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  EASL 48th Annual Meeting
April 24th - 28th 2013
The Netherlands, Amsterdam
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New HCV Drugs: Report 2
  Reported by Jules Levin
EASL 48th Annual Meeting
April 24th - 28th 2013
The Netherlands, Amsterdam
This report is an updated version that was originally distributed live in real-time from EASL on April 28. 2 days ago I reported & distributed by email "New HCV Drugs - report 1" which was a report from the first 2 days on new study data reported for new HCV drugs, this report is a followup on new study data reported for new HCV drugs in the last 2 days of the conference EASL. There are many more reports to be prepared from this conference coming. Daclatasvir, TMC435, Faldaprevir & MK5172 reports below are from studies in combination with Peg/Rbv, but IFN-free all oral combination studies with 2 or perhaps 3 orals are also being studied, one study is reported below: Daclatasvir+GS7977 in 41 patients who previously were treated with boceprevir or telaprevir & did not achieve SVR, this is the first study treating patients who did not achieve SVR when treated previously with a protease triple therapy. Yesterday from 3:30 to 5:30pm, was the oral Late-Breaker session here at EASL in Amsterdam, the city of canals & lots of people using bikes to get around this relatively small but very cosmopolitan urban and yet still old European-style city of 850,000 people, that has a very nice bustling downtown with squares & lots of shopping, clothing stores and walking malls. Presented in the Late Breaker session was (see links below to the study data reports.
- GS7977(nucleotide)+Peg/Rbv for 12 weeks for genotypes 1/4/5/6 in the phase 3 NEUTRINO Study
- TMC435 (protease)+Peg/Rbv for GT1 in the phase 3 QUEST-2 Study
- Faldaprevir (BI335, protease)+Peg/Rbv in the phase 3 study STARTVERS01
- NS5A BMS052+GS7977 in GT1 patients who previously did not achieve an SVR with boceprevir or telaprevir (this captured a lot of attention)
- Daclatasvir (BMS052) + Peg/Rbv for GT2/3 for 12 or 16 weeks
The day before a phase 2 study on MK5172 (Merck 2nd generation protease) + Peg/Rbv for Gt1 was presented.
In the NEUTRINO Study with GS7977+Rbv taken for 12 weeks the overall SVR rate was 90%, there were 327 patients in this study, mostly Gt1 with 89% SVR rate in Gt1, 96% in Gt4, and 100% for Gt5/6. The overall SVR for non-cirrhotics was 92% & 80% for cirrhotics. Regarding resistance they looked at 28 patients who relapsed & 1 patient who discontinued treatment with HCV RNA>1000 IU/Ml and they reported "no S282T mutations, the signatory GS7977 mutation, observed by population or deep sequencing (1%) cutoff, no change in susceptibility to GS7977 or Rbv observed by phenotype amnalyses of other NS5B substitutions". There was a poster here on the QUANTUM Study, I distributed by email yesterday, wherein they retreated 132 patients who had not achieved SVR who were previously treated with GS938 (the discontinued sister drug of GS7977) or GS7977+GS938 and they reported high SVR rates of 76-85%, the point being it is hard to get resistance to GS7977. See link to study below. Gilead has submitted an initial New Drug Application to the FDA for approval of GS7977+Rbv for GT2/3 and for GS7977+Peg/Rbv for Gt1 and I think additional GTs 4....And here at EASL they reported phase 3 results in GT2/3:
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: 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: 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)
The phase 3 QUEST-2 Study reported on TMC435, the new once-daily HCV protease from Janssen, + Peg/Rbv, with an SVR12 rate of 81%, and 94% of patients were eligible for shortened 24 weeks therapy & among them 86% achieved SVR, see link below to the data report that includes the slide presentation, in the report is a slide with an interesting list of studies in the TMC435 development program, of note including numerous IFN-free multi-oral combination studies being conducted. Of note 88% achieved SVR with Pegasys while 77% achieved SVR with PegIntron, and of course this was noted with comments after the presentation with the presenter Michael Manns saying this was not a properly randomized study to address the question of which peg has superior efficacy, Pegasys & Pegintron. 96% IL28B CC achieved SVR, 80% with CT & 57% with TT. Of note SVR rates were the same for GT1a & GT1b: 80.4% & 82% respectively. SVR rate by stage of disease reflecting again that cirrhotics are harder to treat with lower SVR rates seen here & in other studies, thus needing more potent regimens & with null cirrhotics being the hardest to treat: 84.6% with early disease (F0-F2) achieved SVR, 66.7% with F3 & 64.7% with F4. There was some rash & photosensitivity associated with TMC435 but apparently manageable, 97% grade 1/2. and "mild, transient bilirubin increases not accompanied by changes in other liver parameters". Janssen has submitted to the FDA a New Drug Application for TMC435. A FDA hearing is scheduled for mid-October, perhaps to hear & review both the Gilead & Jansssen submissions simultaneously as they did 2 years ago for both telaprevir & boceprevir, apparently it is posted online that the FDA is holding hearings Oct 24 & 25. A 2nd phase 2 study QUEST-1 was presented here at EASL as well.
Faldaprevir is the new once-daily HCV protease from Boehringer Ingelheim, also called BI335. They reported SVR results from the phase 3 study STARTVERS01, they studied 2 doses 120 & 240 mg once daily + Peg/Rbv in over 600 patients, reporting overall SVR12 rates of 79% with the 120mg dose & 80% with the 240mg dose, with 88% achieving what they called ETS, early treatment success at week 4, permitting a shortened therapy of 24 weeks & of these patients 86% with 120mg & 89% with 240mg achieving SVR12. GT1a SVR12s were 69% with 120mg & 76% with 240mg & for Gt1b 84% with 120mg & 83% with 240mg. Boehringer is planning to submit to the FDA their NDA soon. See link below to slide presentation. Those with IL28b, 90% receiving 120mg & 95% receiving 240mg achieved SVR12, for CT 70% & 69% achieved SVR12, and for TT 76% & 79%. There was GI upset, rash & bilirubin increases. Of note several additional phase 3 studies are near completion including one in HCV/HIV coinfection and will be presented publicly later at a conference. BI reported at CROI ART HIV drug-drug interactions which generally are favorable and so they appear to be headed to be the first with a FDA indication for coinfection.
CROI: Pharmacokinetic interactions of darunavir/ritonavir, efavirenz, and tenofovir with the HCV protease inhibitor faldaprevir in healthy volunteers - (03/04/13)
CROI: STARTVerso 4: High rates of early virologic response in HCV genotype 1/HIV-co-infected patients treated with faldaprevir plus pegIFN and RBV - (03/04/13)
CROI: Boerhinger Ingelheim Announes Interim Results Evaluating Virologic Response Rates in HCV/HIV Coinfected Patients Treated with HCV Protease BI201335, and Drug Drug Interaction Studies with HIV ARTs - (03/04/13) press announcement
The first retreatment study of patients who failed (nonresponse, relapse, breakthrough) a triple therapy with either boceprevir or telaprevir with an IFN-free regimen was presented at yesterday's Late Breaker session & perhaps this garnered the most attention & discussion, although all the new data here on all the new oral HCV drugs captured everyone's delight & everyone was very pleased with the great progress in treating HCV. 21 patients received the BMS NS5A BMS052 (Daclatasvir) + GS7977 (Gilead's nucleotide) and 20 patients received this 2 drug combination along with Rbv, treatment was 24 weeks. Of note 81-85% had F2 disease stage or greater and Mark Sulkowski, who presented the data, said some of these patients may have had cirrhosis, the stages of disease by some of these patients varied based on when the test was done etc. At the end of treatment 100% HCV RNA < LLOQ, SVR4 was 100%, and SVR12 was 95%, there was 1 patient who was missing at post-treatment week 12, but "HCV RNA was undetectable at post-treatment week 4 & post-treatment week 24 (preliminary). 21/41 patients have reached PT week 24, all have achieved SVR24. see link below to full slide presentation. Side effects included headache, fatigue. By the way, in the presentation Sulkowski mentioned that it has been I think I recall he said as long as 1.5 or more years, perhaps as much as 2 yrs, since some patients had stopped boceprevir or telaprevir therapy & of note baseline resistance mutations were still detected, but apparently with 95-100% SVR rates, this resistance did not affect outcomes in this regimen with 2 orals from 2 different classes, but this raises a concern that protease resistance may not disappear as easily as has been reported previously in some studies, see the report link to read the slide on baseline mutations.
Results were reported in the Late Breaker session yesterday from the COMMAND GT2/3 Study where 150 patients with Gt2/3 were studied & 100 received the BMS NS5A Dacaltasvir (BMS052) + Peg/Rbv for either 12 or 16 weeks. In the 12 week arm at the End Of Treatment for GT2 100% had < LLOQ-TD (target detected, detectable but < LLOQ) and 96% had < LLOQ-TND (target not detected, undetectable), with 100% & 91% for the 16-week arm, and of note the 24-week Peg/Rbv-placebo arm had similar SVR rates of 96 & 91% (which changed in SVR rates). SVR24 for GT2 in the 12-week group was 88% < LLOQ-TD & 83% < LLOQ-TND, and for the 16 week arm 83% for both measures, they called this modified ITT analysis, so they also said in the graph legend SVR24 observed values (excluding patients with missing post-treatment data: 95% (DCV 12 weeks), 100% DCV 16 weeks). IL28b CC GT2 patients had 100% SVR with 16 weeks (7/7) byt CT & TT had lower SVR rates, see slide graph. Response rates were less for GT3 patients, SVR24 rates of 67-70% & 69-72% after excluding missing post-treatment data and SVR24 for Peg/Rbv-placebo arm was 59%, so clearly GT3 patients did not perform well here either as in the GS7977 study and need extra potency with therapy directed at GT3. For patients with PDR, protocol defined responses (HCV RNA < LLOQ at week 4 & < LLOQ-TND at week 10, SVR24 rates were 81% with 12 weeks for GT2 & 94% with 16 weeks for GT2 & for GT3 73% with 12 weeks or 16 weeks. See link below to the slides presented.
Merck's once-daily MK5172 is a 2nd generation protease with activity against resistant virus. In this study of 332 non-cirrhotic patients, several MK5172 doses were looked at: 100mg, 200mg, 400mg & 800mg, all once daily, + Peg/Rbv. Patients received 12 weeks of MK5172 and the comparison arm was boceprevir+Peg/Rbv. At AASLD in Nov 2012 SVR12 was reported & here SVR24 & HCV-RNA (TND) is reported with 311/332 (94%) patients have reached followup week 24 or have discontinued before week 24 followup. SVR24 & HCV-RNA TND* at last visit with 100mg (the dose to be used) +PR was 86% (55/64) & 92% (61/66), (*HCV RNA TND at last visit: patients who discontinued for reasons other than virologic failure, who completed therapy and are in follow-up, or who completed therapy but did not return for the followup week 24 visit). 91% of patients receiving MK5172 100mg had HCV-RNA TND at week 4 & were eligible for the short-duration of therapy and 98% had HCV-RNA TND at last visit & 90% had SVR 24. See link below to full slide report. Merck & BMS recently announced an agreement to study a 2 oral once-daily regimen IFN-free in genotype 1 with this protease MK5172 + the BMS NS5A BMS052.
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: 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: 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: 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)