New Oral HCV Drugs at EASL - Report 4A
Gilead Reports Interim Data From Phase 2 LONESTAR Study - (05/03/13)
Reported by Jules Levin
Results from many phase 2 & phase 3 studies of new oral HCV drugs were reported at EASL, which just took place in Amsterdam April 24-28. Abbott, Boehringer Ingelheim, Gilead, Janssen, & BMS all reported new data on their drugs. About 8-9 clinical/patient Gilead studies were reported at EASL with GS-7977 in Gt1 and Gt2/3, with therapy taken for as little as 12 weeks. ELECTRON & QUANTUM looked at Gt1 & both were phase 2 studies using GS-7977+rbv, but ongoing are ION phase 3 studies looking at the coformulated 2 oral regimen of GS7977+GS5885 with & without Rbv for 12 & 24 weeks including naives & treatment-experienced & those who failed to respond to triple therapy with a protease. You can read brief summaries of the results from the Gilead studies below & if you scroll down to the bottom of this report you will see links to the full slide & poster presentations. Abbott reported phase 2 results from their 4-drug IFN-free regimen taken for 12 weeks with 99% SVR in naives & 98% in nulls, see link below to read the slide presentation. Boehringer Ingelheim reported phase 3 results of their protease Faldaprevir (BI1335) from 1 study with 80% SVR rates, in combination with Peg/Rbv, several additional phase 3 studies including the coinfection study will be presented later this year. Janssen reported SVR rates of 81% from their 2 QUEST phase 3 studies, links below. BMS reported phase 2 results on their 3 drug IFN/RBV free all oral regimen given for 12 or 24 weeks with 90-94% SVR rates, they are planning a larger phase 3 study, see link below to read full poster. Merck reported phase 2 data with their 2nd generation protease MK5172+Peg/Rbv with 92% SVR rate, they just announced a deal with BMS for a study of the IFN-free regimen of MK5172 plus the BMS NS5A BMS052, plus they have further back in development a study with MK5172 plus their 2nd generation NS5A MK8742. Janssen & Boehringer are planning IFN-free studies looking at combinations of new oral drugs. Boehringer is looking at their protease in combination with their non-nuc BI127 plus the Presidio NS5A, recently announced. Janssen is involved in multiple oral regimen studies including one with their own non-nuc TMC055+the protease TMC435, another one with TMC435+TMC055+IDX719, TMC435+IDX719, one with TMC435+BMS052, & with TMC435 & Vertex in combination with their nucleotide VX135. Vertex is conducting numerous studies with their nucleotide VX135 in combinations with various oral HCV drugs from other companies, see links below to VX135 studies presented at EASL including with GSK NS5A GSK805. BMS just announced a study of their NS5A BMS052 in combination with VX135. Roche, don't forget Roche, they have ongoing, started last spring 2012, a 4-drug oral regimen, IFN-free- called ANNAPURNA, link to information below. Achillion has a protease, a 2nd generation NS5A & a 2nd generation protease in early development & Idenix has their NS5A & a nucleotide program in preclinical with studies perhaps to start with a nucleotide later this year. Presidio has a pangenotypic non-nuc & a NS5A, links below. Gilead submitted a New Drug Application for GS-7977 for 2 indications including for GS7977+Peg/rbv for Gt1, they are expected to be submitting a NDA next year for the coformulation of GS7977+GS5885. Janssen submitted their NDA TMC435. An FDA hearing for both drugs is expected in October this year. Boehringer is expected to an NDA submit to the FDA including for coinfection. As well, BMS will file a NDA including for BMS052, their NS5A. Abbott started their phase 3 program for their 4-drug IFN-free regimen in the Fall of 2012.
Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The NEUTRINO Study....relapse accounted for all failures....no resistance (deep sequencing) was seen among relapsers
327 total patients (genotypes 1, 4, 5, 6) were treated with GS-7977+Peg/Ribavirin for 12 weeks in the phase 3 NEUTRINO Study, results reported at EASL. 292 patients with GT1 received GS-7977+Peg/Rbv for 12 weeks with 89% achieving SVR12. For GT4, 96% (27/28) patients achieved SVR12. And 100% (7/7) with genotypes 5/6 achieved SVR. Overall, 92% without cirrhosis achieved SVR12 & 80% without cirrhosis achieved SVR12. Among the 28 patients who relapsed & the 1 patient who discontinued with HCV RNA viral load >1000 no S282T mutation was observed, this is the signature mutation for GS-7977, and no change in susceptibility by phenotypic analyses of other NS5B substitutions was observed. Side effects reported appeared to be mostly related to ribavirin with 21% anemia.
phase 2: ELECTRON: All-Oral Sofosbuvir-Based 12-Week Regimens for the Treatment of Chronic HCV GT 1 Infection
GS-7977+Rbv was taken for 12 weeks in this small phase 2 study of genotype 1 patients, 25 treatment-naives & 10 null responders with 84% of the naives achieving SVR12 & only 10% of the nulls achieving SVR. But GS-7977+GS5885 (once daily NS5A) + Rbv was given to 25 naives with 100% SVR & 9 nulls with 100% SVR, and the large ION-1 & ION-2 ongoing phase 3 studies are looking at these regimens & will provide more results. This study also looked at the Gilead non nuc Gs-9669+GS7977+Rbv for 12 weeks duration of therapy and 23/25, 92%, of naives & 3/3 nulls achieved SVR12.
Phase 3 Randomized Controlled Trial of All-Oral Treatment With Sofosbuvir + Ribavirin for 12 Weeks Compared to 24 Weeks of PEG + Ribavirin in Treatment-Naïve GT 2/3 HCV-Infected Patients (FISSION)
This study of 500 treatment-naive genotype 2/3 patients compared 12 weeks GS-7977+Rbv to 24 weeks of Peg/RBV. After 12 weeks of GS-7977+Rbv 99% had undetectable viral load but SVR12 was 67%. For those receiving 24 weeks Peg/Rbv 99% had undetectable viral load after 24 weeks but 67% SVR12. Certainly GS-7977+Rbv is more tolerable & safe than Peg/Rbv. For those genotype 2 patients receiving GS7977+Rbv for 12 weeks 92% had SVR12 but only 56% Gt3 had SVR12. For Gt2 patients taking Peg/rbv for 24 weeks 78% achieved SVR12 but 63% with Gt3 achieved SVR12. For Gt2 patients receiving GS7977+Rbv both cirrhotics & non-cirrhotics did well, there was not much of a difference in SVR rate with 98% of non-cirrhotics & 91% of cirrhotics achieving SVR12. But fot Gt3 patients the degree of liver disease affected outcomes with 61% without cirrhosis achieving SVR12 vs 34% with cirrhosis. There were no unusual side effects reported, SOF+Rbv was well tolerated, safety profile consistent with Rbv.
All Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment-Experienced Genotype 2/3 HCV-Infected Patients: Results of the Phase 3
This study of about 200 patients compared 12 vs 16 weeks of GS-7977+Rbv for treatment-experienced patients (Peg/Rbv). 30% of study subjects had cirrhosis, 70% were non-CC IL28b. At the end of treatment in both groups 100% had undetectable SVR, all patients finished treatment, relapse accounted for all failures. SVR12 was 50% for 12 weeks & 73% for 16 weeks. The difference in response between GT2 & Gt3 reflected results: for Gt2 patients, 86% receiving 12 weeks & 94% receiving 16 weeks achieved SVR12 while for Gt3 patients 30% receiving 12 weeks & 62% receiving 16 weeks achieved SVR. And the presence of cirrhosis affected outcomes. Gt2 patients without cirrhosis had 96% with 12 weeks & 100% with 16 weeks SVR12, but for cirrhotics 60% (6/10) with 12 weeks & 78% (7/9) with 16 weeks achieved SVR12. For Gt3 without cirrhosis 37% with 12 weeks & 63% with 16 weeks achieved SVR12 & for those with cirrhosis 19% with 12 weeks (5/26) & 61% with 16 weeks achieved SVR12. Again resistance to GS7977 was not an issue and there were no unusual side effects.
Treatment With Sofosbuvir + Ribavirin for 12 Weeks Achieves SVR12 of 78% in GT 2/3 Interferon-Ineligible, -Intolerant, or -Unwilling Patients: Results of the Phase 3 POSITRON Trial
207 patients received GS-7977+rbv. SVR was 93% for Gt2 & 61% for Gt3. Relapse accounted for all failures, no resistance seen in any relapse patient, and Gs-7977+Rbv was well tolerated. At the end of treatment 100% of patients had undetectable viral load & SVR12 was 78% with 92% for Gt2 & 61% for Gt3. Gt2 patients with or without cirrhosis did well, cirrhosis did not affect their outcomes with both groups achieving the same SVR, but cirrhosis did affect outcomes for Gt3 with 68% without cirrhosis achieving SVR12 % 21% with only cirrhosis achieving SVR12. Side affects were again consistent with those expected from Rbv.
Ongoing phase 3 studies ION-1 & ION-2 with coformulated once-daily GS7977+GS5885 :
ION-1, a Phase 3 clinical trial evaluating a once-daily fixed-dose combination of the nucleotide sofosbuvir and the NS5A inhibitor ledipasvir with and without ribavirin (RBV) for 12 or 24 weeks among treatment-naïve genotype 1 patients with hepatitis C virus (HCV) infection (n=800)
ION-2 initiated in January 2013, which is now fully enrolled. ION-2 is evaluating sofosbuvir/ledipasvir with RBV for 12 weeks, and with and without RBV for 24 weeks, among 400 treatment-experienced genotype 1 HCV patients. Participants in this study failed to respond to past therapy containing pegylated interferon (peg-IFN) or peg-IFN plus a protease inhibitor.
EASL: DATA FROM PHASE 3 STUDIES OF GILEAD'S SOFOSBUVIR FOR HEPATITIS C TO BE PRESENTED AT 48TH ANNUAL EASL MEETING; FINDINGS PUBLISHED ONLINE TODAY IN THE NEW ENGLAND JOURNAL OF MEDICINE - Press Release - (04/23/13)
Amsterdam, The Netherlands, April 23, 2013 - Gilead Sciences, Inc. (Nasdaq: GILD) today announced that detailed results from four Phase 3 clinical trials (NEUTRINO, FISSION, POSITRON and FUSION) evaluating sofosbuvir, the company's investigational once-daily nucleotide NS5B inhibitor for the treatment of chronic hepatitis C virus (HCV) infection, will be presented this week in oral sessions at the 48th Annual Meeting of the European Association for the Study of the Liver (International Liver Congress 2013) in Amsterdam, The Netherlands. In addition, detailed results from the four clinical studies have also been published online in two papers, ahead of print, in The New England Journal of Medicine (NEJM).
In the four trials, sofosbuvir was administered to nearly 1,000 patients with chronic HCV infection as part of an all-oral 12-week or 16-week treatment regimen in combination with ribavirin (RBV) in genotypes 2 and 3, or with RBV and pegylated interferon (peg-IFN) for 12 weeks in genotypes 1, 4, 5 and 6. Overall SVR12 rates (sustained viral response 12 weeks after completing therapy) from 50 to 90 percent were observed. Patients who achieve SVR12 are considered cured of their HCV infection.
A description of the four Phase 3 studies and SVR12 results are summarized in the table below. Detailed results from the Phase 3 studies of sofosbuvir are available at www.nejm.org/online-first., you can read the published articles on the 4 studies with links to them below, scroll down.
EASL: SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY - (04/25/13)
EASL: FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAIVE PATIENTS - (04/27/13)
EASL: Simeprevir (TMC435) with peginterferon/ribavirin for chronic hCV genotype 1 infection in treatment-naïve patients: results from QUEST-1, a Phase III trial - (04/25/13)
EASL: Simeprevir (TMC435) with peginterferon-α2a or -α2b and ribavirin in treatment-naïve HCV genotype 1 patients: QUEST-2, a randomised Phase III trial - (04/27/13)
EASL: Combination Therapy of TMC647055 With Simeprevir (TMC435) in Genotype 1 HCV Patients - (04/30/13)
EASL: NS5A BMS052 + nucleotide GS-7977 100% or 95% SVR for Patients Who Did Not Achieve SVR with Boceprevir/Telaprevir Triple Therapy, Resistance & Gt3 - (05/11/13)
EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13)
EASL: Interim Analysis of an Interferon (IFN)- and Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 in Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients - (04/25/13)
EASL: Evaluation of Pharmacokinetic Drug-Drug Interaction (DDI) Between BMS-791325, an NS5B Non-Nucleoside Polymerase Inhibitor, Daclatasvir and Asunaprevir in Triple Combination in HCV Genotype 1-Infected Patients - (04/25/13)
EASL: DACLATASVIR COMBINED WITH PEGINTERFERON ALFA 2A ALFA-AND RIBAVIRIN FOR 12 OR 16 WEEKS IN PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 2 OR 3 INFECTION: COMMAND GT 2/3 STUDY - (04/27/13)
EASL: High Sustained Viral Response of MK-5172 with Pegylated Interferon Alfa-2b and Ribavirin in HCV Genotype 1 Treatment-Naive Non-Cirrhotic Patients - (04/27/13)
EASL: ALS-2200, A Novel Once-daily Nucleotide HCV Polymerase Inhibitor, Demonstrated Potent Antiviral Activity In Treatment-naïve Patients with Compensated Cirrhosis or Genotype 2-4 Chronic Hepatitis C - (04/27/13)
EASL: VX-135, A POTENT SINGLE DIASTEREOMER OF ALS-2200, FOR THE TREATMENT OF CHRONIC HEPATITIS - (04/29/13)
3 & 4 Oral IFN-Free Roche HCV Regimens Studies, Treatment Naïve or Null Responders: setrobuvir+mericitabine+danoprevir/r+rbv. ANNAPURNA Study
GSK2336805 HCV NS5A Inhibitor Demonstrates Potent Antiviral Activity in Chronic Hepatitis C (CHC) Genotype 1 Infection: Results from a First Time in Human (FTIH) Single and Repeat Dose Study
EASL: Treatment With Sofosbuvir + Ribavirin for 12 Weeks Achieves SVR12 of 78% in GT 2/3 Interferon-Ineligible, -Intolerant, or -Unwilling Patients: Results of the Phase 3 POSITRON Trial - (04/27/13)
EASL: Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The NEUTRINO Study - (04/27/13)
EASL: Phase 3 Randomized Controlled Trial of All-Oral Treatment With Sofosbuvir + Ribavirin for 12 Weeks Compared to 24 Weeks of PEG + Ribavirin in Treatment-Naïve GT 2/3 HCV-Infected Patients (FISSION) - (04/25/13)
EASL: All Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment-Experienced Genotype 2/3 HCV-Infected Patients: Results of the Phase 3 FUSION Trial - (04/25/13)
EASL: ELECTRON: All-Oral Sofosbuvir-Based 12-Week Regimens for the Treatment of Chronic HCV GT 1 Infection - (04/27/13)
EASL: No S282T Mutation Detected by Deep Sequencing in a Large Number of HCV Patients Who Received Sofosbuvir With RBV and/or GS-0938: the Quantum Study - (04/29/13)
EASL: Once-Daily Sofosbuvir Plus Ribavirin Given for 12 or 24 Weeks in Treatment-Naïve Patients With HCV Infection: the QUANTUM Study - (04/28/13)
PPI-383, gt3/Pan-genotypic Non Nuc - (04/25/13)
EASL: VAST MAJORITY OF DETECTED NS5A RESISTANT VARIANTS ARE NOT AMPLIFIED IN HCV PATIENTS DURING 3-DAY MONOTHERAPY WITH THE OPTIMIZED NS5A INHIBITOR PPI-668 - (04/29/13)
IDX719, HCV NS5A Inhibitor, Demonstrates Pan-Genotypic Activity after Three Days of Monotherapy in Genotype 1, 2, 3 or 4 HCV-Infected Subjects
EASL: No S282T Mutation Detected by Deep Sequencing in a Large Number of HCV Patients Who Received Sofosbuvir With RBV and/or GS-0938: the Quantum Study - (04/29/13)
New 2nd Generation NS5A with Gt3 activity
EASL: GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier - (04/29/13)
EASL: Healthy Volunteer First-in-Human Evaluation of GS-5816, a Novel Second Generation Broad-Genotypic NS5A Inhibitor With Potential for Once-Daily Dosing - (04/29/13)
EASL: Resistance Analyses Using Deep and Population Sequencing After 3 Day Monotherapy With GS-9669, a Novel Non-Nucleoside NS5B Inhibitor in Genotype 1 HCV Patients - (04/30/13)
EASL: Antiviral Efficacy of the Once Daily NS3 Protease Inhibitor GS-9451, the Non-Nucleoside NS5B Inhibitor Tegobuvir (GS-9190), and Pegylated Interferon + Ribavirin in Treatment-Naïve Patients With Genotype 1 Hepatitis C Infection - (04/27/13)
EASL: 6-Week Treatment With Ledipasvir (NS5A Inhibitor) Plus GS-9451 (NS3 Inhibitor) With Peg-IFN/RBV in Naïve IL28B CC Subjects With Genotype 1 CHC: High Rates of Sustained Virological Response - (04/27/13)
EASL: Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection: 2 phase 3 studies - FISSION (gt2/3), NEUTRINO (gt1) - (04/29/13)
Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial - (04/24/13)
EASL: Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options - (04/24/13) POSITON, FUSION