Treatment of Hepatitis C GT 3

Transcription

1 Frontier AIDS Education and Training Center Treatment of Hepatitis C GT 3 John Scott, MD, MSc Associate Professor, Medicine University of Washington Dec 3, 2015 This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice related to any specific patient.

2 Disclosures I have served on the DSMB for Tacere Therapeutics, Advisory Board for Gilead Sciences, and my institution has received research funding from Merck.

3 BACKGROUND Genotype 3

4 Background 10% of all US cases Faster rates of fibrosis progression More steatosis Higher incidence of hepatocellular carcinoma SOF/RBV x 24 wks is expensive and not much better cure rate c/w IFN/RBV (~70%) Least activity of SOF Current AASLD/IDSA recs: - 1) PegIFN/RBV/SOF x 12 wks - 2) SOF/DCV x wks Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370:

5 All-Oral Treatment With Daclatasvir Plus Sofosbuvir Plus Ribavirin for 12 or 16 Weeks in HCV Genotype 3-Infected Patients With Advanced Fibrosis or Cirrhosis: The ALLY-3+ Phase 3 Study Leroy V, Angus P, 2 Bronowicki JP, 3 Dore G, 4 Hézode C, 5 Pianko S, 6 Pol S, 7 Stuart K, 8 Tse E, 9 McPhee F, 10 Bhore R, 11 1 Jimenez-Exposito MJ, 11 Thompson A 4 1CHU de Grenoble, La Tronche, France; 2 Austin Hospital, Heidelberg, Australia; 3 CHU Nancy & Lorraine University, Nancy, France; 4 St. Vincent s Hospital and Kirby Institute, Sydney, Australia; 5 CHU Henri Mondor, Créteil, France; 6 Monash Medical Centre, Clayton, Australia; 7 Hôpital Cochin, Paris, France; 8 Gallipoli Medical Research Foundation, Greenslopes, Australia; 9 Royal Adelaide Hospital, Adelaide, Australia; 10 Bristol-Myers Squibb Research & Development, Wallingford, CT; 11 Bristol-Myers Squibb Research & Development, Princeton, NJ. The Liver Meeting 2015 San Francisco, CA, November 2015 Oral LB-3

6 ALLY-3+ Study Design

7 Baseline Demographics and Disease Characteristics

8 SVR12: All Treated Patients

9 SVR12: Patients with Cirrhosis

10 Resistance-associated Variants (RAVs) at Baseline and Failure

11 Sofosbuvir/Velpatasvir Fixed-Dose Combination for 12 Weeks Compared to Sofosbuvir with Ribavirin for 24 Weeks in Genotype 3 HCV-Infected Patients: The Randomized Controlled Phase 3 ASTRAL-3 Study Alessandra Mangia 1, Stuart K. Roberts 2, Stephen Pianko 3, Alex Thompson 4, Curtis Cooper 5, Brian Conway 6, Marc Bourliere 7, Tarik Asselah 8, Thomas Berg 9, Stefan Zeuzem 10, William Rosenberg 11, Kosh Agarwal 12, Edward J. Gane 13, Catherine Stedman 14, Francesco Mazzotta 15, Tram T. Tran 16, Stuart Gordon 17, Evguenia Svarovskaia 18, Lingling Han 18, John McNally 18, Anu Osinusi 18, Diana M. Brainard 18, John G. McHutchison 18, Nezam Afdhal 19, Graham R. Foster 20 1 Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy; 2 Alfred Health and Monash University, Prahran, Victoria, Australia; 3 Monash Health and Monash University, Clayton, Victoria, Australia; 4 St Vincent s Hospital, Melbourne, Victoria, Australia; 5 Ottawa General Hospital, Ottawa, Ontario, Canada; 6 Vancouver Infectious Diseases Centre, Vancouver, British Columbia, Canada; 7 Hôpital Saint Joseph, Marseille, France; 8 University Paris Diderot, INSERM U773, Paris, France; 9 Leipzig University Hospital, Germany; 10 Johann Wolfgang Goethe University, Frankfurt, Germany; 11 University College London, UK; 12 Kings College Hospital, London, UK; 13 Auckland Clinical Studies, New Zealand; 14 Christchurch Clinical Studies Trust and University of Otago, Christchurch, New Zealand; 15 Santa Maria Annunziata Hospital, Florence, Italy; 16 Cedars-Sinai Medical Center, Los Angeles, CA; 17 Henry Ford Health System, Detroit, MI; 18 Gilead Sciences, Inc., Foster City, CA; 19 Beth Israel Deaconess Medical Center, Boston, MA; 20 Queen Mary University of London, UK AASLD 2015, San Francisco

12 Study Design ASTRAL-3 Week n=250 SOF/VEL SVR12 n=250 SOF + RBV SVR12 Open-label, active-comparator trial Broad inclusion criteria 1:1 randomization to SOF/VEL or SOF + RBV - Stratified by prior treatment (TN/TE) and cirrhosis (presence/absence) Conducted at 76 sites in US, Canada, UK, Germany, France, Italy, Australia, and New Zealand

13 Results: Demographics ASTRAL-3 SOF/VEL 12 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 (17 48) 27 (17 56) 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 (range) 6.2 ( ) 6.3 ( )

14 Results: Disposition ASTRAL-3 Patients, n (%) SOF/VEL 12 Weeks n=277 SOF + RBV 24 Weeks n=275 Completed drug 275 (99) 254 (92) Discontinued 2 (<1) 21 (8) AE 0 9 (3) Lost to follow-up 0 4 (1) Noncompliance 1 (<1) 2 (<1) Withdrew consent 0 3 (1) Death 0 2 (<1) Lack of efficacy 1 (<1) 1 (<1)

15 SVR12 (%) Results: SVR12 ASTRAL-3 p <0.001* / /275 SOF/VEL 12 Weeks SOF + RBV 24 Weeks *p-value for superiority of SOF/VEL compared with SOF+ RBV. Error bars represent 95% confidence intervals.

16 SVR12 (%) Results: SVR12 by Cirrhosis or Treatment History ASTRAL-3 SOF/VEL SOF + RBV No Yes Naïve Experienced Cirrhosis Status Treatment History Error bars represent 95% confidence intervals.

17 SVR12 (%) Results: SVR12 by Cirrhosis or Treatment History ASTRAL-3 SOF/VEL SOF + RBV relapses 2 other relapses 8 other relapses 22 relapses 6 other relapses 2 other relapses 13 other relapses 1 non-response 23 relapses 2 other No Yes Naïve Experienced Cirrhosis Status Treatment History Error bars represent 95% confidence intervals.

18 Results: Resistance Analysis ASTRAL-3: SOF/VEL Group Total, n=274 97% SVR12 84% No BL NS5A RAVs n=231 16% BL NS5A RAVs n=43 88% SVR12 225/231 38/43 SVR12 was 84% (21/25) in patients with Y93H

19 Summary Treatment options for GT 3: Regimen SVR Cost Comments PegIFN/RBV/SO F x 12 wks SOF/DCV x wks 88-95% $ ,000 Highest SE profile 83-92% $ ,000 Add RBV if cirrhotic or treat for 24 wks SOF/VEL 90-97%???, similar to Harvoni? Expected in May 2016, pan-genotypic

20 Questions?