Pan-Genotypic Diret-Acting Antivirals: Opportunity to Achieve HCV Elimination

Transcription

1 Pan-Genotypic Diret-Acting Antivirals: pportunity to Achieve HCV Elimination HEPDART 2017 USA December 6 th, 2017 Tarik Asselah (MD, PhD) Professor of Medicine Hepatology, Chief ISERM UMR 1149, Hôpital Beaujon, Clichy, France.

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 2

3 Pan-Genotypic Diret-Acting Antivirals: pportunity to Achieve HCV Elimination 1 Introduction 2 Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Mavyret ) 4 HCV Elimination 5 Conclusion

4 Estimated 70 Million Persons Living With HCV Prevalence (Viremic) 0% to < 0.6% 0.6% to < 0.8% 0.8% to < 1.3% 1.3% to < 2.9% 2.9% to < 6.7% Polaris bservatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:

5 Worldwide : Diagnosis and treatment rates Estimated chronic HCV prevalence, diagnosis rate and treatment rate in Germany France Treatment rate (%) ote: size of bubble depicts viraemic HCV prevalence Egypt Czech Republic Turkey Brazil Austria England Portugal Spain Switzerland Belgium Canada Denmark Sweden Australia Diagnosis rate (%) Dore GJ, et al. J Viral Hepat 2014;21(Suppl 1):1 4

6 H 3 C H 3 C SF CH 3 H P H CH 3 H F H H F F LDV H H H H 3 C H H 3 C H VEL H H CH 3 VX SF + RBV weeks SF/LDV ± RBV 8 24 weeks SF/VEL ± RBV 12 weeks SF/VEL/VX 12 weeks Jan 2014 May 2014 Sept 2014 ov 2014 Jan 2015 July 2016 July 2017 SF + SMV ± RBV weeks SF + DCV ± RBV weeks MV/PTV/RTV ± DSV ± RBV weeks GRZ/EBV ± RBV weeks GLE/PIB 8 12 weeks SMV DCV PTV GRZ GLE MV DSV EBV PIB PIB Asselah, Marcellin & Schinazi. Liver Int 2018, in press.

7 Pan-Genotypic Diret-Acting Antivirals: pportunity to Achieve HCV Elimination 1 Introduction 2 Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Mavyret ) 4 HCV Elimination 5 Conclusion

8 Velpatasvir/Sofosbuvir: A Single Tablet Regimen (STR) SF ucleotide S5B polymerase inhibitor H 3 C H 3 C CH 3 Sofosbuvir (SF) 1,2 H H P H F CH 3 Potent antiviral activity against HCV GT 1 6 nce-daily, oral, 400-mg tablet H 3 C H H 3 C H H H CH 3 VEL S5A inhibitor Velpatasvir (VEL; GS-5816) 3-5 Picomolar potency against GT nd -generation inhibitor with improved resistance profile SF VEL SF/VEL Single Tablet Regimen (STR) nce daily, oral, STR (400/100 mg) 1. Jacobson IM, et al. Engl J Med 2013;368: ; 2. Lawitz E, et al. Engl J Med 2013;368: ; 3. Cheng G, et al. EASL 2013, poster 1191; 4. German P, et al. EASL 2013, poster 1195; 5. Lawitz E, et al. EASL 2013, poster 1082.

9 Voxilaprevir/Velpatasvir/Sofosbuvir: STR SF ucleotide polymerase inhibitor VEL S5A inhibitor Sofosbuvir (SF)/Velpatasvir (VEL) SF: ucleotide polymerase inhibitor with activity against HCV GT 1 6 VEL: Potent pangenotypic S5A inhibitor VX VX S3/4A S3/4A protease Protease inhibitor inhibitor Voxilaprevir (VX) HCV S3/4A PI with potent antiviral activity against GT 1 6, including most RASs SF/VEL/VX SF ucleotide polymerase inhibitor VEL S5A inhibitor VX S3/4A protease inhibitor nce daily, oral, fixed-dose combination (400/100/100 mg) for GT 1 6

10 Velpatasvir/Sofosbuvir (Epclusa ) for 12 weeks across all genotypes (ASTRAL-1, ASTRAL-2 and ASTRAL-3) SVR12 (%) 2 relapses 2 LTFU 1 D/C 1 D/C 11 relapses 2 D/C 1 death 1015/ / / / / / 35 41/ 41 2% of patients experienced one or more SAE; no SAEs were considered study drug related 2 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 2016; Poster #SAT-195; Jacobson I, et al. EASL 2016; Poster #SAT-168

11 Velpatasvir/Sofosbuvir (Epclusa )for 12 weeks in patients with Advanced Fibrosis and Cirrhosis (ASTRAL 1, 2 & 3) Patients with SVR (%) / / / verall Advanced fibrosis Cirrhosis Asselah T, et al. Liver Int 2017;doi: /liv.13534

12 Real-World Experience of SF/VEL in HCV GT 1 6 HCV-TARGET 407 patients treated with SF/VEL from the HCV-TARGET registry (patients who started July Feb 2017) Baseline Demographics SF/VEL n=407 Male, n (%) 228 (56) Age 60, n (%) 164 (40) HCV GT, % 1 / 2 / 3 / ther 17 / 39 / 38 / 6 Treatment duration 12 weeks, n (%) 330 (81) ther, n (%) 39 (10) ngoing 38 (9) Cirrhosis, n (%) 113 (28) History of DC, n (%) 30 (7) TE*, n (%) 67 (17) Liver transplant, n (%) 8 (2) SVR12, % / / 31 SVR12 (PP) / 95 95/ / verall GT 1 GT 2 GT 3 T TE C CC DC 36/ / / 53 14/ 15 * 21 (5%) were DAA treatment failures (per abstract only). SVR12 for SF/VEL in this real-world cohort was similar to that reported in registration trials T=treatment-naïve TE=treatment-experienced C=non-cirrhotic CC=compensated cirrhotic DC=decompensated cirrhotic Landis, AASLD 2017, Poster

13 SF/VEL for 12 Weeks in People with HCV GT 1-6 and Recent Injecting Drug Use SIMPLIFY Efficacy Results (ITT) % 94% 80 Response (%) LTFU 1 death ET LTFU: loss to follow-up; RI: re-infection n=4 did not complete treatment (3 LTFU, 1 overdose death) n=6 did not have an SVR12 (4 LTFU, 1 overdose death, 1 reinfection) SVR12 SF/VEL for 12 weeks in patients with recent injecting drug use led to high SVR12 rates despite ongoing drug use 4 LTFU 1 death 1 RI Grebely J, IHSU 2017, ral_thu-1040

14 SF/VEL/VX for 12 Weeks in DAA-Experienced Patients Integrated Efficacy Analysis of PLARIS-1 and SVR12, % Total GT 1 Total GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT 6 ther Breakthrough 1* Relapse ther The SVR12 rate was 97% (431/445) in DAA-experienced patients treated with SF/VEL/VX for 12 weeks; Rates were similar regardless of genotype *Patient had drug levels consistent with nonadherence. Roberts, EASL 2017, SAT-280

15 Resistance Analysis of SF/VEL/VX for 12 Weeks in DAA-Experienced Patients Integrated Resistance Analysis of PLARIS-1 and -4 Prevalence and Impact on Treatment utcome of VX- and VEL-Specific RASs in DAA-Experienced Patients 98% SVR12 1.4% VX 6/417 98% SVR12 55% o RASs 229/417 42% VEL 177/ /229 Sarrazin, EASL 2017, THU % VX + VEL 5/ /188 Drug-specific RASs had no impact on treatment outcome of DAA-experienced patients treated with SF/VEL/VX for 12 weeks

16 Pan-Genotypic Diret-Acting Antivirals: pportunity to Achieve HCV Elimination 1 Introduction 2 Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Mavyret ) 4 HCV Elimination 5 Conclusion

17 Glecaprevir/Pibrentasvir (Mavyret ) Glecaprevir (ABT-493) pangenotypic S3/4A protease inhibitor Pibrentasvir (ABT-530) pangenotypic S5A inhibitor 2 nd generation 3 2 nd generation 3 Collectively: G/P In vitro: 1,2 Clinical PK & metabolism: High barrier to resistance Potent against common S3 polymorphisms (eg., positions 80, 155, and 168) and S5A polymorphisms (eg., positions 28, 30, 31 and 93) Additive/synergistic antiviral activity nce-daily oral dosing Minimal metabolism and primary biliary excretion egligible renal excretion (<1%) G/P is co-formulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg. Glecaprevir was identified by AbbVie and Enanta. 1. g TI, et al. Abstract 636. CRI, g TI, et al. Abstract 639. CRI, Pawlotsky, Gastroenterology 2016

18 Glecaprevir Glecaprevir demonstrates potent pangenotypic activity against HCV in vitro Stable HCV Replicon EC 50 (nm) GT1a GT1b GT2a GT2b GT3a GT4a GT5a GT6a Glecaprevir (0.12) a 0.86 Paritaprevir (0.42) a 0.68 Simeprevir 1, A 472 A 36 A Asunaprevir A 1162 A A A Grazoprevir A Voxilaprevir Protease Inhibitor a EC 50 for stable GT5a replicon not available for S3 protease inhibitors; listed value is EC 50 for transient GT5a replicon A, not available. 1. Simeprevir prescribing information 2. Chase R, et al. IAPAC, McPhee F, et al. AAC, Yang H, et al. AAC, Taylor J, et al. EASL, 2015 M Site Training Visit 5Sep17 Company Confidential 2017

19 Activity of Glecaprevir Against Common GT1 S3 Substitutions 1 st Generation S3/4A PIs 2 nd Generation S3/4A PIs GLE is potent against common GT1 S3 substitutions at positions 80, 155, and 168 A156T/V in GT1 confer resistance to GLE, but these substitutions have low viral fitness and are rarely detected clinically

20 Pibrentasvir Pibrentasvir demonstrates potent pangenotypic activity against HCV in vitro Stable HCV Replicon EC 50 (pm) GT1a GT1b GT2a GT2b GT3a GT4a GT5a GT6a Pibrentasvir mbitasvir Daclatasvir ,000 A Ledipasvir ,000 16, , Velpatasvir Elbasvir MK ACH ~150 A A A A IDX A A S5A Inhibitor A, not available. 1. Wang C, et al. AAC, Cheng G, et al. EASL, 2012; Harvoni prescribing information. 3. Cheng G, et al. EASL, Liu R, et al. EASL, Asante-Appiah E, AASLD, Zhao Y, et al. EASL, Dousson C, et al. EASL, 2011

21 Activity of Pibrentasvir Against Common GT1 S5A Substitutions 1 st Generation S5A Inh 2 nd Generation S5A Inh PIB demonstrates an improved resistance profile relative to 1 st and 2 nd generation S5A inhibitors Highly active against common GT1 S5A substitutions at positions 28, 30, 31 or 93 that confer resistance to 1 st and 2 nd generation S5A inhibitors Retains activity against GT1 Y93 substitutions; many 1 st and 2 nd generation S5A inhibitors have significantly lower activity against these substitutions The superior resistance profile also occurs in other genotypes

22 Glecaprevir/Pibrentasvir (Mavyret) in Patients with HCV GT1, 2, 4-6 Infection with or without Compensated Cirrhosis MAVIRET for 8 Weeks in T/TE C Patients: EDURACE-1 and SURVEYR-2 MAVIRET for 12 Weeks in T/TE CC Patients: EXPEDITI SVR12 (%) n verall GT1 GT2 GT4 GT5 GT6 verall GT1 GT2 GT4 GT5 GT6 BT 1 1 Relapse on-vf* All analyses are using the ITT population. T, treatment-naïve; TE, treatment-experienced with IF or pegif ± RBV, or SF + 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 Asselah T, et al. Clin Gastroenterol Hepatol. 2017

23 Glecaprevir/Pibrentasvir (Mavyret) in Patients with HCV GT1, 2, 4-6 Infection with or without Compensated Cirrhosis MAVIRET for 8 Weeks in T/TE C Patients: EDURACE-1 and SURVEYR-2 MAVIRET for 12 Weeks in T/TE CC Patients: EXPEDITI SVR12 (%) n verall GT1 GT2 GT4 GT5 GT6 verall GT1 GT2 GT4 GT5 GT6 BT 1 1 Relapse on-vf* All analyses are using the ITT population. T, treatment-naïve; TE, treatment-experienced with IF or pegif ± RBV, or SF + 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 Asselah T, et al. Clin Gastroenterol Hepatol. 2017

24 Glecaprevir/Pibrentasvir (Mavyret) in Patients with HCV GT3 Infection with or without Compensated Cirrhosis SVR12 (%) n 0 MAVIRET for 8 or 12 Weeks in T C Patients: EDURACE MAVIRET 8 weeks BT MAVIRET 12 weeks Relapse on-vf * DCV + SF 12 weeks SVR12 (%) n 0 MAVIRET for 12 Weeks in T CC Patients, or 16 Weeks in TE C/CC Patients: SURVEYR-2 Part 3 BT 1 Relapse 2 on-vf * T CC 12 weeks TE TE, C/CC 16 weeks All analyses are using the ITT population. T, treatment-naïve; TE, treatment-experienced with IF or pegif ± RBV, or SF + RBV ± pegif; BT, breakthrough; CC, compensated cirrhosis; C, noncirrhotic; DCV, daclatasvir; ESRD, end-stage renal disease; SF, 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 2017.

25 Glecaprevir/Pibrentasvir (Mavyret) in Patients with HCV GT3 Infection with or without Compensated Cirrhosis SVR12 (%) n 0 MAVIRET for 8 or 12 Weeks in T C Patients: EDURACE MAVIRET 8 weeks BT MAVIRET 12 weeks Relapse on-vf * DCV + SF 12 weeks SVR12 (%) n 0 MAVIRET for 12 Weeks in T CC Patients, or 16 Weeks in TE C/CC Patients: SURVEYR-2 Part 3 BT 1 Relapse 2 on-vf * T CC 12 weeks TE TE, C/CC 16 weeks All analyses are using the ITT population. T, treatment-naïve; TE, treatment-experienced with IF or pegif ± RBV, or SF + RBV ± pegif; BT, breakthrough; CC, compensated cirrhosis; C, noncirrhotic; DCV, daclatasvir; ESRD, end-stage renal disease; SF, 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 2017.

26 8 and 12 Weeks of Glecaprevir / Pibrentasvir in GT1 6 Patients without Cirrhosis (Integrated Analysis ) Integrated efficacy analysis of 8- or 12-weeks Maviret treatment in non-cirrhotic patients with GT1 6 infection across seven phase 2 or 3 clinical trials Failure rate was similar between 8 and 12 week T/TE* (mitt) Maviret 8 week G/P 12 week G/P 99 99, SVR12 (%) BT 1 BT 7 3 relapse relapse n verall GT1 GT2 GT3 GT4 GT5 GT6 BT, breakthrough; mitt, modified intent-to-treat, (excludes non-virologic failures); *TE, treatment-experienced (includes patients with prior SF use); T, treatment-naive Includes patients with prior SF use (8-week Maviret [n = 7] and 12-week Maviret [n = 9]); All GT3 patients were treatment-naïve. GP VHC RMR 093 sept17 R A DLU sept18 v2 Puoti M, et al. J Hepatol 2017; 66(Suppl):S721 (poster presentation SAT- 233).

27 Safety Glecaprevir / Pibrentasvir vs placebo (EDURACE-2, in non cirrhotic GT2 patients) Adverse events Laboratory abnormalities Event, n (%) G/P 12 Weeks = 202 Placebo = 100 Any AE * 131 (65) 58 (58) AEs leading to study drug discontinuation 0 0 SAEs 3 (1) 1 (1) AEs occurring in 10% total patients Headache 24 (12) 12 (12) G/P Placebo Characteristic, n (%) 12 Weeks = 202 = 100 AST Grade 2 (>3 UL) Grade 3 (>5 UL) 0 2 (1) 2 (2) 1 (1) ALT Grade 2 (>3 UL) Grade 3 (>5 UL) 0 1 (0.5) 2 (2) 2 (2) Total Bilirubin Grade 3 (3-10 UL) 1 (0.5) 0 Fatigue 23 (11) 10 (10) o SAEs were assessed as being related to DAAs, and none led to discontinuation of G/P * Includes all AEs regardless of relation to study drugs; ne patient each experienced a broken ankle, hemorrhoids, and a bile duct stone; Rheumatoid arthritis; Patient achieved SVR12. GP VHC RMR 093 sept17 R A DLU sept18 v2 Kowdley K, et al. Hepatology 2016; 64(Suppl 1):39A (ral presentation, 73).

28 Safety Glecaprevir / Pibrentasvir vs placebo (EDURACE-2, in non cirrhotic GT2 patients) Adverse events Laboratory abnormalities Event, n (%) G/P 12 Weeks = 202 Placebo = 100 Any AE * 131 (65) 58 (58) AEs leading to study drug discontinuation 0 0 SAEs 3 (1) 1 (1) AEs occurring in 10% total patients Headache 24 (12) 12 (12) G/P Placebo Characteristic, n (%) 12 Weeks = 202 = 100 AST Grade 2 (>3 UL) Grade 3 (>5 UL) 0 2 (1) 2 (2) 1 (1) ALT Grade 2 (>3 UL) Grade 3 (>5 UL) 0 1 (0.5) 2 (2) 2 (2) Total Bilirubin Grade 3 (3-10 UL) 1 (0.5) 0 Fatigue 23 (11) 10 (10) o SAEs were assessed as being related to DAAs, and none led to discontinuation of G/P * Includes all AEs regardless of relation to study drugs; ne patient each experienced a broken ankle, hemorrhoids, and a bile duct stone; Rheumatoid arthritis; Patient achieved SVR12. GP VHC RMR 093 sept17 R A DLU sept18 v2 Kowdley K, et al. Hepatology 2016; 64(Suppl 1):39A (ral presentation, 73).

29 SDAPI study : Response-Guided Therapy Day Plasma HCV RA < 500 IU/ml by Day 2 GT-1b oncirrhotic Chinese =26 Patient randomly assigned Group 1: SF+LDV+ASV =12 Group 2: SF+DCV+SMV =6 Group 3: SF+DCV+ASV =8 Group 1: SF+LDV+ASV =6 Group 2: SF+DCV+SMV =6 Group 3: SF+DCV+ASV =6 Follow up Follow up Follow up Lau G et al. Lancet Gastro & Hepato 2017

30 Pan-Genotypic Diret-Acting Antivirals: pportunity to Achieve HCV Elimination 1 Introduction 2 Sofosbuvir/Velpatasvir (Epclusa ) 3 Glecaprevir/Pibrentasvir (Mavyret ) 4 HCV Elimination 5 Conclusion

31 France : Indications for therapy : Recent evolution 2014 F3-F4 (Fibrosis stage) (by any evaluation) Extra-hepatic manifestations HIV/HCV coinfected patients 2015 F2 (Fibrosis stage) («severe» F2) June 2016 Transplants Genotype 3 At risk of contamination January 2017 : Universal Treatment Individual Impact (collective Impact) Collective Impact (& individual)

32 Treatment of HCV infections in France ( 20,000 in 2017) b of Patients Treated per months (based on 12 weeks duration per patients) ct 2017 (Base GERS)

33 Majority of Patients with Advanced Fibrosis have been treated (Hepather) 30% 85%

34 HCC reduction (already a reallity) CirVir C12 ahon P et al. Gastroenterology 2017

35 Conclusion Burden of HCV : Major Public Health Problem Global elimination of HCV is now achievable HCV cure has a positive impact by: Improving survival Decreasing the incidence of cirrhosis Decreasing hepatocellular carcinoma Improving overall quality of life for patients with HCV Multiple common barriers exist for implementation of programs to control HCV across low, middle, and high income countries We must continue to be active in our respective countries with increasing screening and linkage to care for all patients

36 The need to take care of all Humans, o patient left behind WH region Incidencerate(per100000) Map key Best estimate Africa 31,0 America 6,4 Middle East 62,5 Europa a 61,8 South Est Asia 14,8 West Pacific 6,0 Total 23,7 Hutin J-F, Suisse, WH, EASL 2017 Asselah et al. Eliminating Hepatitis C within Low Income Countries the need to cure Genotypes 4, 5, 6. Journalof Hepatology, 2018 in press