Treatment of HCV : 100 % cure?

Transcription

1 Treatment of HCV : % cure? PHC 8 PARIS January 5th, 8 Tarik Asselah (MD, PhD) Professor of Medicine Hepatology, Chief ISERM UMR 49, Hôpital Beaujon, Clichy, France. PHC 8 -

2 Disclosures Employee of Paris Public University Hospitals (AP-HP, Beaujon s Hospital) and University of Paris Principal investigator for research grants : Funds paid to Hospital (AP-HP) Consultant, expert and speaker for: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp Dohme, Roche. Grants from : AR, CRS, ISERM, University of Paris, ARS

3 Treatment of HCV : % cure? Introduction Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Maviret ) 4 Grazoprevir/Elbasvir (Zepatier ) 5 Challenges to achieve HCV elimination

4 Estimated 7 Million Persons Living With HCV Prevalence (Viremic) % to <.6%.6% to <.8%.8% to <.3%.3% to <.9%.9% to < 6.7% Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 7;:6-76.

5 Direct-acting antivirals : a Revolution 5 TR Capsid C Structural proteins Envelope glycoproteins E E Protease inhibitors «previr» Paritaprevir Glecaprevir Grazoprevir Voxilaprevir S S on-structural proteins Metalloprotease Serine protease RA helicase Cofactors S3 S4A S4B S5A inhibitors «.asvir» Ledipasvir Velpatasvir Pibrentasvir Ombitasvir Elbasvir Daclatasvir 3 TR RA polymerase S5A S5B Polymerase inhibitors «..buvir» ucs on-ucs Sofosbuvir Dasabuvir Asselah et al. Liver Int 8, in press.

6 O F F O O H SOF LDV Jan 4 May 4 SOF + SMV ± RBV 4 weeks SMV VEL SOF/LDV ± RBV 8 4 weeks SOF + RBV 4 weeks Sept 4 ov 4 SOF + DCV ± RBV 4 weeks OMV/PTV/RTV ± DSV ± RBV 4 weeks O O O SOF/VEL ± RBV weeks Jan 5 H O H F F VOX SOF/VEL/VOX weeks July 6 July 7 GRZ/EBV ± RBV 6 weeks GLE/PIB 8 weeks PTV DCV O O S GLE GRZ EBV OMV PIB DSV Asselah et al. Liver Int 8, in press. PIB

7 Priorities for Direct-acting antivirals SVR > 95% Safety Tolerability Pangenotypic: High barrier to resistance Short duration; Low pill burden Minimal drug drug interactions Access/cost Top Priorities

8 Priorities for Direct-acting antivirals SVR > 95% Safety Top Priorities Tolerability High barrier to resistance Short duration; Low pill burden Minimal drug drug interactions Pan-genotypic Access/cost Secondary Priorities

9 Treatment of HCV : % cure? Introduction Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Maviret ) 4 Grazoprevir/Elbasvir (Zepatier ) 5 Challenges to achieve HCV elimination

10 Velpatasvir/Sofosbuvir: A Single Tablet Regimen (STR) SOF ucleotide S5B polymerase inhibitor Sofosbuvir (SOF), Potent antiviral activity against HCV GT 6 Once-daily, oral, 4-mg tablet VEL S5A inhibitor Velpatasvir (VEL; GS-586)3-5 Picomolar potency against GT 6 nd-generation inhibitor with improved resistance profile SOF/VEL Single Tablet Regimen (STR) SOF VEL Once daily, oral, STR (4/ mg). Jacobson IM, et al. Engl J Med 3;368:867-77;. Lawitz E, et al. Engl J Med 3;368:878-87; 3. Cheng G, et al. EASL 3, poster 9; 4. German P, et al. EASL 3, poster 95; 5. Lawitz E, et al. EASL 3, poster 8.

11 Voxilaprevir/Velpatasvir/Sofosbuvir: STR Sofosbuvir (SOF)/Velpatasvir (VEL) SOF VEL ucleotide polymerase inhibitor SOF: ucleotide polymerase inhibitor with activity against HCV GT 6 S5A inhibitor VEL: Potent pangenotypic S5A inhibitor O F F O O H H O O H O O F O O S F VOX VOX S3/4A S3/4A Protease protease inhibitor inhibitor Voxilaprevir (VOX) HCV S3/4A PI with potent antiviral activity against GT 6, including most RASs SOF/VEL/VOX SOF ucleotide polymerase inhibitor VEL VOX S5A S3/4A inhibitor protease inhibitor Once daily, oral, fixed-dose combination (4// mg) for GT 6

12 SVR (%) Velpatasvir/Sofosbuvir (Epclusa ) for weeks across all genotypes (ASTRAL-, ASTRAL- and ASTRAL-3) relapses LTFU D/C 33/ 38 death D/C D/C 5/ 35 relapses 37/ 38 64/ 77 6/ 6 34/ 35 4/ 4 % of patients experienced one or more SAE; no SAEs were considered study drug related patients discontinued treatment due to AEs AE: adverse event; D/C: discontinuation; LTFU: lost to follow-up; SAE: serious adverse event Agarwal K, et al. EASL 6; Poster #SAT-95; Jacobson I, et al. EASL 6; Poster #SAT-68

13 Patients with SVR (%) SOF/VEL (Epclusa ) is effective in patients with advanced fibrosis and cirrhosis (ASTRAL, & 3) / 5 78/ 8 / Overall Advanced fibrosis Cirrhosis Asselah T, et al. Liver Int 8, in press

14 SOF/VEL/VOX for Weeks in DAA-Experienced Patients Integrated Efficacy Analysis of POLARIS- and VR, % Total GT Total Breakthrough GT a GT b GT GT 3 GT GT GT 6 Other * Relapse 7 4 Other 6 3 The SVR rate was 97% (43/445) in DAA-experienced patients treated with SOF/VEL/VOX for weeks; Rates were similar regardless of genotype *Patient had drug levels consistent with nonadherence. Roberts, EASL 7, SAT-8

15 Treatment of HCV : % cure? Introduction Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Maviret ) 4 Grazoprevir/Elbasvir (Zepatier ) 5 Challenges to achieve HCV elimination

16 Glecaprevir/Pibrentasvir (Maviret ) Glecaprevir Pibrentasvir (ABT-493) (ABT-53) pangenotypic S3/4A protease inhibitor pangenotypic S5A inhibitor nd generation3 nd generation3 Collectively: G/P In vitro:, Clinical PK & metabolism: High barrier to resistance Potent against common S3 polymorphisms (eg., positions 8, 55, and 68) and S5A polymorphisms (eg., positions 8, 3, 3 and 93) Additive/synergistic antiviral activity Once-daily oral dosing Minimal metabolism and primary biliary excretion egligible renal excretion (<%) G/P is co-formulated and dosed once daily as three mg/4 mg pills for a total dose of 3 mg/ mg. Glecaprevir was identified by AbbVie and Enanta.. g TI, et al. Abstract 636. CROI, 4.. g TI, et al. Abstract 639. CROI, Pawlotsky, Gastroenterology 6

17 Glecaprevir/Pibrentasvir (Maviret) in Patients with HCV GT,, 4-6 Infection with or without Compensated Cirrhosis MAVIRET for 8 Weeks in T/TE C Patients: EDURACE- and SURVEYOR- SVR (%) BT Relapse on-vf* n MAVIRET for Weeks in T/TE CC Patients: EXPEDITIO All analyses are using the ITT population. T, treatment-naïve; TE, treatment-experienced with IF or pegif ± RBV, or SOF + RBV ± pegif; C, non-cirrhotic; CC, compensated cirrhotic; ITT, intent-to-treat; BT, breakthrough; VF, virologic failure. *Includes patients who discontinued due to adverse events, lost to follow-up, or withdrew. MAVIRET Summary of Product Characteristics; Accessed August 7.. Asselah T, et al. Clin Gastroenterol Hepatol. 7

18 Integrated Efficacy Analysis: High SVR Rates with 8 and Weeks of Glecaprevir/Pibrentasvir in GT 6 Patients without Cirrhosis Integrated efficacy analysis of 8- or -weeks Maviret treatment in non-cirrhotic patients with GT 6 infection across seven phase or 3 clinical trials Failure rate was similar between 8 and week Maviret 8 SVR (%) 6 4 n 99 99,6 BT T/TE* (mitt) 8 week G/P 99,7 99 week G/P BT 7 3 relapse relapse Overall GT GT BT, breakthrough; mitt, modified intent-to-treat, (excludes non-virologic failures); *TE, treatment-experienced (includes patients with prior SOF use); T, treatment-naive Includes patients with prior SOF use (8-week Maviret [n = 7] and -week Maviret [n = 9]); All GT3 patients were treatment-naïve. GP VHC RMR 93 sept7 R A DLU sept8 v GT3 GT4 GT5 Puoti M, et al. J Hepatol 7; 66(Suppl):S7 (poster presentation SAT-33). GT6

19 Glecaprevir/Pibrentasvir (Maviret) in Patients with HCV GT3 Infection with or without Compensated Cirrhosis MAVIRET for 8 or Weeks in T C Patients: EDURACE-3 MAVIRET for Weeks in T CC Patients, or 6 Weeks in TE C/CC Patients: SURVEYOR- Part 3 95 n MAVIRET 8 weeks 33 MAVIRET weeks 98 SVR (%) SVR (%) n DCV + SOF weeks BT Relapse 5 3 on-vf* T CC weeks TE C/CC 6 weeks BT Relapse All analyses are using the ITT population. on-vf* T, treatment-naïve; TE, treatment-experienced with IF or pegif ± RBV, or SOF + RBV ± pegif; BT, breakthrough; CC, compensated cirrhosis; C, noncirrhotic; DCV, daclatasvir; ESRD, end-stage renal disease; SOF, sofosbuvir; TE, treatment experienced; T, treatment naive; VF, virologic failure. *Includes patients who discontinued due to adverse events, lost to follow-up, or withdrew. MAVIRET Summary of Product Characteristics; Accessed August 7.

20 Treatment of HCV : % cure? Introduction Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Maviret ) 4 Grazoprevir/Elbasvir (Zepatier ) 5 Challenges to achieve HCV elimination

21 Elbasvir/Grazoprevir (Zepatier ) HCV S5A inhibitor, 5 mg Elbasvir (MK-874) HCV S3/4A inhibitor, mg Grazoprevir (MK-57) High activity in vitro 3 Efficacious in GT & GT4 treatment-naive and treatment- experienced cirrhotic and noncirrhotic patients with HCV, and in HIV/HCV coinfected patients4 6 All-oral, once-daily regimen HCV = hepatitis C virus; HIV = human immunodeficiency virus.. Summa V et al. Antimicrob Agents Chemother. :56; Coburn CA et al. ChemMedChem. 3;8: Harper S et al. ACS Med Chem Lett. ;3: Zeuzem S et al. Ann Intern Med. 5;63: Lawitz E et al. Lancet. 5;385: Rockstroh JK et al. Lancet HIV. 5;:e39 e37.

22 EBR/GZR in Treatment-aive Patients With Cirrhosis Treatment-naive With or without HIV- coinfection Patients Achieving SVR, % Integrated analysis of patients with cirrhosis from 6 clinical trials in the Phase /3 clinical program Patient population Efficacy of Weeks of EBR/GZR Without RBV in Patients With Compensated Cirrhosis LTFU/early discontinuation Breakthrough FAS mfas a b b Relapse a mfas excludes patients who discontinued treatment for reasons unrelated to study medication. bdeath (coronary artery disease). EBR/GZR = elbasvir/grazoprevir; RBV = ribavirin; FAS = full analysis set; SVR = sustained virologic response weeks after the cessation of treatment; GT = genotype; LTFU = lost to follow up; mfas = modified full analysis set.. Jacobson I et al. AASLD 5, Abstract 4.

23 Elbasvir/Grazoprevir (Zepatier): Efficacy in Different Patient Populations Overall mfasa SVR rates from the Phase 3 clinical trial program Patients Achieving SVR, % Phase 3 studies vs placebo Comorbidity Genotypes Treatment Experience Treatmentexperienced Stage 4-5 OAT/PWID IBLD ± HIV CKD ± HIV 4 4 HIV ± HIV ± HIV,4,6,4,6,4,4,6,4,6,4,6 T T/PR-PTF T T/PR-PTF T PR-PTF PR-PTF Weeks EBR/GZR Without RBV 6 Weeks EBR/GZR + RBV amfas excludes patients who failed for reasons unrelated to study medication. EBR/GZR = elbasvir/grazoprevir; SVR = sustained virologic response weeks after the cessation of treatment; CKD = chronic kidney disease; OAT = opioid agonist therapy; PWID = people who inject drugs; IBLD = inherited blood disorders; T = treatment naive; HIV = human immunodeficiency virus; TE = treatment experienced; RBV = ribavirin; PR = peginterferon + ribavirin; PTF = prior-treatment failure; mfas= modified full analysis set.. Roth D et al. Lancet. 5;386: Dore GJ et al. EASL 6, SAT Hezode C et al. EASL 6, SAT Zeuzem S et al. Ann intern Med. 5;63: Rockstroh JK et al. Lancet HIV. 5;:e39 e Kwo P et al. Gastroenterology. 7;5:64 75.

24 Treatment of HCV : % cure? Introduction Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Maviret ) 4 Grazoprevir/Elbasvir (Zepatier ) 5 Challenges to achieve HCV elimination

25 ASCED: onrandomized Phase IV Trial of HCV Treatment Outcomes by DAA Prescriber Type Pts ( = 6) from 3 urban, FQHCs in DC, all treated with LDV/SOF per FDA prescribing info; all providers given 3-hr training in AASLD/IDSA HCV guidance / 5 39/ 6 43/ 9 56/ 6 SVR (%) n/ = P/PA Primary MD Specialist MD Overall Kattakuzhy S, et al. Ann Intern Med. 7;67:3-38.

26 IF-Free DAA Therapy: Opioid Substitution Therapy vs o Opioid Substitution Therapy o OST OS T / / 69/ SVR (%) n/ = 455/ / 56 OBV/PTV/RTV + DSV + RBV[,] 445 4/ / OBV/PTV/RTV + DSV ± RBV[3] 8/ 88 66/ 7 LDV/SOF + RBV[4] 49/ 5 SOF/VEL[5] EBR/GZR[6,7] 44/ 437 7/ 8 Wks 543 /57 4/ 4 8 Wks SOF/VEL/VOX[8]. Feld JJ, et al. Engl J Med. 4;37: ;. Puoti M, et al. AASLD 4. Abstract Grebely J, et al. EASL 7. Abstract FRI-36.; 4. Grebely J, et al. Clin Infect Dis. 6;63: Grebely J, et al. Clin Infect Dis. 6;63: ; 6. Zeuzem S, et al. Ann Intern Med. 5;63: Dore GJ, et al. Ann Intern Med. 6;65: ; 8. Grebely J, et al. EASL 7. Abstract FRI-35.

27 The need to cure of all HCV infected Patients, o patient left behind Incidence rate (per ) WHO region Map key Best estimate Africa 3, America 6,4 Middle East 6,5 Europa South Est Asia a 6,8 4,8 Hutin J-F, Suisse, WHO, EASL 7 West Pacific 6, Total 3,7 Asselah et al. Eliminating Hepatitis C within Low Income Countries the need to cure Genotypes 4, 5, 6. Journalof Hepatology, 8 in press

28 How to achieve HCV elimination PREVETIO Harm reduction Infection control Blood safety

29 How to achieve HCV elimination AWAREESS PREVETIO Harm reduction Infection control Blood safety Increase awareness Fights barriers & stigma Advocacy

30 How to achieve HCV elimination TEST AD TREAT PREVETIO Harm reduction Infection control Blood safety HCV screening (universal) Linkage to care : Treat with optimal DAAs AWAREESS Increase awareness Fights barriers & stigma Advocacy

31 How to achieve HCV elimination HCV elimination TEST AD TREAT PREVETIO Harm reduction Infection control Blood safety HCV screening (universal) Linkage to care : Treat with optimal DAAs AWAREESS Increase awareness Fights barriers & stigma Advocacy Asselah et al. Liver Int 8, in press.