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The development of compounds that directly target hepatitis C virus (direct acting antivirals or DAA's), used with and without pegylated interferon (PEG-IFN) and ribavirin is moving rapidly and with a burgeoning pipeline.
The following report is an edited summary of a rapid summary from Jules Levin whose natap.org website posted numerous studies from this meeting.
A limited number of web casts are due to be posted online but were not yet available when HTB went to press.
This has been a landmark meeting with the leading developments being the oral late breaker in the last clinical session late yesterday afternoon where BMS reported 4/11 genotype 1 non-responders achieved SVR24 cure using only the two oral BMS HCV drugs (the protease inhibitor BMS-650032 and the NS5A inhibitor BMS-790052).1
This was proof of concept that we can cure at least some patients without PEG-IFN and ribavirin.
We know that genotype-1a will not respond as well to therapies coming out in the near future, genotype-1b responds better. In the BMS study and others genotype-1a comprised more of the failures.
Patients with viral failure quickly added PEG-IFN plus ribavirin and all responded with undetectable HCV viral load. This was reported in November 2010 at American Association for the Study of Liver Diseases conference (AASLD) and is equally important. BMS also reported that using the QUAD therapy (BMS-650032, BMS-790052 plus PEG-IFN and ribavirin) 9/10 patients achieved SVR24 cure and the outlying patient had <LLOQ at week 24 post treatment undetectable on retesting 35 days later.
BMS also reported impressive data on their peg-lambda interferon in a study comparing it to Pegasys with it showing safety benefit and also surprisingly activity benefit as well, the programme is moving ahead.2
The second major story at EASL was the development of potent nucleotides by the small biotech company Pharmasset that appear to have a high barrier to resistance. So far no resistance has been seen and this is a key to the success of these drugs. Pharmasset reported three studies on PSI-938 and PSI-7977 in combination without PEG-IFN and ribavirin in patients with genotype-1. More than 90% patients essentially achieved undetectable over relatively short-term follow up.3
They also reported a nucleotide in combination with PEG-IFN and ribavirin that also displayed essentially 100% undetectability in patients in early follow up, and they reported similar results for people with genotype 2 and 3.4,5
Taking these two developments together, the cure data and the potency of these nucleotides, we can perhaps cure HCV with nucleotide therapy using short-term oral combination regimens.
Recently, BMS & Pharmasset announced a joint study that will combine the BMSNS5A with a Pharmasset nucleotide, 2 potent drugs expected to perform well together. Events are unfolding in an accelerated way now in HCV drug development coming out of this meeting.
BMS also reported the first SVR12 results in a dose-ranging study of its NS5A inhibitor BMS-790052 plus PEG-INF plus ribavirin vs PEG-INF plus ribavirin. SVR12 were 92% (11/12) receiving BMS-790052 vs 42% (5/12) receiving standard of care.6
Roche reported SVR data on their ritonavir-boosted HCV protease inhibitor danoprevir (RG7227) and on their nucleoside analogue polymerase inhibitor mericitabine (RG7128), both used in combination with PEG-IFN plus ribavirin.7,8
Of particular note, this is the first-time data reported on low-dose ritonavir boosting danoprevir. In with HIV protease inhibitors, ritonavir-boosting provides better efficacy compared to unboosted PIs, and although HCV is different boosted HCV PIs may provide additional benefits.
The danoprevir/r results were under-reported due to many other headline studies but preliminary data after 12 weeks in null-responders reported undetectable viral load in 88% (14/16) of genotype-1b patients and 50% (4/8) of genotype 1a. Roche was the first company to report combination therapy with two oral drugs with the INFORM study but their development programme was delayed because of an ALT elevation observation seen with their PI. Ritonavir-boosting lowers the Cmax and appears to have resolved that issue development is continuing.
Numerous studies were reported by Vertex on telaprevir and by Merck on boceprevir regarding IL28B and other data on how the drug will be used in support of the phase 3 studies reported at AASLD in November. The FDA hearing is scheduled for April 2011 and both drugs are expected to be approved.
Pharmasset announced the start of a cutting edge study called Atomic which will look at various treatment schedules.9
Novartis presented SVR rates in a phase 2b study of a non-immunosuppressive cyclosporine-A derivative called alisporivir (DEBO25) used with PEG-IFN plus ribavirin in genotype-1 treatment-naive patients of 76% rate compared to 55% for the PEG-IFN plus ribavirin.10
Alisporivir is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the hepatitis C virus directly, alispirovir, targets host proteins that the hepatitis C virus uses for replication. This therapy has particular appeal because not only does resistance appear hard to develop but cross-resistance to other classes of HCV drugs is unlikely. This increases options for non-responders who could use other experimental compounds. A phase 3 study in gentotype 1 naives is underway and study in non-responders is also planned. A Phase 2b trial looking at the potential of the agent in HCV patients with genotypes 2 and 3 is also underway. The host proteins are needed for replication in all types of HCV infection so there is potential for the agent to have broad activity in all six variations of HCV.
Tibotec had a few presentations on their once daily TMC435 protease inhibitor but as they have already entered Phase 3 having shown an impressive 84% SVRs in treatment-naive patients in phase 2 and are on a fast track to get to the market. These included IL28B data and a couple of other posters including the ASPIRE Study with preliminary data in nonresponders and a poster of five patients treated with TMC435 monotherapy & retreated with TMC435 plus PEG-IFN and ribavirin showing they were at least in short-term followup able to reach undetectable.11,12,13,14
Boerhinger Ingelheim reported phase 2 data on their protease inhibitor BI201335 plus PEG-IRN plus ribavirin in naives & treatment-experienced and announced publicly they are starting phase 3.15
Presidio had a poster on their NS5A development programme and issued an announcement about the clinical efficacy of their lead candidate PPI-461 in patients in an ongoing study.16
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