Population Viral Kinetic Modeling: SVR Prediction in HCV GT-3 Cirrhotic Patients With 24 Weeks of Daclatasvir + Sofosbuvir Administration Emi Tafoya, Yasong Lu, Melody Luo, Premkumar Narasimhan, Neelima Thanneer, Brenda Cirincione, Timothy Eley, Nannan Zhou, Dennis Hernandez, Fiona McPhee, Tarek Leil Bristol-Myers Squibb, Princeton, NJ, USA; Bristol-Myers Squibb, Wallingford, CT, USA 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. Washington DC, USA, 26 28 May 2015 Oral Presentation #3
Disclosures All authors are a full time employee and may also be stockholders of Bristol-Myers Squibb 2
An Unmet Medical Need: Effective and Safe Treatment for HCV GT 3 24 weeks of SOF + RBV approved in US Suboptimal in some populations/ anemia issues with RBV DCV+SOF now preferred regimen in EU for GT-3 Treatment experience Drug Duration (weeks) SVR12 (%) No cirrhosis SVR12 (%) With cirrhosis Naive IFNintolerant, ineligible, unwilling Previously IFN treated SOF+RBV Previously IFN treated Naive Previously IFN treated 12 12 12 16 24 24 61 68 37 63 94 85 34 21 19 61 92 60 Study FISSION POSITRON FUSION VALENCE Sovaldi (sofosbuvir) US label 2013; SOF, sofosbuvir; RBV, ribavirin; HCV, hepatitis C virus (HCV); GT, genotype (GT) 3
An Unmet Medical Need: Effective and Safe Treatment for HCV GT 3 cont. Even lower SVR for GT-3 reported in real-world studies Study Boson EASL 2015 Abstract L05 (Foster G et al) Patient Population SOF+RBV 16 weeks %SVR12 SOF+RBV 24 weeks %SVR12 Cirrhosis- 80 87 Cirrhosis+ 51 79 Treatment Naïve 74 88 Treatment experienced 64 80 HCV-TARGET Abstract P0840 EASL 2015 (Alqahtani S et al) Cirrhosis- - 80 Cirrhosis+ - 53 Treatment Naïve - 78 Treatment experienced - 55 4
ALLY-3 Study (AI444218) Phase 3 patients with chronic HCV GT 3 infection Treatment experienced subjects includes patients who previously failed treatment with interferon-based therapies or other anti-hcv therapies, including sofosbuvir Treatment-naive (N = 101) Treatment-experienced (N = 51) DCV 60 mg + SOF 400 mg QD DCV 60 mg + SOF 400 mg QD Follow-up Day 1 Week 12 Week 24 Week 36 SVR12 a DCV, daclatasvir; (DCV); CHC, chronic hepatitis C; SVR12, sustained virologic response rate at 12 weeks posttreatment; naive; treatment naive 5
ALLY-3 Study Patients Parameter HCV RNA level, n (%) Treatment-Naive Treatment-Experienced N=101 N=51 < 800,000 IU/mL 31 (31) 13 (25) 800,000 IU/mL 70 (69) 38 (75) IL28B genotype, n (%) CC 40 (40) 20 (39) CT 47 (47) 21 (41) TT 14 (14) 10 (20) Cirrhosis, n (%) d,e 19 (19) 13 (25) Fibrosis stage by FibroTest, n (%) f F0-F3 76 (75) 43 (84) F4 22 (22) 8 (16) d Cirrhosis was determined by liver biopsy (METAVIR F4; n=14), FibroScan (>14.6 kpa; n=11), or FibroTest score 0.75 and APRI >2 (n=7); for 11 patients, cirrhosis status was missing or inconclusive (FibroTest score >0.48 to <0.75 or APRI >1 to 2). e Of the 32 patients with cirrhosis, 11 (34%) had baseline platelet counts of 100 10 9 cells/l. f Per the study protocol, FibroTest assessments were performed during screening (FibroTest scores not available for 3 treatment-naive patients); F0-F3 defined as FibroTest score of 0.74 and F4 defined as FibroTest score of >0.74. 6
ALLY-3 Study Result and Question Drug Duration Cirrhosis Observed SVR12 (%) DCV + SOF 12 wks 24 wks YES 63% NO 96% YES? NO? Reduced SVR12 rate in cirrhotic subjects HCV GT-3 cirrhotic patients may benefit from longer treatment duration without RBV However, longer duration was not studied 7
Population Viral Kinetic (PVK) M&S Goal Supporting 24 weeks of DCV + SOF without added RBV by SVR simulation Drug Duration Cirrhosis DCV + SOF 12 wks 24 wks Observed SVR12 (%) Simulated SVR12 (%) Simulated SVR24 (%) YES 63% Z Y NO 96% Z Y YES Not tested Y Y NO Not tested Y Y Y for prediction and Z for validation SVR12 data base lock was used 8
PVK Modeling Characteristics PVK model was characterized by a competition between a drug-susceptible strain and a drug-resistant strain in a HCV two-strain model Drug-resistant strain for each patient was identified by Population-based sequencing data of HCV RNA Resistance profiles established by using cell-based HCV replicon assays 9
PVK Modeling Characteristics cont. Base Model Covariates Replication capacity of drug-resistant strain Cirrhosis status Statistical Methodology MCMC Bayesian Laplacian algorithm (NONMEM 7.2) Diagnostic tests: conditional prediction of VK, VPC and convergence test SVR simulation 12 wks/24 wks of therapy, cirrhosis+ / cirrhosis For each scenario, 500 trials were simulated 100 hypothetical subjects were included in each trial 10
HCV Kinetics in Patients With DCV + SOF Reality: More HCV variants The two-strain model: a plausible and feasible simplification Other negligible mutants The most significant variant resistant to DCV Wildtype Mutation The most significant doubleresistant variant The most significant variant resistant to SOF 11
HCV Kinetics in Patients With DCV + SOF Drug-susceptible strains (Treatment effective) Other negligible mutants The most significant variant resistant to DCV Drug-resistant strains (Treatment ineffective) Wildtype Mutation The most significant doubleresistant variant The most significant variant resistant to SOF What will be the most significant variant? 12
Method to Identify the Most Significant Resistant Variant Replication capacity EC 50 Ranked resistance data (DCV) Rank Mutation 1 L31M 2 A30K 3 Y93H 4 S62N 5 M28V 6 S62I 7 S62T 8 A30S Linear stability analysis of the non-infectious steady state in the two-strain model was used for ranking HCV genome Total # of amino acids (Population Sequencing) NS5B ~591 NS5A 448-466 Clinical Prevalence Population-based sequencing data (baseline) Subject N5A-M28 N5A-A30 N5A-L31 N5A-S62 N5A-Y93 1 2 T H 3 T 4 V Result Subject Resistant strains 1 None 2 Y93H 3 S62T 4 None 13
Variables in the BMS HCV Two-strain Model 14
Infection and Spontaneous Clearance of HCV RNA 15
Virion Clearance and Cell Death Virion clearance and cell death 16
Liver Cell Proliferation 17
Virion Production and Mutation Before Treatment p s cr 1 c : Replication capacity r f 1 18
Virion Production and Mutation With Treatment 19
Pre-specified Cirrhosis Covariates Based on Biology/Clinical Knowledge Inflammation in the liver possibly alters the parameters Theoretical difference in PK profile in cirrhotics within liver (systemic minimal Δ) 20
VK and SVR12 Achievement Adequately Described in 150/150 Subjects O: Observed VK Green: Estimated VK Blue: End of Treatment Red: Follow-up after treatment (4 wks and 12 wks) 21
Improved SVR for Patients With Cirrhosis Was Predicted by 24 Weeks of DCV + SOF Median SVR rate (5% - 95% CI) across 500 trials 100 hypothetical subjects were included in each trial Drug Duration Cirrhosis DCV + SOF 12 wks 24 wks Observed SVR12 (%) Simulated SVR12 (%) Simulated SVR24 (%) YES 63 59 (50-70) 57 (47-68) NO 96 93 (90-96) 93 (89-95) YES Not tested 89 (78-97) 89 (78-97) NO Not tested 99 (97-100) 99 (97-100) 22
Summary Mechanistic PVK M&S effectively characterized the 12 week DCV + SOF treatment efficacy data in GT 3 cirrhotic and non-cirrhotic patients Mechanistic PVK M&S predicted the efficacy of 24 weeks of therapy in GT 3 cirrhotic and non-cirrhotic patients This PVK approach supports 24 weeks of DCV + SOF without ribavirin for HCV GT 3 cirrhotic patients, a population with high unmet medical need 23