Date: 2013-11-04
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C. during the late-breaking oral session on Monday, November 4.
Company: Medivir (Sweden) Janssen Pharmaceutical (J&J - USA)
Product: simeprevir (TMC435) and sofosbuvir (GS7977)
Action
mechanism: Simeprevir is a NS3/4A protease inhibitor.
direct-acting antiviral agent/nucleotide analog. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. This direct-acting agent interferes directly with the HCV life cycle by suppressing viral replication.
Disease: hepatitis C
Therapeutic area: Infectious diseases
Country:
Trial
details: Simeprevir is being studied with sofosbuvir in the COSMOS phase IIa, randomized, open-label study to investigate the efficacy and safety of 12 or 24 weeks of simeprevir (150 mg QD) and sofosbuvir (400 mg QD) with or without ribavirin (RBV) in HCV genotype 1 (GT1) patients.
Cohort 1 included a total of 80 HCV GT1 prior null responders to PegIFN/RBV therapy with METAVIR score F0-F2, who were stratified by IL28B status and genotype 1 subtype, into one of four arms including once-daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 24 weeks with or without ribavirin, or once-daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks with or without ribavirin.
Cohort 2 of the study will investigate similar treatment regimens and durations in genotype 1 prior null-responder and treatment-naïve patients with METAVIR scores of F3-F4. The Metavir score is used to quantify the degree of inflammation and fibrosis of the liver. Liver fibrosis is scored on a four-point scale.
Latest
news: * On November 4, 2013, Medivir has announced data from the interferon-free COSMOS study demonstrating safety and efficacy of simeprevir (TMC435) in combination with sofosbuvir (GS-7977), with and without ribavirin, in genotype 1 chronic hepatitis C adult patients with compensated liver disease was presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C. during the late-breaking oral session on Monday, November 4. Final sustained virologic response 12 weeks after the end of treatment (SVR12) data from cohort 1 in previous null responder patients with METAVIR scores F0-F2 were presented, along with sustained virologic response 4 weeks after the end of treatment (SVR4) data from the 12 week arms of cohort 2 in treatment-naïve and previous null-responder patients with METAVIR scores F3-F4. The METAVIR score is used to quantify the degree of inflammation and fibrosis of the liver. Liver fibrosis is scored on a four-point scale. COSMOS – Efficacy Summary: In cohort 1, the SVR12 rate was 93 percent in genotype 1 null-responder patients with METAVIR scores of F0-F2 treated with simeprevir and sofosbuvir for either 12 or 24 weeks. Efficacy results with 150 mg simeprevir (SMV) and 400 mg sofosbuvir (SOF) once daily with or without ribavirin (RBV). Intent-to-treat (ITT) population. Cohort 1: % (n) SMV / SOF + RBV 24-week SMV / SOF SMV / SOF + RBV 12-week SMV / SOF SVR12 79* (19/24) 93 (14/15) 96 (26/27) 93 (13/14) *17% (4/24) non-virologic failure Cohort 2**: % (n) SMV / SOF+ RBV Naive SMV / SOF SMV / SOF + RBV SMV / SOF SVR4 100 (12/12) 100 (7/7) 93 (14/15) 100 (7/7) **SVR4 data was only available for 12-week arms at time of interim analysis cut-off * On August 28, 2013, Medivir has announced interim results from the second cohort in the ongoing COSMOS study evaluating a once daily combination of simeprevir and sofosbuvir in hard to cure hepatitis C patients. SVR4 results from the 12 week arms of Cohort 2, including treatment naïve or previous null responder HCV patients all with METAVIR score F3-F4 were reported. Treatment for 12 weeks with simeprevir and sofosbuvir, with or without ribavirin, led to SVR4 rates of 96% and 100%, respectively. Interim results from Cohort 1 of the COSMOS study, which include only prior null responder HCV patients (METAVIR F0-F2) have been reported earlier and demonstrated SVR8 rates of 96% and 93% after 12 weeks treatment simeprevir and sofosbuvir with and without ribavirin, respectively (see below). * Data reported at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) in March 2013 in Atlanta, USA. SVR: Sustained Virologic Response 4 or 8 weeks (SVR4 or SVR8) after end of treatment. Summary of data available at the time of the interim analysis: Efficacy results with 150 mg Patients n/N (%) SMV + SOF +RBV SMV + SOF SMV + SOF +RBV SMV + SOF 24 weeks 24 weeks 12 weeks 12 weeks RVR (week 4) 18/22 (81.8) 10/15 (66.7) 23/27 (85.2) 8/14 (57.1) EoT* 10/12 (83.3) 8/9 (88.9) 27/27 (100) 14/14 (100) Relapse, n 0 0 1 1 SVR4 4/6 (66.7) 5/5 (100) 26/27 (96.3) 13/14 (92.9) SVR8 4/6 (66.7) 5/5 (100) 26/27 (96.3) 13/14 (92.9) q.d.: once daily; RVR: Rapid Viral Response; EoT: End of Treatment; SVR4 and SVR8: patients with undetectable HCV RNA (* = Undetectable at EoT
In cohort 1, 77 percent of the patients had genotype 1a (GT1a) subtype with 50 percent of those having baseline Q80K polymorphism. Seventy percent had IL28B CT genotype, 24 percent hadIL28B TT genotype and 59 percent had METAVIR score F2.
In cohort 2, 78 percent of patients had GT1a subtype with 40 percent of those having baseline Q80K polymorphism. Fifty-six percent had IL28B CT genotype, 23 percent had IL28B TT genotype, 47 percent had METAVIR score F4 (cirrhosis) and 54 percent were prior null responders.
In an interim analysis of cohort 2, the SVR4 rate was 100 percent in both genotype 1 treatment-naive patients and prior null-responder patients with METAVIR scores of F3-F4 treated with simeprevir and sofosbuvir for 12 weeks.
In a pooled analysis of the 12-week treatment arms in cohorts 1 and 2, SVR4 was achieved among patients treated with simeprevir and sofosbuvir with or without ribavirin, in 96 percent of patients with IL28B non-CC genotype, 91 and 100 percent of patients with a METAVIR score of F4, respectively, and 95 percent of prior null responders.
All patients who completed treatment were HCV RNA undetectable at end of treatment and there were no viral breakthroughs in either cohort 1 or 2. The COSMOS study interim results show no benefit from adding ribavirin to simeprevir and sofosbuvir in this difficult to treat groups of hepatitis C patients and that 12 week treatment may confer similar clinical benefit to 24 week treatment.
Prior null-responder HCV patients with METAVIR scores F0-F2
24-week
12-week
Prior null-responder and
treatment-naïve HCV patients with METAVIR scores F3-F4
12-week
Naive
12-week
Null response 12-week
Null response 12-week
At the time of the interim analysis, SVR4 results were available for all patients (n=41) in the 12 week arms of Cohort 2. In this Cohort, 78.2% of patients had GT1a subtype with 40% of those having a Q80K baseline polymorphism, 79.3% had IL28B CT or TT genotype, 47.1% had Metavir score F4 (cirrhosis) and 54.0% were prior null responders.
In the previously reported Cohort 1, 77.5% of the patients had GT1a subtype with 50% of those having a Q80K baseline polymorphism, 93.7%, had IL28B CT or TT genotype and 58.8% had METAVIR score F2.
COSMOS - Summary Interim Results: Efficacy
Efficacy results with 150 mg simeprevir (SMV) and 400 mg sofosbuvir (SOF) once daily for 12 weeks with or without ribavirin (RBV). Intent-to-treat (ITT) population.
Cohort 1*
Prior null responder HCV
patients (METAVIR score F0-F2)Cohort 2
Prior null responder and treatment naïve
HCV patients (METAVIR scores F3 or F4)
SMV / SOF+ RBV (n=27)
SMV / SOF (n=14)
SMV / SOF + RBV (n=27)
SMV / SOF(n=14)
SVR4
26/27(96%)
13/14(93%)
26/27(96%)
14/14(100%)
SVR8
26/27(96%)
13/14(93%)
-
-
There were no viral breakthroughs in either Cohort. At the time of respective cut-off there was 1 relapse in Cohort 2, which was detected 4 weeks after end of treatment. As previously reported there were 2 relapses detected in Cohort 1 both at the 4 week time point after end of treatment.
COSMOS - Summary Interim Results: Safety
Once-daily simeprevir and sofosbuvir with or without ribavirin for 12 weeks was generally considered safe and well tolerated. Among events defined in the protocol as being of special interest, increased bilirubin was observed in 9.3% of the patients in the ribavirin containing arms, compared with 0%, for the non-ribavirin containing arms. Anemia was observed in 13.0% of the patients in the ribavirin containing arms, compared with 0% for the non-ribavirin containing arms.
* On March 6, 2013, Medivir has announced the presentation of first interim results from the cohort 1 of a Phase IIa study of simeprevir (TMC435) administered once daily with sofosbuvir (GS-7977) with and without ribavirin for 12 and 24 weeks in genotype 1 prior null-responder hepatitis C patients with mild to moderate fibrosis (METAVIR F0-2). These date have been presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, Georgia, USA.
At the time of the interim analysis, 26 out of 27 patients (96.3%) in the 12-week arm with RBV achieved SVR4 and 13 out of 14 patients (92.9%) in the 12-week arm without RBV achieved SVR4. A subsequent analysis confirmed that all patients with SVR4 have also achieved SVR8. In the 24-week arms, SVR4 rates with RBV were 66.7% (one patient discontinued due to an AE and one withdrew consent in this arm) and without RBV 100 percent. The number of patients reaching this time point was limited, however.
The COSMOS regimen of once-daily simeprevir and sofosbuvir with or without ribavirin was generally well tolerated and no serious adverse events occurred during the treatment period.
simeprevir (SMV) and 400 mg sofosbuvir (SOF) q.d. +/- ribavirin (RBV);
(n=24)
(n=15)
(n=27)
(n=14)
The COSMOS (Combination Of SiMeprevir and sOfosbuvir in HCV genotype 1 infected patientS) study will also include a second cohort that will investigate similar treatment regimens and durations in HCV genotype 1 prior null-responder and treatment-naïve patients with METAVIR scores of F3-F4.
Janssen Pharmaceutical recently announced that it has entered into a non-exclusive collaboration with Vertex Pharmaceuticals to evaluate in a phase II study the safety and efficacy of an all-oral regimen of simeprevir and Vertex’s investigational nucleotide analogue polymerase inhibitor VX-135 for the treatment of HCV. As a first step, Janssen Pharmaceutical Inc. will conduct a drug-drug interaction (DDI) study with simeprevir and VX-135.
Janssen Pharmaceutical also recently announced plans to initiate a phase IIa trial of an investigational interferon-free regimen with simeprevir, TMC647055 and Idenix’s IDX719, a once-daily NS5A inhibitor, with and without ribavirin.
* On December 13, 2012, Medivir has announced the initiation of cohort 2 in the interferon-free phase II trial combining simeprevir with sofosbuvir (GS7977) based on a safety and efficacy planned interim analysis of cohort 1 including prior null responder HCV genotype 1 infected patients without advanced hepatic fibrosis. Patient screening for cohort 2 was recently initiated. Data from the cohort 1 study will be presented at a scientific conference during H1-2013.
Global phase III studies of simeprevir include QUEST-1 and QUEST-2 in treatment naïve patients, PROMISE in patients who have relapsed after prior IFN-based treatment and ATTAIN in treatment experienced patients. In parallel to these trials, phase III studies for simeprevir are ongoing in both treatment naïve and treatment experienced HIV-HCV co-infected patients, HCV genotype 4 infected patients and in Japanese HCV genotype 1 patients.
The phase II interferon-free combinations of simeprevir, include:
• Simeprevir in combination with Gilead Sciences’ sofosbuvir (GS7977) in hepatitis C genotype 1 treatment-naïve or prior null responder patients.
• Simeprevir in combination with BMS’s, daclatasvir in hepatitis C genotype 1 treatment-naïve or prior null responder patients
• Simeprevir in combination with Janssen’s TMC647055 and low dose ritonavir in hepatitis C genotype 1 treatment-naïve, prior relapser or null responder patients
• Simeprevir in combination with Vertex’s VX-135 in hepatitis C genotype 1 treatment-naïve patients.
