EASL 2014 CARE Liver Disease Faculty. LBA O165. COSMOS STUDY

EASL 2014 Abstract. LBA O165. SIMEPREVIR PLUS SOFOSBUVIR WITH/WITHOUT RIBAVIRIN IN HCV GENOTYPE 1 PRIOR NULL-RESPONDER/TREATMENT-NAÏVE PATIENTS (COSMOS STUDY): PRIMARY ENDPOINT (SVR12) RESULTS IN PATIENTS WITH METAVIR F3-4 (COHORT 2)

E. Lawitz1, R. Ghalib2, M. Rodriguez-Torres3, Z.M. Younossi4, A. Corregidor5, M.S. Sulkowski6, E. DeJesus7, B. Pearlman8, M. Rabinovitz9, N. Gitlin10, J.K. Lim11, P.J. Pockros12, B. Fevery13, T. Lambrecht14, S. Ouwerkerk-Mahadevan13, K. Callewaert13, W.T. Symonds15, G. Picchio16, K. Lindsay16, M. Beumont-Mauviel13, I.M. Jacobson17

1Texas Liver Institute, San Antonio, 2Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, 3Fundación de Investigación, San Juan, PR, 4Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, 5Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, 6Johns Hopkins University School of Medicine, Baltimore, MD, 7Orlando Immunology Center, Orlando, FL, 8Atlanta Medical Center, Atlanta, GA, 9University of Pittsburgh Medical Center, Pittsburgh, PA, 10Atlanta Gastroenterology Association, Atlanta, GA, 11Yale School of Medicine, New Haven, CT, 12Scripps Clinic, La Jolla, CA, United States, 13Janssen Research & Development, Beerse, 14Novellas Healthcare, Zellik, Belgium, 15Gilead Sciences Inc, Foster City, CA, 16Janssen Research & Development LLC, Titusville, NJ, 17Weill Cornell Medical College, New York, NY, United States

Background and aims: Simeprevir (protease inhibitor;SMV) + pegylated interferon/ribavirin (PR) and sofosbuvir (polymerase inhibitor;SOF)+ PR or ribavirin (R) have recently been approved for treating hepatitis C infection. The Phase 2 COSMOS trial evaluates their use in combination +/- R. We present the primary analysis of SVR12 results in genotype (GT) 1-infected, treatment-naïve and null responders to PR with advanced fibrosis (METAVIR F3-4).

Results: 87 patients were randomized and treated: 54% null responders;47% METAVIR F4;79% IL28B genotype non-CC;78% GT1a(40% with Q80K);9.2% Black/African-American. Table: 3 patients discontinued treatment for non-virologic failure; in ITT and modified ITT analyses, overall SVR12 were 94.3% (82/87) and 96.4% (81/84), respectively; SVR12 rates were high in both patients with advanced fibrosis/cirrhosis (92.7%) and in GT1a Q80K-positive patients (96.3%). No viral breakthroughs occurred. Relapse occurred in 3 GT1a-infected patients (one with Q80K) within 8 weeks after EOT. Adverse events (AEs; 87.4%) were mostly Grade 1/2 (77.0%, most commonly: fatigue 37.9%, headache 19.5%). Four serious AEs were reported. Two patients (2/87, 2.3%) discontinued treatment due to AEs.

Conclusions: SMV+SOF±RBV for 12/24wks led to overall SVR rates >96% in a modified ITT analysis, and >90% in subgroups of HCV GT1 patients with advanced fibrosis/cirrhosis including prior null responders, and in GT1a patients with baseline Q80K polymorphism. RBV did not improve SVR in any subgroup. The SMV+SOF combination was safe and well tolerated.

The recently approved Simeprevir (PI) and Sofosbuvir nucleotide NS5B inhibitor) represent major improvements in the treatment cure rates of HCV infection when combined with Peg-Interferon and RBV in G1 infected patients.

COSMOS is a Phase-IIa, randomized, open-label trial to evaluate the SVR12 efficacy of these two DAAs in combination across two cohorts: 1) prior Null Responders with METAVIR F0-2 and 2) Treatment Naïve/Null-Responders with more advanced F3-4 fibrosis. Cohort-2 contained 87 patients randomized to both DAAs +/- RBV for 12 or 24 weeks.

Overall SVR12 was 94% (3 patients relapsed in the 12 week arms, 1 with the Q80K mutation and 2 patients experienced non-virological failure) with SVR12 ranging from 93-100% in ITT analysis across all groups. No differences were observed in either the RBV containing arms or 12 versus 24 weeks of treatment. SVR12 rates were high, regardless of baseline characteristics that included HCV GT1a, Q80K polymorphism, biopsy proven cirrhosis (50% of patients), and prior NR (54% of patients). No factors including early viral kinetics were predictive for treatment failures.

These data demonstrate that the combination of SMV+SOF can achieve very high cure rates in traditionally difficult to treat patients such that the IDSA-AASLD HCV guidelines recommend SMV-SOF for the treatment of G1 interferon ineligible patients and for previous treatment failures. In Canada, access to this combination is and will probably remain very challenging. However, if these two drugs were vastly more affordable and could be co-formulated one wonders why any further Genotype 1 trials in these patient populations need be conducted at all. The planned Phase 3 OPTIMIST trials will try to prove this hypothesis correct.
— CARE Liver Disease Faculty Commentary