based on time of exposure to program therapy: 6 patients initiated SOF + RBV before adding DCV; 12 week arm includes 4 patients who received treatment <10 Weeks (3 D/C due to AEs; 1 death); 1 achieved SVR12.Liver txp recipientsHIV coinfected patients

9. Changes in Liver Disease Parameters From Baseline to Post-Treatment Week 1210Data indicate median, IQR, range.AlbuminPlateletsALTTotal Bilirubinn = 100n = 69n = 87n = 60n = 75n = 56n = 101n = 70

10. On-Treatment Safety SummaryPatients, n (%)DCV + SOFN = 62DCV + SOF + RBVN = 40All PatientsN = 102Total AEs40(65)28(70)68(67)Serious AEs14(23)7(18)21(21)Treatment-related serious AEs2(3)2(5)4(4)AEs leading to discontinuation or death3(5)3(8)6(6)Death2(3)02(2)Most frequent AEs (≥5% of patients)Fatigue8(13)4(10)12(12)Nausea4(6)6(15)10(10)Anemia2(3)11(28)13(13)Treatment-emergent grade 3 or 4 laboratory abnormalitiesHemoglobin < 90 g/L3(5)4(11)7(7)ALT > 5 × ULN000AST > 5 × ULN000Total bilirubin > 2.5 × ULN1(2)4(15)5(7)Creatinine > 1.8 × ULN00010

11. On-Treatment Safety SummaryPatients, n (%)DCV + SOFN = 62DCV + SOF + RBVN = 40All PatientsN = 102Treatment-emergent serious AEsPancytopenia1(2)1(1)Hepatocellular carcinoma1(3)1(1)Hepatic encephalopathy1(2)1(1)Circulatory collapse1(3)1(1)AEs leading to discontinuation or deathaMultiorgan failureb2(3)02b(2)General physical health deterioration1(3)1(1)Pneumonia1(2)1(1)Hepatic encephalopathy1(2)1c(1)Dyspnea1(3)1c(1)Circulatory collapse1(3)1c(1)a Includes more than 1 event in some patients.b Deaths: multiorgan failure/pneumonia (n=1), multiorgan failure/liver failure (n=1); none were considered treatment-related.c Reported as treatment-related.

12. Summary and ConclusionIn a real-life clinical setting, DCV + SOF ± RBV achieved high SVR rates (87%) in HCV GT 3–infected patients at high risk of hepatic decompensation or death 87% SVR12 in cirrhotic patients (including decompensated cirrhosis)Comparable SVR12 rates with or without RBV in the regimen Improvements in liver function were observed DCV + SOF ± RBV was generally safe and well tolerated Few discontinuations due to AEs, treatment-related serious AEs, or grade 3/4 laboratory abnormalities These findings suggest that DCV + SOF  RBV is an effective and well tolerated oral treatment for patients with GT 3 infection, including those with most advanced disease11

13. AcknowledgmentsThe authors thank the patients and their families, and physicians and research staff at all program sitesEditorial support was provided by J Bergen of Articulate Science and was funded by Bristol-Myers SquibbClinicalTrials.gov registration number NCT02097966 12

14. 14Characteristics of Patients With Virologic Failure Baseline CharacteristicsaPtReason for VirologicFailurePrior HCVTherapyHCV RNA (log10 IU/mL)Fibrosis Stage/ CirrhosisChild-Pugh ClassMELD ScoreTreatment RegimenTherapy Duration (Weeks)1RelapseExperienced5.2F3--DCV+SOF242RelapseExperienced5.6---DCV+SOF243RelapseExperienced-CirrhosisA9DCV+SOF+RBV244RelapseExperienced6.0CirrhosisA13DCV+SOF+RBV7b5RelapseExperienced5.4CirrhosisB11DCV+SOF246RelapseExperienced6.6CirrhosisB11DCV+SOF+RBV247Virologic breakthroughcExperienced5.7CirrhosisB12DCV+SOF24a No patients were HIV/HCV coinfected or liver transplant recipients; b Discontinuation due to AE at Week 7; HCV RNA > LLOQ at posttreatment Week 12;c Patient never undetectable during treatment.