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Simeprevir, Faldaprevir and Sofosbuvir

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Simeprevir, Faldaprevir and Sofosbuvir 2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir. Paris Hepatitis Conference Pr Tarik Asselah 14 janvier 2014 MD, PhD Service d’Hépatologie & INSERM U773 University Paris Diderot Hôpital Beaujon, Clichy [email protected] 2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir. • Introduction • New IFN-based triple therapy for HCV genotype 1 Protease inhibitors - Simeprevir (Quest-2, Promise) - Faldaprevir (StartVerso 1, StartVerso 3) - Other PI : MK5172, Asunaprevir, etc…. Polymerase inhibitor - Sofosbuvir (Neutrino) • Summary and Conclusion Direct-acting antivirals 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA Capsid RNA helicase Cofactors Polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir ACH-3102 IDX-20963 BMS- ABT-450 PPI-668 791325 MK-5172 GSK-2336805 ACH-3422 PPI-383 Sovaprevir Samatasvir GS-9669 ACH-2684 MK-8742 TMC-647055 Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2014 Investigational HCV Regimens in Phase III Trials in 2014 Triple Therapy: 1 DAA + PegIFN alfa/RBV IFN-Free Regimens . Simeprevir (PI) . Sofosbuvir + RBV . Faldaprevir (PI) . Sofosbuvir + GS-5885 (FDC) ± RBV . Sofosbuvir (NI) . Daclatasvir + asunaprevir . Daclatasvir (NS5A) . ABT-450/RTV + ABT-267 ± ABT-333 ± RBV . MK 5172 (PI) . Faldaprevir + BI207127 + RBV . Danoprevir (PI) . MK 5172 + MK 8742 . Alisporivir (CYP) Asselah and Marcellin P,. Liver International 2014 General Characteristics of Direct-Acting Antivirals NS5A NS5A NS5B NS5B Non PI, 1st PI, 2nd Inhibitors, 1st Inhibitors, 2nd Nucleoside Nucleoside Generation Generation Generation Generation Inhibitors Inhibitors Efficacy Resistance Profile Pangenotypic Efficacy Adverse events Drug-drug interactions Good profile Average profile Least favorable profile Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013 Priorities for Direct-Acting Antivirals Potency Genotype Coverage Highest Importance Resistance Barrier Safety/Tolerability Treatment Duration Half life & Pills burden Drug-drug Interaction Secondary Priorities Cost Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013 2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir. • Introduction • New IFN-based triple therapy for HCV genotype 1 Protease inhibitors - Simeprevir (Quest-2, Promise) - Faldaprevir (StartVerso 1, StartVerso 3) - Other PI : MK5172, Asunaprevir, etc…. Polymerase inhibitor - Sofosbuvir (Neutrino) • Summary and Conclusion Simeprevir (SMV) (PI): G1, phase III trial design Response-guided treatment QUEST-1, naïve n=264 PR SMV 150mg + PR Follow-up PR Follow-up n=130 Placebo + PR PR Placebo + PR Follow-up 0 12 24 48 72 QUEST-2, naïve SMV 150mg + PR N=257 PR Follow-up PR Follow-up N=134 Placebo + PR PR PR Follow-up Week 0 12 24 48 72 PROMISE, relapsers SMV 150 mg PR N=260 PR Follow-up + PR Follow-up N=133 PBO + PR PR PR Follow-up Week 0 12 24 48 72 9 Simeprevir (SMV) SVR12 (%) Proportion of patients, % *Based on the Cochran-Mantel-Haensze test controlling for type of PegIFN/ribavirin and stratification factors Placebo/PR 67/134 50 (PI): G1 naïve, phase III (QUEST-2) (PI): G1 naïve, phase III (QUEST-2) P <0.001* Manns et al. EASL 2013, Abstract 1413. Abstract 2013, EASL al. Manns et 209/257 SMV/PR 81,3 QUEST-2: Response-guided Treatment (RGT) allows shortened treatment duration with high SVR12 SVR12 in SMV/PR 100 86 80 s 91.4% (235/257) t n e of patients met ti a 60 p RGT criteria and f o n were eligible for o ti r 40 24 weeks of o p o treatment r P 20 202/235 0 202/235 • 8.6% (22/257) of patients did not meet RGT criteria – among them, 31.8% (7/22) achieved SVR12 RGT, response-guided therapy; RGT criteria: HCV RNA < 25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12 10 Quest-2: Changes in haemoglobin Hemoglobin Entire treatment phase – hemoglobin, µmol/L 200 Placebo 180 E SMV S ± , 160 s e u l a 140 v n a e 120 M 100 0 2 4 8 12 16 20 24 36 48 Weeks Manns et al. EASL 2013, Abstract05.03.2013 1413. 11 Simeprevir (SMV) (PI): G1 relapsers (Promise) SMV/PR Placebo/PR SVR12 (%) 100 84 85 75 80 58 52 53 60 47 43 40 20 62/131 191/254 23/44 49/84 36/83 138/165 70/133 228/267 0 G1a G1a G1a G1b with Q80K without Q80K Lawitz et al. DDW 2013, Abstract 869b. Simeprevir: adverse events (phase III trials) QUEST-1 QUEST-2 PROMISE Placebo + PR, Placebo + PR, SMV + PR, % Placebo + PR, % SMV + PR, % SMV + PR, % % % (N = 264) (N = 134) (N = 257) (N = 264) (N = 130) (N = 130) Serious AEs 4 3 2 2 4 3 Discontinuation 3 3 1 2 3 3 due to AEs Fatigue 38 40 39 35 Pruritus 11 21 15 19 28 28 Rash (any type) 25 27 11 24 23 23 Anaemia 11 16 14 16 20 17 Jacobson et al. DDW 2013, Abstract 1674582. Manns et al. EASL 2013, Abstract 1413. Lawitz et al. DDW 2013, Abstract 869b. Simeprevir (PI): 12 weeks phase III trial (G1 naïve) Ongoing trial Response-guided therapy of 12 or 24 weeks guided by HCV-RNA measurements at treatment weeks 2, 4, and 8. Baseline Week 4 Week 12 Week 24 Week 36 Week 48 Follow up N=150 patients. Single arm, open-label Triple Therapy SMV + PR Continue PR to Wk 24 Follow up PR: PegIFNα-2a 180 ug/wk + RBV 1000-1200mg/day Clinicaltrials.gov: NCT01846832 Faldaprevir (FDV) (PI): phase III trial, G1 naïve (StartVerso1) Arm 1 Placebo + PR PR Follow-up (n=133) ETS Placebo + PR Follow-up Arm 2 FDV 120 mg + (n=261) PR No ETS FDV 120 mg + PR PR Follow-up ETS Follow-up Arm 3 FDV 240 mg + Placebo + PR (n=262) PR No ETS PR Follow-up Day 1 Week 12 Week 24 Week 48 Week 72 Ferenci et al. EASL 2013, abstract LB 1416. Faldaprevir (FDV) (PI): G1 naïve, results (StartVerso1) (∆ = 26.7; 95% CI, 17.1–36.3; p<0.0001) (∆ = 28.6; 95% CI, 19.0–38.2; p<0.0001) ) % ( 2 1 R V S 69/132 204/259 210/261 SVR12 rates adjusted for race and genotype ITT, intention-to treat shortened treatment duration with high SVR12 Faldaprevir (FDV) and <25 IU/mL (undetected) at Week 8. aDenominator 8. patientswithETS = Week (undetected) at and<25IU/mL 4 Week undetected) orat (detected <25IU/mL HCVsuccess: RNA early treatment ETS, Proportion of patients (%) : Early treatment success (ETS) allows(ETS) success : Early treatment FDV 120 mg ETS 226/259 ETS ETS + SVR12a FDV 120 mg 194/226 Changes in haemoglobin Mean haemoglobin ± SD (g/dL) 16 10 14 12 18 8 0 4 8 Weeks 12 16 FDV 120 mg + PR PR + mg 120 FDV Placebo + PRPlacebo + FDV 240 mg + PR + mg 240 FDV 20 24 Faldaprevir: adverse events (phase III trial results) Placebo + PR FDV 120 mg + PR FDV 240 mg + PR N=264 N=521 N=524 AEs leading to discontinuation of all 10 (4) 27 (5) 40 (8) medication, n (%) AEs leading to discontinuation of FDV 1 (<1) 6 (1) 14 (3) or placebo only, n (%) Serious AEs, n (%) 16 (6) 39 (7) 43 (8) AEs of at least moderate intensity 156 (59) 302 (58) 332 (63) (any)a, n (%) Rash 11 (4) 39 (7) 50 (10) Photosensitivity 0 (0) 0 (0) 3 (1) GI 19 (7) 58 (11) 96 (18) Anemia 38 (14) 73 (14) 70 (13) Bilirubin associated 2 (1) 18 (3) 47 (9) One patient with cirrhosis at baseline developed acute-on-chronic liver failure after 16 days of FDV (24 0mg) and PR, discontinued all treatment and died 12 days later. The event was considered not related to FDV but to pegylated interferon by investigator. aDAIDS Grade 2 to 4; protocol-defined AEs of special interest. DAIDS, Division of AIDS table for grading the severity of adult and pediatric adverse events; DC, discontinuation; GI, gastrointestinal. Faldaprevir (PI): phase III trial design, G1 experienced (StartVerso3) Prior relapse Relapser: Rebound from HCV Arm 1 (n=49) Placebo + PR PR RNA undetectable at end of 48 week treatmenta but Arm 2 (n=99) FDV 240 mg + PR Placebo + PR PR (RGT a) detectable within 24 weeks of follow-up Arm 3 (n=102) FDV 240 mg + PR PR (RGT a) Prior partial response Partial responder: HCV RNA Placebo + PR PR drop by ≥2 log10 from baseline Arm 1 (n=29) to week 12, but never FDV 240 mg undetectable Arm 2 (n=57) + PR Placebo + PR PR Breakthrough: HCV RNA undetectable during treatment, Arm 3 (n=55) FDV 240 mg + PR PR but rebound to detected during ongoing treatment Prior null response Arm 1 (n=146)b FDV 240 mg + PR Placebo + PR PR Null responder: Absence of HCV RNA drop by ≥2 log10 Arm 2 (n=141) FDV 240 mg + PR from baseline to week 12 PR Day 1 Week 12 Week 24 Week 48 aStopping rule for RGT criteria: all relapsers, who did not achieve ETS (HCV RNA <25 IU/mL (detected or undetected) at week 4 and <25 IU/mL (undetected) at week 8, had extended PR treatment to week 48; bN=146 patients randomized, but N=145 patients treated. PR, pegylated interferon α-2a/ribavirin; QD, once daily; RGT, response-guided therapy. Jacobson et al. AASLD 2013, abstract 1100. Faldaprevir (FDV) (PI): SVR12, G1 experienced (StartVerso3) 100 Prior relapse Prior partial response 80 70 70 60 58 Prior null response 47 40 33 33 20 14 3 7/49 69/99 71/102 1/29 33/57 26/5526/55 48/145 46/14146/141 0 FDV FDV FDV FDV FDV FDV Placebo Placebo 12 weeks 24 weeks 12 weeks 24 weeks 12 weeks 24 weeks MK-5172 (PI) plus PEG-IFN/RBV: G1 naïve non-cirrhotic SVR24 and HCV-RNA TND at Last Visit* 99 % 96 % 98 % 92 % (67/68) (64/67) (64/65) 100 (61/66) ) % ( t 67 % i s i 75 (44/66) v t s a l t a 50 D 86 % 92 % 91 % 87 % N T (55/64) (61/66) (58/64) (52/60) r o 25 54 % 4 2 (31/57) R V S 0 BOC + PR MK-5172 MK-5172 MK-5172 MK-5172 100 mg + PR 200 mg + PR 400 mg + PR 800 mg + PR SVR24 HCV RNA TND at last visit Manns et al.
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