Debate: Do We Need More HCV Drugs Con Standpoint

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1 Debate: Do We Need More HCV Drugs Con Standpoint 18 th Antivirals PK Workshop, Friday 16 th June 2017, Chicago Jürgen Rockstroh Department of Medicine I University Hospital Bonn, Bonn, Germany

2 Conflict of Interest: JKR Honoraria for lectures and/or consultancies from Abbott, AbbVie, Bionor, BMS, Cipla, Gilead, Janssen, Merck, Roche, ViiV. Research grants from Dt. Leberstiftung, DZIF, NEAT ID.

3 Debate» This debate is not about who is more beautiful but really do we need even more HCV DAAs than we already have. Seite 3

4 p7 HCV DAAs 5 UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3 UTR Protease Polymerase Ribavirin NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non-NUC Inhibitors Telaprevir Boceprevir Simeprevir Paritaprevir Asunaprevir Grazoprevir Glecaprevir Voxilaprevir Daclatasvir Ledipasvir Ombitasvir Velpatasvir Elbasvir Pibrentasvir GS-5816 Ruzasvir Sofosbuvir VX-135 Uprifosbuvir ACH-3422 Dasabuvir Beclabuvir -previr -asvir -buvir

6 2016 EASL Guidelines G/P Summer 2017 for all genotypes Journal of Hepatology 2017;66:

7 SVR24 rate (%) Summary of EASL % J-M Pawlotsky

8 HCV therapy: Game over! A. Aghemo and M. Buti, Gastroenterology 2017 Seite 8

9 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices.» Any special patient populations left?» Need for shorter treatment durations?» Need for better tolerated drugs?» Need for drugs with less drug-drug interactions?» How about treatment of DAA failures? Seite 9

10 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices.» Any special patient populations left?» Need for shorter treatment durations?» Need for better tolerated drugs?» Need for drugs with less drug-drug interactions?» How about treatment of DAA failures? Seite 10

11 Box price of DAA in current use in Egypt as of April 2017 DAA Manufactuturer NCCVH Pharmacies Sofosbuvir Generic 450 LE (25$) Simeprevir Brand 1315 (73$) Daclatasvir Brand 1315 (73$) Daclatasvir Generic 60 LE (3$) OMB/PAR Brand 3050 LE (170$) SOF/LDV Brand 3050 LE (170$) SOF/LDV Generic Not available Price of ribavirin 1200mg/d for a month is 125 LE (7$) in NCCVH EASL 2017 Seite 11

12 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices.» Any special patient populations left?» Need for shorter treatment durations?» Need for better tolerated drugs?» Need for drugs with less drug-drug interactions?» How about treatment of DAA failures? Seite 12

13 SVR12 (%) High SVR in adult patients with HIV/HCV co-infection treated with DAAs ALLY-2: 1 GT 1 4, TN & TE SOF + DCV ION-4: 2 GT 1 or 4, TE & TN LDV/SOF TURQUOISE-1, part 2: 3 GT 1 or 4, TN and TE OMV/PTV/RTV + DSV ± RBV C-EDGE: 4 GT 1, 4 or 6, TN GRZ/EBV /101 51/52 TN TE 12 weeks 0 322/3 217/ weeks 12 or 24 weeks 0 210/ Weeks 1. Wyles D, et al. N Engl J Med 2015;373:714 25; 2. Naggie S, et al. N Engl J Med 2015;373:705 13; 3. Rockstroh JK, et al. IAS 2016; Abstract # 10333; 4. Rockstroh JK, et al. Lancet HIV 2015;2:e NOT HEAD-TO-HEAD COMPARISONS Studies included non-cirrhotic and cirrhotic patients. TE: treatment-experienced

14 EXPEDITION-I Study: Next Generation Direct-Acting Antivirals Glecaprevir (formerly ABT-493) pangenotypic NS3/4A protease inhibitor Coformulated: G/P Pibrentasvir (formerly ABT-530) pangenotypic NS5A inhibitor In vitro: 1,2 Clinical PK & metabolism: High barrier to resistance Potent against common NS3 polymorphisms (e.g., positions 80, 155, and 168) and NS5A polymorphisms (e.g., positions 28, 30, 31 and 93) Synergistic antiviral activity Once-daily oral dosing with food Minimal metabolism and primary biliary excretion Negligible 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.Ng TI, et al. Antimicrobial Agents and Chemotherapy; 2017 (in press). 2.Ng TI, et al. Abstract 636. CROI, 2014

were enrolled at 40 study sites in Belgium, Canada, Germany, South Africa, Spain, and the United States G/P is coformulated and dosed once

15 EXPEDITION-1 Study: Objective and Study Design Objective» Evaluate the efficacy and safety of G/P for 12 weeks in patients with HCV GT1, 2, 4, 5 or 6 infection and compensated cirrhosis G/P 300 mg/120 mg N=146 0 Week 24 Week 36 Week 12 Open-label Treatment SVR12 assessment Patients were enrolled at 40 study sites in Belgium, Canada, Germany, South Africa, Spain, and the United States G/P is coformulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg. Forns X, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, Abst. GS-006.

16 % Patients with SVR12 EXPEDITION-1 Study: SVR12 by Intent-to-Treat (ITT) Analysis GT1 GT2 GT4 GT5 GT6 Total *Patient with HCV GT1a infection relapsed at PTW8 - No treatment-emergent substitutions were present in NS3 - In NS5A, Y93N was present at baseline; Y93N, Q30R and H58D were present at the time of failure Forns X, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, Abst. GS-006.

17 SURVEYOR-II, Part 3: SVR12: GT3 98% of patients had HCV RNA <LLOQ by treatment week 4

18 SVR, % SVR12 (mfas) 100 Treatment- Treatment- naive experienced EBR/GZR + SOF + RBV (8 weeks) EBR/GZR + SOF (12 weeks) EBR/GZR + SOF (12 weeks) EBR/GZR + SOF + RBV (12 weeks) EBR/GZR + SOF (16 weeks) Relapse mfas excluded patients who discontinued treatment for reasons unrelated to study medication.

19 Any special patient populations left?» HIV coinfected (SVR >95%)» Renal insufficiency (SVR up to 99%)» Cirrhotics (SVR up to 99%)» GT3 treatment experineced with cirrhosis (SVR 96%)» Inherited blood disorders (SVR 94%)» Transplant patients (SVR >95%)» you name it Seite 19

20 So what does Nancy really think and that already in Seite 20

21 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices.» Any special patient populations left?» Need for shorter treatment durations?» Need for better tolerated drugs?» Need for drugs with less drug-drug interactions?» How about treatment of DAA failures? Seite 21

22 SVR12 (%) 8-week LDV/SOF in non-cirrhotic, treatment naïve GT 1 patients: real-world confirmation of clinical data» *Two patients received LDV/SOF + RBV. LDV/SOF + RBV for 8 weeks is not licensed in the EU. ITT: intention-to-treat Real world virological response (>4000 patients) Post hoc analysis; per protocol; ITT analysis / / / / / 48 ION-3 ifi DHC-R Burman's US Com. pharmacy * -Centers 236/ 240 Kaiser LA 127/ 131 HCV Target 242/ 254 TRIO Cohort 1878/ 1975 VA 32/ 34 HEPA-C Registry 186/ 199 GECCO 238/ 258 Kaiser Permanente 1. Kowdley KV, et al. N Engl J Med 2014;370: ; 2. Buggisch P, et al. EASL 2016; Poster #SAT-243; 3. Buggisch P, et al. EASL 2016; Poster #SAT-241; 4. Qureshi K, et al. EASL 2016; Poster #SAT-192; 5. Marshall V, et al. AASLD 2015; Poster #1154; 6. Latt NL, et al. EASL 2016; Poster #SAT-227; 7. Terrault N, et al. AASLD 2015; Oral #94; 8. Curry M, et al. AASLD 2015; Poster #1046; 9. Ioannou GN, et al. Gastroenterology 2016;151:457 71; 10. Creso J, et al. EASL 2016; Poster #LBP-511; 11. Ingiliz P, et al. Clin Infect Dis 2016;doi: /cid/ciw567; 12. Lai JB, et al. EASL 2016; Poster #SAT-177

(2) non-inferiority (1) non-inferiority 2:1 Randomized ENDURANCE-3 Study: Objective and Study Design Treatment Period Arm A N = 233 G/P Post-treatment Period SVR12 Arm B N = 115 SOF + DCV SVR12 Arm C

24 (2) non-inferiority (1) non-inferiority 2:1 Randomized ENDURANCE-3 Study: Objective and Study Design Treatment Period Arm A N = 233 G/P Post-treatment Period SVR12 Arm B N = 115 SOF + DCV SVR12 Arm C N = 157 G/P SVR Weeks Arm C: 8-week treatment duration Per discussion with regulatory authorities after phase 2 treatment data became available, an 8 week treatment Arm of G/P was added to the study design SVR12: Non-inferiority of 8 weeks of G/P compared to 12 weeks of G/P* *Endpoint was tested only after 12 weeks of G/P was determined non-inferior to 12 weeks of SOF + DCV Foster G, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, Abst. GS-007.

25 ENDURANCE-3 Study: Baseline Demographics and Clinical Characteristics Characteristic G/P 12 weeks N = 233 2:1 randomized Non-randomized SOF + DCV 12 weeks N = 115 G/P 8 weeks N = 157 Male, n (%) 121 (52) 52 (45) 92 (59) White race, n (%) 205 (88) 103 (90) 134 (85) Age, median years (range) 48 (22 71) 49 (20 70) 47 (20 76) BMI, median kg/m 2 (range) 25 (17 49) 25 (18 42) 26 (18 44) HCV RNA, median log 10 IU/mL (range) 6.1 ( ) 6.0 ( ) 6.1 ( ) History of injection drug use, n (%) 149 (64) 73 (63) 104 (66) Baseline fibrosis stage, n (%) F0 F1 201 (86) 97 (84) 122 (78) F2 12 (5) 8 (7) 8 (5) F3 20 (9) 10 (9) 27 (17) Subtype GT3a, n/n (%) * 226/229 (99) 113/113 (100) 154/155 (99) BMI, body mass index; DCV, daclatasvir; G/P, coformulated glecaprevir/pibrentasvir; GT, genotype; HCV, hepatitis C virus; SOF, sofosbuvir *HCV subtype determined by phylogenetic analysis; N = total number of patients with sequence data available Foster G, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, Abst. GS-007.

26 SVR12 (% Patients) ENDURANCE-3 Study: Results SVR12 by Intent-to-Treat (ITT) Analysis Treatment Duration G/P 12 weeks (1) non-inferior (2) non-inferior SOF + DCV 12 weeks G/P 8 weeks Non-inferiority: Lower bound of the confidence interval (CI) of the difference in SVR12 must be above -6%* (1) -1.2% (95% CI ) (2) -0.4% (97.5% CI ) Both G/P treatments met non-inferiority criteria for the primary endpoint *Conventional statistical methods were used in multiplicity comparison for determining non-inferiority Foster G, et al. 52nd EASL; Amsterdam, Netherlands; April 19-23, Abst. GS-007.

27 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices.» Any special patient populations left?» Need for shorter treatment durations?» Need for better tolerated drugs?» Need for drugs with less drug-drug interactions?» How about treatment of DAA failures? Seite 27

28 DAAs were well-tolerated in clinical trials of HIV/HCV co-infected patients Adverse events common across all DAA regimens in HIV/HCV co-infection trials ALLY-2 DCV + SOF N=203 ION-4 LDV/SOF N=335 TURQUOISE-I Part 2 OMV/PTV/RTV + DSV ± RBV N=228 C-EDGE CO-INFECTION GRZ/EBV N=218 ASTRAL-5 SOF/VEL N=106 Fatigue 17% 21% 23% 13% 25% Headache 11% 25% 14% 12% 13% Diarrhoea 7% 11% 14% 7% 8% Nausea 13% 10% 20% 9% 7% D/C due to AE (2%) Wyles D, et al. N Engl J Med 2015;373:714 25; Rockstroh JK, et al. IAS 2016; Abstract # 10333; Naggie S, et al. N Engl J Med 2015;373:705 13; Rockstroh JK, et al. Lancet HIV 2015;2:e319 27; Brau N, et al. IAS 2016; Abstract #708 NOT HEAD-TO-HEAD COMPARISONS This table illustrate adverse events obtained between different regimens from different studies and are therefore not directly comparable as study populations are NOT matched

29 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices.» Any special patient populations left?» Need for shorter treatment durations?» Need for better tolerated drugs?» Need for drugs with less drug-drug interactions?» How about treatment of DAA failures? Seite 29

30 Drug-drug Interactions between DAAs and ARVs Don`t undermine your own existence as a clinical pharmacologist.

31 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices.» Any special patient populations left?» Need for shorter treatment durations?» Need for better tolerated drugs?» Need for drugs with less drug-drug interactions?» How about treatment of DAA failures? Seite 31

32 Re-treatment after failure to LDV/SOF 9 patients without SVR in ION-4 after 12 weeks of LDV/SOF Wk 0 Wk 12 Wk 24 Wk 36 LDV/SOF Failure N=9 LDV/SOF + RBV SVR12 GT NS5A RAVs Before Primary Study (%) NS5A RAVs at Virologic Rlapse After Primary Study (5) 1a None None Yes 1a None None Yes 1a L31M (>99), H58D (92) L31M (>99), H58D (92) Yes 1a Y93F (1), Y93N (10) Y93N (<99) Yes 1a L31M (>99), Y93N (<25) L31M (>99), Y93N (>99) Yes 1a* None Y93N (>99) Yes 1b Y93H (>99) L31I (11), Y93H (>99) Yes 1b None L31V (>99) Yes 1a None L31M (>99) No SRV12» SVR in 8/9» 1 relapse 4 weeks after EOT: GT1a, no cirrhosis Cooper C, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 573.

% Patients with SVR12 (95% CI) C-SWIFT: Retreatment for 12 Weeks with EBR/GZR + SOF + RBV in GT1-infected Patients Who Relapsed on Short-duration DAA Therapy PURPOSE: Evaluate 12 weeks of EBR/GZR +

33 % Patients with SVR12 (95% CI) C-SWIFT: Retreatment for 12 Weeks with EBR/GZR + SOF + RBV in GT1-infected Patients Who Relapsed on Short-duration DAA Therapy PURPOSE: Evaluate 12 weeks of EBR/GZR + SOF + RBV for HCV GT1-infected patients who failed prior treatment with EBR/GZR + SOF; shorter durations of 4, 6, or 8 weeks. RESULTS: SVR12 = 100% for retreatment of 12 weeks, regardless of cirrhosis, subgenotype, or baseline RAVs No discontinuations due to AEs or laboratory abnormalities The only AE occurring in > 10% of patients was fatigue (12%) SVR12: Overall and By Subgroup mfas / 23 Overall 18/ 18 No Cirrhosis 5/ 5 Yes Cirrhosis 15/ 15 4 weeks Prior treatment duration 6 or 8 weeks Prior treatment duration KEY MESSAGES: Addition of RBV, and lengthened treatment duration to 12 weeks improves SVR rates in patients who failed prior short-duration DAA therapy. If patients fail short-term treatment, other options are available. 8/ 8 5/ 5 No Baseline NS5A RAVs 18/ 18 Yes Baseline NS5A RAVs Excludes two patients lost to follow-up at Day 3 and treatment Week Lawitz E, et al. Presented at AASLD 2015; Poster #LB-12.

34 Debate: Do we need more HCV drugs?» More drugs, more competition and eventually lower prices. Price already down to 28$» Any special patient populations left? no» Need for shorter treatment durations? Already down to 8 weeks» Need for better tolerated drugs? DC in trials for adverse events < 1%» Need for drugs with less drug-drug interactions? All solvable with the help of a clinical pharmacologist» How about treatment of DAA failures? 3-drug combinations from 3 drug classes already available as salvage therapy Seite 34

Direct-acting Antiviral (DAA) Regimens in Late-stage Development: Which Patients Should Wait? Fred Poordad, MD

Direct-acting Antiviral (DAA) Regimens in Late-stage Development: Which Patients Should Wait? Fred Poordad, MD The HCV Lifecycle: Multiple Targets Polymerase Inhibitors Protease Inhibitors NS5A Inhibitors