THE ROLE OF SOFOSBUVIR/VELPATASVIR IN HCV CURE MARIA SCHINA INTERNIST-HEPATOLOGIST ATHENS EUROCLINIC

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1 THE ROLE OF SOFOSBUVIR/VELPATASVIR IN HCV CURE MARIA SCHINA INTERNIST-HEPATOLOGIST ATHENS EUROCLINIC ATHENS, MARCH 10 th 2017

2 DISCLOSURES Research grants from Roche, Bristol-Myers Squibb Lectures for Bristol-Myers Squibb Advisory board for Abbvie

3 Cure in chronic HCV HCV does not integrate into the host cell genome, and the life cycle is confined to the cytoplasm of hepatocytes 1 Patients infected with HCV 75 85% develop chronic HCV 2 Historically, 40 50% of GT1 patients and 70 90% of GT2/3 patients achieve SVR 3 Evidence suggests that sustained virologic response (SVR) at 24 weeks after treatment end is equivalent to cure in HCV 4 1. Schaefer EAK & Chung RT. Gastroenterology 2012;142: WHO. HCV factsheet. Available at: 3. Ilyas JA & Vierling JM. Clin Liver Dis 2011;15: Pearlman BL & Traub N. Clin Infect Dis 2011;52:

4 Cure in chronic HCV HCV Sustained virologic response 3 Is essentially HCV infection cure SVR 24 defined as the absence of detectable HCV RNA in the serum, six months after completion of therapy Very low incidence of late relapse (< 1%)

5 Cure in chronic HCV Van der Meer et al. JAMA 2012

6 SVR 24 (%) Cure success in HCV From IFN to direct-acting antiretrovirals (DAAs) %* 83 96%** % % 38 43% 45 47% 54 63% 20 6% 13 19% 0 IFN 24 wk (daily) IFN 48 wk 3 times/wk IFN/RBV 24 wk IFNα/RBV 48 wk IFNα/RBV 48 wk pifnα/rbv 48 wk pifnα/rbv + 1st gen DAA 24 wk DAAs ± RBV 12 wk STR ±RBV 12wk *In patients with HCV genotype 1; ** In treatment-naïve patients DAA, direct-acting antiviral; IFN, interferon; RBV, ribavirin, STR, single tablet regimen 1. Adapted from Manns MP, et al. Gut 2006;55: Tran TT. Am J Manag Care 2012;18(14 Suppl):S Kowdley KV et al. EASL 2013, oral 3. URL: 4. Feld JJ, et al. N Engl J Med DOI: /NEJMoa

Drug classes and targets in HCV Recognition and entry NS3 protease inhibitors NS3/4 protease

nuc inhibitors NS5B non-nuc inhibitors Cyclophilin A inhibitors Pan-genotypic IFNfree

Figure adapted from Manns MP, et al. Nat Rev Drug Discov 2007;6:991 1000 and Rice C.

7 Drug classes and targets in HCV Recognition and entry NS3 protease inhibitors NS3/4 protease inhibitors Endocytosis and uncoating Translation and proteolytic cleavage Replication NS5B nuc inhibitors NS5B non-nuc inhibitors Cyclophilin A inhibitors Pan-genotypic IFNfree regimens are the new goal for HCV 1 Assembly NS5A replication complex inhibitors Release Figure adapted from Manns MP, et al. Nat Rev Drug Discov 2007;6: and Rice C. Top Antivir Med 2011;19(3): Gonzalez-Moreno J, et al. Scientific World J 2013; Apr 9 [Epub ahead of print].

8 Different combination regimens Alfa NS5A RBV In different patient types Different genotypes Treatment-naive Treatment-experienced Intolerant to previous therapy PIs, NS5As failures Cirrhotics, DCC Alfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirin This slide represents just a small selection of studies and regimens in current clinical development other combinations are therefore possible

9 Sofosbuvir/Velpatasvir: A Single Tablet Regimen (STR) SOF Nucleotide NS5B polymerase inhibitor SOF VEL NS5A inhibitor VEL Sofosbuvir (SOF) 1,2 Potent antiviral activity against HCV GT 1 6 Once-daily, oral, 400-mg tablet Velpatasvir (VEL; GS-5816) 3-5 Picomolar EC 50 against GT nd -generation NS5A inhibitor with improved resistance profile Long half-life of ~13-23 h supports once-daily dosing No food effect Single Tablet Regimen (STR) Once daily, oral, STR (400/100 mg) U.S. PDUFA June 28, 2016; EU MAA July 2016 MAA, marketing authorization application 1. Jacobson IM, et al. N Engl J Med 2013;368: ; 2. Lawitz E, et al. N 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. AASLD 2013, poster

10 Greek recommendations Priority treatment groups for IFN-free treatments: a. At least moderate fibrosis or cirrhosis (Ishak: 2-6, METAVIR: F2-F4, Fibroscan >7.5 kpa or equivalent noninvasive method) b. Decompensated Cirrhosis Child B or C (treatment of Child C patients should continue to rely on liver transplantation. c. HCV recurrence post hepatic transplant d. HCV/HIV coinfection e. HCV/HBV coinfection f. Severe extrahepatic manifestation of HCV infection (Mixed Cryoglobulinemia type II and B-NHL) g. Chronic hemolytic syndromes (thalassemia major, sickle cell disease etc) with severe hepatic or extrahepatic complications due to chronic hemolysis h. Hemophilia and other disorders of hemostasis i. Chronic Renal Failure (with or without dialysis) j. Immunosuppression of any cause that accelerates disease progression k. Contraindication to ΙFN or RBV regardless of the severity of fibrosis Disease transmission: Priority for IFNα-free treatment, due to the ease of use and the high adherence rates, should be granted to HCV positive patients of high risk groups for disease transmission (eg. active PWIDs, prisoners, people with multiple sex partners), because cure of a significant percentage of these patients is the most effective way of limiting the spead of HCV infection CTP: Child-Turcotte-Pugh;GT: genotype; IFN: interferon; RBV: Ribavirin, PWID: people who inject drugs Treatment guidelines for patients with Chronic Hepatitis C (Jan2017) of the Hellenic Association for the Study of Liver & dr aft version of Greek Center of Diseases Control and Prevention (KEELPNO)

11 HCV Treatment recommendations depending on genotype Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotypes 5,6 SOF+RBV* NO 12 wk NO NO NO SOF+DCV SOF+DCV+RBV 12 wk 12 wk (TE/CC) 12 wk 12 wk 12-24wk (TE or CC) 12 wk 12 wk TE NO SOF/LDV SOF/LDV+RBV PRV/r/OBV+DSV* PRV/r/OBV+DSV+RBV* 12 wk (8 wk for TN/NC) 12 wk (TE/CC) 12 wk for 1b (8 wk for 1b TN/NC) 12 or 24 wk for 1a NO NO 12 wk 12 wk TE NO NO NO NO PRV/r/OBV+RBV NO NO NO 12 wk NO +RBV 12 wk 12 wk 12 wk 12 wk (TE or CC) 12 wk 12 wk GZR/EBR GZR/EBR+RBV 12 wk (1b or 1a with no negative factors ) 16 wk (1a with negative factors ) NO NO 12 wk 16 wk (VL> 800,000IU/mL) NO *Not in patients with BOC/TPV failure, # 24 wk for TE null responders, Negative factors: ΝS5A resistance associated strains (RASs) in amino acid positions 28, 30, 31, 93 and/or HCV RNA viral load >800,000 IU/mL. CC: compensated cirrhosis, DCV: daclatasvir; GZR/EBR: Grazoprevir/Elbasvir; LDV: ledipasvir; NC: Non-cirrhotics, OBV: ombitasvir; PRV: patitaprevir; RBV: ribavirin; r: ritonavir; SOF: sofosbuvir; TE: treatment-experienced; TN: treatment-naïve; wk: week; VEL: Velpatasvir; VL: Viral Load. Treatment guidelines for patients with Chronic Hepatitis C (Jan2017) of the Hellenic Association for the Study of Liver & draft version of Greek Center of Diseases Control and Prevention (KEELPNO)

12 EASL HCV Treatment recommendations depending on genotype EASL Recommendations on Treatment of Hepatitis C J Hepatol (2016), jhep

15 The ASTRAL Phase 3 Program (N=1408) ASTRAL-1 GT 1, 2, 4 6 TN, TE NC, CC ASTRAL-2 GT 2 TN, TE NC, CC ASTRAL-3 GT 3 TN, TE NC, CC ASTRAL-4 GT 1 6 TN, TE CTP-B Cirrhosis ASTRAL-5 GT 1 4 TN, TE NC, CC HIV/HCV Co-Infection Wk 0 Wk 12 Wk 0 Wk 12 Wk 0 Wk 12 Wk 24 Wk 0 Wk 12 Wk 24 Wk 0 Wk 12 n=624 n=134 n=277 n=90 n=106 n=116 Placebo n=132 SOF+RBV n=275 SOF + RBV n=87 + RBV Primary endpoints SVR12 Discontinuations due to AEs n=90 Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med. 2015; Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med ; Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med. 2015, Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med Wyles, EASL 2016, PS104

16 ASTRAL-1 STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients Week 0 Week 12 Week 24 n=624 SVR12 n=116 Placebo SVR12 Double-blind, placebo-controlled 5:1 randomisation :placebo Stratified by HCV genotype and cirrhosis (presence/absence) GT 5 patients not randomised GT 1, 2, and 4 6 US, Canada, UK, Germany, France, Italy, Belgium, Hong Kong VEL, velpatasvir. Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa

17 ASTRAL-1: STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients Demographics Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa n=624 Placebo n=116 Mean age, y (range) 54 (18 82) 53 (25 74) Male, n (%) 374 (60) 68 (59) White, n (%) 54 (18 82) 90 (78) Mean BMI, kg/m 2 (range) 54 (18 82) 27 (17 57) 26 (18 40) Cirrhosis, n (%) 121 (19) 21 (18) Treatment experienced, n (%) 201 (32) 33 (28) IL28B CC, n (%) 186 (30) 36 (31) Median HCV RNA, log 10 IU/mL (range) 6.4 ( ) 6.4 ( ) GT (53) 65 (56) 1a 210 (34) 46 (40) 1b 118 (19) 19 (16) GT (17) 21 (18) GT (19) 22 (19) GT 5 35 (5) 0 GT 6 41 (7) 8 (7)

18 SVR12 (%) ASTRAL-1: STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients SVR12 by Genotype /624 Total 206/ / / /116 34/35 41/41 1a 1b LTFU=lost to follow up; WC=withdrew consent Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa Genotype

19 SVR12 (%) ASTRAL-1: STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients SVR12 by Cirrhosis Status or Treatment History / / / /423 Total Non-Cirrhotic Cirrhotic Treatment- Naïve 200/201 Treatment- Experienced Error bars represent 95% confidence intervals. Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa

20 SVR12 (%) ASTRAL-1: STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients Resistance Analysis (1% cut-off) Total, n= % SVR12 99% SVR % No BL NS5A RAVs N=359 42% BL NS5A RAVs N= / /257 Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa

21 ASTRAL-1: STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients Common Adverse Events Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa n=624 Placebo n=116 Headache 182 (29) 33 (28) Fatigue 126 (20) 23 (20) Nasopharyngitis 79 (13) 12 (10) Nausea 75 (12) 13 (11) Insomnia 50 (8) 11 (9) Diarrhoea 48 (8) 8 (7) Asthenia 41 (7) 9 (8) Arthralgia 40 (6) 9 (8) Cough 39 (6) 4 (3) Back pain 29 (5) 11 (9) Myalgia 25 (4) 6 (5)

22 ASTRAL-1: STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients Safety Patients, n (%) n=624 Placebo n=116 AE 485 (78) 89 (77) Grade 3 4 AE 18 (3) 1 (<1) Adverse Events Laboratory Abnormalities Serious AE 15 (2) 0 D/C due to AE 1 (<1) 2 (2) Death 1* (<1) 0 Grade (7) 14 (12) Hb <10 g/dl 2 (<1) 0 Hb <8.5 g/dl 0 0 *55-year-old white male died in sleep 8 days after completing treatment; death assessed as unrelated to study drug by investigator Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa

23 ASTRAL-3 STR for 12 Weeks Compared to SOF+RBV for 24 Weeks in GT 3 HCV-Infected Patients Phase 3, open-label, randomised study of for 12 weeks in GT 3 Week n=277 SVR12 n=275 SOF + RBV SVR12 Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med DOI: /NEJMoa Weeks n=277 SOF + RBV 24 Weeks n=275 Mean age, y (range) 49 (21 76) 50 (19 74) Male, n (%) 170 (61) 174 (63) White, n (%) 250 (90) 239 (87) Mean BMI, kg/m 2 (range) 26.4 ( ) 26.6 ( ) Cirrhosis, n (%) 80 (29) 83 (30) Treatment experienced, n (%) 71 (26) 71 (26) IL28B CC, n (%) 105 (38) 111 (40) HCV RNA, log 10 IU/mL (SD) 6.2 (0.7) 6.3 (0.7)

24 SVR12 (%) ASTRAL-3: STR for 12 Weeks in GT 3 HCV-Infected Patients SVR12 P<0.001* *P-value for superiority of compared with SOF+RBV. Error bars represent 95% confidence intervals. Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med DOI: /NEJMoa / /275 SOF + RBV 12 Weeks 24 Weeks

25 SVR12 (%) ASTRAL-3: STR for 12 Weeks in GT 3 HCV-Infected Patients SVR12 by Cirrhosis Status and Treatment History SOF + RBV / /156 40/43 33/45 31/34 22/31 33/37 22/38 Non-Cirrhotic Cirrhotic Non-Cirrhotic Cirrhotic Treatment Naïve Treatment Experienced Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med DOI: /NEJMoa

26 SVR12 (%) ASTRAL-3: STR for 12 Weeks in GT 3 HCV-Infected Patients Resistance Analysis (1% cut-off) Total, n= % SVR12 84% No BL NS5A RAVs N=231 16% BL NS5A RAVs N=43 88% SVR /231 38/43 SVR12 was 84% (21/25) in patients with Y93H Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med DOI: /NEJMoa

27 ASTRAL-3: STR for 12 Weeks in GT 3 HCV-Infected Patients Safety Adverse Events Laboratory Abnormalities Patients, n (%) 12 Weeks n=277 SOF + RBV 24 Weeks n=275 AE 245 (88) 260 (95) Grade 3 4 AE 12 (4) 23 (8) Serious AE 6 (2) 15 (6) D/C due to AE 0 9 (3) Death 0 3 (1) Grade (7) 47 (17) Hb <10 g/dl 0 10 (4) Hb <8.5 g/dl 0 0 Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med DOI: /NEJMoa

28 SVR12 (%) Summary of Genotype 3 (TN, TE, NC, C) SVR Results from ASTRAL-3, VALENCE, ALLY-3 and ALLY-3+ Overall SVR of SOF-Based Regimens for HCV GT P<0.001* / / / 250 ASTRAL-3 ASTRAL-3 VALENCE ALLY-3 ALLY / / 39 21/ weeks SOF+RBV 24 weeks SOF+DCV 12 weeks SOF+DCV+RBV 12 weeks for 12 weeks yielded high SVR12 rates without the need for RBV in HCV GT 3 subjects DISCLAIMER: These graphics illustrate SVRs obtained between different regimens from different studies and therefore not directly comparable *P-value for superiority of compared with SOF+RBV. Foster GR, et al. N Engl J Med 2015;373(27): ; SOVALDI [PI]. Gilead Sciences, Inc. Foster City, CA August 2015; Daklinza US PI April 2016; Nelson, Hepatology 2015;61(4): ; Leroy V. et al. Hepatology 2016;63(5):

29 SVR12 (%) ASTRAL-3 ALLY-3 VALENCE ASTRAL-3 ASTRAL-3 VALENCE ASTRAL-3 ALLY-3 ASTRAL-3 ALLY-3 VALENCE ASTRAL-3 ASTRAL-3 ALLY-3+ ALLY-3 VALENCE ASTRAL Summary of SVR Results from ASTRAL-3, VALENCE, ALLY-3 and ALLY-3+ SVR of SOF-Based Regimens for HCV GT 3 by Prior Treatment Experience and Cirrhosis Status / weeks 73/ 75 SOF+DCV 12 weeks 86/ / 156 SOF+RBV 24 weeks Treatment-naïve Non-cirrhotic 40/ weeks for 12 weeks yielded high SVR12 rates without the need for RBV in HCV GT 3 subjects *SOF+DCV+RBV for 16 weeks resulted in SVR of 86% (12/14) in treatment-experienced, cirrhotic patients 12/ 13 33/ 45 SOF+RBV 24 weeks Treatment-naïve Cirrhotic 11/ 19 SOF+DCV 12 weeks Foster GR, et al. N Engl J Med 2015;373(27): ; SOVALDI SmPC Gilead Sciences, January 2016; Daklinza SmPC, Bristol-Myers Squibb, January 2016; Nelson, Hepatology 2015;61(4): ; Leroy V. et al. Hepatology 2016;63(5): / weeks 32/ 34 SOF+DCV 12 weeks 85/ / 31 SOF+RBV 24 weeks Treatment-experienced Non-cirrhotic 33/ weeks 14/ 16 SOF+DCV +RBV 12 weeks 9/ 13 SOF+DCV 12 weeks 27/ 45 Treatment-experienced Cirrhotic 22/ 38 SOF+RBV 24 weeks DISCLAIMER: These graphics serve to illustrate SVRs obtained between different regimens from different studies and therefore not directly comparable

30 ASTRAL-2 STR for 12 Weeks in GT 2 HCV-Infected Patients Phase 3, open-label, randomised study of for 12 weeks in GT 2 Week 0 Week 12 Week 24 n=134 n=132 SOF + RBV SVR12 SVR12 n=134 SOF + RBV n=132 Mean age, y (range) 57 (26 81) 57 (23 76) Male, n (%) 86 (64) 72 (55) White, n (%) 124 (93) 111 (84) Black, n (%) 6 (4) 12 (9) Mean BMI, kg/m 2 (range) 28 (17 45) 29 (19 61) Cirrhosis, n (%) 19 (14) 19 (14) Treatment experienced, n (%) 19 (14) 20 (15) IL28B CC, n (%) 55 (41) 46 (35) Mean HCV RNA, log 10 IU/mL (range) 6.5 ( ) 6.4 ( ) Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med DOI: /NEJMoa

31 SVR12 (%) ASTRAL-2: STR for 12 Weeks in GT 2 HCV-Infected Patients SVR12 P=0.018* / /132 SOF + RBV *P-value for superiority of compared with SOF+RBV. Error bars represent 95% confidence intervals. Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med DOI: /NEJMoa

32 SVR12 (%) ASTRAL-2: STR for 12 Weeks in GT 2 HCV-Infected Patients SVR12 by Cirrhosis Status and Treatment History SOF + RBV /100 92/96 15/15 14/15 15/15 13/16 4/4 4/4 Non-Cirrhotic Cirrhotic Non-Cirrhotic Cirrhotic Treatment Naïve Treatment Experienced Error bars represent 95% confidence intervals. Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med DOI: /NEJMoa

33 SVR12 (%) ASTRAL-2: STR for 12 Weeks in GT 2 HCV-Infected Patients Resistance Analysis (1% cut-off) Total, n= % SVR12 100% SVR % No BL NS5A RAVs N=53 60% BL NS5A RAVs N= /53 80/80 Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med DOI: /NEJMoa

34 ASTRAL-2: STR for 12 Weeks in GT 2 HCV-Infected Patients Safety Patients, n (%) n=134 SOF + RBV n=132 AE 92 (69) 101 (77) Grade 3 4 AE 3 (2) 3 (2) Adverse Events Serious AE 2 (1) 2 (2) D/C due to AE 1 (<1) 0 Death 2 (1) 0 Grade (9) 19 (14) Laboratory Abnormalities Hb <10 g/dl 0 6 (5) Deaths Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med DOI: /NEJMoa Hb <8.5 g/dl 0 0 Metastatic lung cancer, 58-year-old white male (112 days after completing treatment) Cardiac arrest, 56-year-old white female (131 days after completing treatment) Both assessed by investigator as unrelated to study drug

35 SVR12 (%) Summary of GT 2 SVR from ASTRAL-1, ASTRAL-2, VALENCE, FISSION, and FUSION Overall SVR of SOF-Based Regimens for HCV GT 2 P=0.018* / 104 ASTRAL-1 TN, TE 133/ 134 ASTRAL-2 TN, TE 124/ 132 ASTRAL-2 TN, TE 68/ 73 VALENCE TN, TE 69/ 73 FISSION TN 32/ 39 FUSION TE 12 weeks SOF+RBV 12 weeks for 12 weeks yielded high SVR12 rates without the need for RBV in HCV GT 2 subjects *P-value for superiority of compared with SOF+RBV. Feld JJ, et al. N Engl J Med DOI: /NEJMoa ; Foster GR, et al. N Engl J Med 2015;373(27): ; SOVALDI [PI]. Gilead Sciences, Inc. Foster City, CA August 2015

36 SVR12 (%) ASTRAL-1 ASTRAL-2 VALENCE ASTRAL-2 FISSION ASTRAL-1 ASTRAL-2 VALENCE ASTRAL-2 FISSION ASTRAL-1 ASTRAL-2 VALENCE FUSION ASTRAL-2 ASTRAL-1 ASTRAL-2 ASTRAL-2 VALENCE FUSION Summary of GT 2 SVR from ASTRAL-1, ASTRAL-2, VALENCE, FISSION, and FUSION SVR of SOF-Based Regimens for HCV GT 2 by Prior Treatment Experience and Cirrhosis Status / 72 99/ weeks 29/ 30 92/ 96 59/ 61 SOF+RBV 12 weeks Treatment-naïve Non-cirrhotic 12 weeks SOF+RBV 12 weeks 12 weeks SOF+RBV 12 weeks 12 weeks SOF+RBV 12 weeks for 12 weeks yielded high SVR12 rates without the need for RBV in HCV GT 2 subjects *1 treatment-naïve patient did not have fibrosis level confirmed 6/ 6 15/ 15 2/ 2 14/ 15 10/ 12 Treatment-naïve Cirrhotic Feld JJ, et al. N Engl J Med DOI: /NEJMoa ; Foster GR, et al. N Engl J Med 2015;373(27): ; SOVALDI [PI]. Gilead Sciences, Inc. Foster City, CA August 2015; Sulkowski, M et al. AASLD 2015, 205; Data on File, Gilead Sciences. 21/ 21 15/ 15 30/ 33 26/ 29 13/ 16 Treatment-experienced Non-cirrhotic 4/ 4 4/ 4 4/ 4 7/ 8 6/ 10 Treatment-experienced Cirrhotic

37 ASTRAL-4 ± RBV in HCV Patients with Decompensated Liver Disease Phase 3, open-label, randomised study of ±RBV for 12 or 24 weeks in patients with HCV GT 1, 2, 3, 4, 6 and decompensated liver disease Week n=90 n=87 n=90 + RBV RBV was weight-based (1000 or 1200 mg daily) Patients 12 weeks n=90 +RBV 12 weeks n=87 24 weeks n=90 Median MELD (range) 10 (6 24) 10 (6 18) 11 (6 19) MELD < 15, n (%) 86 (96) 83 (95) 85 (84) CTP B, n (%) 86 (96) 77 (89) 77 (86) Ascites, n (%) 74 (82) 65 (75) 75 (83) Encephalopathy, n (%) 52 (58) 54 (62) 59 (66) Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med DOI: /NEJMoa

38 ASTRAL-4: ± RBV in HCV Patients with Decompensated Liver Disease Baseline Host and Viral Characteristics Patients 12 weeks n=90 +RBV 12 weeks n=87 24 weeks n=90 Mean age, years (range) 58 (42-73) 58 (40-71) 58 (46-72) Male, n (%) 57 (63) 66 (76) 63 (70) White, n (%) 79 (88) 79 (91) 81 (90) Prior HCV treatment, n (%) 58 (64) 47 (54) 42 (47) IL28B non-cc, n (%) 70 (78) 65 (75) 68 (76) HCV RNA, log 10 IU/mL (SD) 6.0 (0.5) 5.9 (0.6) 5.9 (0.6) HCT GT 1, n (%) 68 (76) 68 (78) 71 (79) HCV GT 3, n (%) 14 (16) 13 (15) 12 (13) HCV GT 2/4/6, n (%) 8 (9) 6 (7) 7 (8) Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med DOI: /NEJMoa

39 SVR12 (%) ASTRAL-4: ± RBV in HCV Patients with Decompensated Liver Disease SVR12 12 wk +RBV 12 wk 24 wk /90 82/87 77/90 60/68 65/68 65/71 7/14 11/13 6/12 GT2 4/4 GT4 4/4 GT2 4/4 GT4 2/2 Overall GT 1 GT 3 GT 2, 4, and 6 GT2 3/4 GT4 2/2 GT6 1/1 + RBV resulted in highest SVR12 in patients with decompensated liver disease *Patient with nondetectable drug levels at time of virologic failure. Charlton M, et al., AASLD, 2015, #LB-13

40 ASTRAL-4: ± RBV in HCV Patients with Decompensated Liver Disease Change in CTP Class: Patients with SVR12* Baseline CTP A CTP B CTP C CTP A 71 (10/14) 17 (34/205) 10 (1/10) Follow-Up Week 12, % (n/n) CTP B 29 (4/14) 81 (167/205) 50 (5/10) CTP C 0 (0/14) 2 (4/205) 40 (4/10) *n=234; 5 patients had no follow-up Week 12 assessment. Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med DOI: /NEJMoa

41 Patients (%) Patients (%) ASTRAL-4: ± RBV in HCV Patients with Decompensated Liver Disease MELD Change from Baseline to Follow Up Week % Improved 27% Worsened Baseline MELD <15 n=208 Change in MELD n= <1 < % Improved 8% Worsened 27 Baseline MELD >15 n= n= Change in MELD Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med DOI: /NEJMoa

42 ASTRAL-4: ± RBV in HCV Patients with Decompensated Liver Disease Safety Results Overall Safety Summary Patients, n (%) 12 weeks n=90 +RBV 12 weeks n=87 24 weeks n=90 Any AE 73 (81) 79 (91) 73 (81) Grade 3 or 4 AE 16 (18) 11 (13) 17 (19) Serious AE 17 (19) 14 (16) 16 (18) Treatment related 0 1 (1) 1 (1) AE leading to D/C 1 (1) 4 (5) 4 (4) Transplant (1) Death 3 (3) 3 (3) 3 (3) Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med DOI: /NEJMoa

43 ASTRAL-5 for 12 Weeks in HCV/HIV Co-Infected Patients with HCV GT 1-6 Week 0 Week 12 Week 24 N=106 Mean age, y (range) 54 (25 72) Male, n (%) 91 (86) Black, n (%) 48 (45) Mean BMI, kg/m 2 (range) 27 (19 43) Cirrhosis, n (%) 19 (18) Treatment experienced,* n (%) 31 (29) IL28B CC, n (%) 24 (23) Mean HCV RNA, log 10 IU/mL (range) HCV genotype TN and TE n= ( ) 1a / 1b 66 (62) / 12 (11) 2 11 (10) 3 12 (11) 4 5 (5) N=106 Mean CD4 count, cells/µl (range) 598 ( ) NRTI backbone TDF-based with boosted agent (RTV or COBI) 56 (53) TDF-based without boosted agent 35 (33) ABC/3TC-base 15 (14) ART use at baseline SVR12 PI (DRV, LPV or ATV) 50 (47) NNRTI (RPV) 13 (12) Integrase inhibitor (RAL or EVG) 36 (34) Other (>1 of the above classes) 7 (7) *Includes PegIFN+RBV failures and PI + PegIFN+RBV failures. Wyles, EASL 2016, PS104

44 SVR12 (%) ASTRAL-5 Results: SVR12 by Genotype * Total GT 1a GT 1b GT 2 GT 3 GT 4 High SVR12 achieved in HIV-coinfected patients regardless of genotype *Two patients pending results Patients LTFU were incarcerated, one patient on Day 1 and one patient on Week 4 Error bars represent 95% confidence intervals. Wyles, EASL 2016, PS104

45 SVR12 (%) ASTRAL-5 Results: SVR12 by Cirrhosis or Prior Treatment * Total Noncirrhotics *Two patients pending results Patients LTFU were incarcerated, one patient on Day 1 and one patient on Week 4 Error bars represent 95% confidence intervals. Wyles, EASL 2016, PS104; Data on File, Gilead Sciences Cirrhotics Treatment Naïve Treatment Experienced High SVR12 achieved in HIV-coinfected patients regardless of cirrhosis status and treatment experience Black Non-black

46 Median Creatinine Clearance (ml/min) ASTRAL-5 Results: Renal Function 140 Non-boosted TDF Boosted TDF Non-TDF containing regimen Weeks Median CL cr, ml/min BL FU-4 FU FU-4/12, follow-up Week 4/12; Creatinine Clearance calculated using the Cockroft-Gault method; errors bars represent Q1, Q3. Wyles, EASL 2016, PS104

47 ASTRAL-5 Overall Safety Patients, n (%) Total N=106 AE 75 (71) Grade 3 4 AE 9 (8) Serious AE 2 (2) D/C due to AE 2 (2) Death 0 Grade 3 or 4 laboratory abnormality 19 (18) No patient with confirmed on-treatment HIV virologic rebound The most common laboratory abnormality was elevated bilirubin in patients receiving ATV/r treatment for 12 weeks resulted in 95% SVR12 rate in patients coinfected with HIV and HCV GT 1, 2, 3, and 4 Wyles, EASL 2016, PS104

48 NNRTIs NRTIs Drug-Drug interactions: HIV ARVs SOF * LDV/ SOF SOF/ VEL OBV/PT V/RTV+ DSV GZR/ EBR Abacavir DCV SMV Emtricitabine Lamivudine Tenofovir Efavirenz Etravirine Nevirapine Rilpivirine SOF: sofosbuvir; LDV: ledipasvir; VEL: velpatasvirl OBV: ombitasvir; PTV: paritepravir; DSV: dasabuvir; GZR: grazoprevir; EBR: elbasvirl DCV: daclatasvir; SMV: simeprevir No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring These drugs should not be co-administered. EASL Recommendations on Treatment of Hepatitis C 2016; Journal of Hepatology (Accessed September 2016)

49 Entry/Integrase inhibitors Protease inhibitors Drug-Drug interactions: HIV ARVs * SOF LDV/ SOF SOF/ VEL OBV/PT V/RTV+ DSV Atazanavir; atazanavir/r; atazanavir/cobicistat GZR/ EBR DCV SMV Darunavir/rl darunavir/cobicistat Lopinavir/r Dolutegravir Elvitegravir/cobi/emtricitabine/TDF Elvitegravir/cobi/emtricitabine/TAF Maraviroc Reltegravir SOF: sofosbuvir; LDV: ledipasvir; VEL: velpatasvirl OBV: ombitasvir; PTV: paritepravir; DSV: dasabuvir; GZR: grazoprevir; EBR: elbasvirl DCV: daclatasvir; SMV: simeprevir: TDF: tenofovir disoproxil fumarate: TAF: tenofovir alafenamide No clinically significant interaction expected Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring These drugs should not be co-administered. EASL Recommendations on Treatment of Hepatitis C 2016; Journal of Hepatology (Accessed September 2016)

50 Conclusions ASTRAL-1 Treatment with for 12 weeks resulted in a 99% SVR12 rate in patients with HCV GT 1, 2, 4, 5, or 6 infection 99% SVR12 rate in patients with cirrhosis 99% SVR12 rate in patients with prior treatment failure Presence of baseline NS5A RAVs did not impact SVR12 ASTRAL-2 Treatment with for 12 weeks resulted in a 99% SVR12 rate in patients with HCV GT 2 infection Statistically superior to SOF + RBV for 12 weeks (p=0.018)

51 Conclusions ASTRAL-3 for 12 weeks resulted in a 95% SVR12 rate in patients with HCV GT 3 infection Statistically superior to SOF + RBV for 24 weeks (p <0.001) 91% SVR12 rate in patients with cirrhosis ASTRAL-5 treatment for 12 weeks resulted in 95% SVR12 rate in patients coinfected with HIV and HCV GT 1, 2, 3, and 4 100% SVR12 in patients with cirrhosis 97% SVR12 in patients who failed prior HCV therapy Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med DOI: /NEJMoa

52 Conclusions ASTRAL-4 for 12 or 24 weeks or + RBV for 12 weeks resulted in high SVR12 rates in HCV patients with decompensated liver disease Among patients who achieved SVR12, virologic response was associated with improved MELD and CTP scores for 12 or 24 weeks or + RBV for 12 weeks well tolerated, with AEs consistent with clinical sequelae of advanced liver disease and RBV toxicity Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med DOI: /NEJMoa

53 Conclusions In general Treatment with was well tolerated, with a very good safety profile Treatment with provides a simple, and highly effective treatment for patients with HCV GT 1-6 HCV/HIV coinfection as well as HCV patients with decompensated cirrhosis

Hepatitis C in Special Populations

Hepatitis C in Special Populations David E. Bernstein, MD, FACG Vice Chairman of Medicine for Clinical Trials Chief, Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases Northwell Health