APASL: Alisporivir Resistance/CC/TT Gt Phase 2b Study...

Lovingly swiped from the great NATAP.org newsletter - a report from intrepid advocate/reporter Jules Levin from the Asian Pacific Association for the Study of the Liver conference on Alisporivir (formerly known as DEBIO-025) resistance analysis from the ESSENTIAL study.  Alisporivir is a Cyclophilin Inhibitor under development by Novartis. I thought that this was an interesting poster, as viral resistance to the DAAs is somewhat uncharted territory/conveniently overlooked depending on your particular position. A solid knowledge base regarding HCV resistance will be essential to HCV drug developers in regards to successfully sequencing therapy to achieve and SVR in patients that have failed previous therapy.  Cyclophilin Inhibitors, long the unsexy underdog in HCV drug developmen,t may have an important role in possible interferon-free combinations. With Alisporivir's polymerase and protease inhibitor brethren,   genotypic resistance is the primary driver to viral resistance, thus breakthrough and relapse.  With the Cyclophilin Inhibitor class, it appears that a combination of suboptimal drug exposure, frequent PEG/RBV dose reduction or host factors seem to be the reason for the rare breakthrough seen in this particular study. This harkens back to HIV Antiretroviral 101 - drug exposure and adherence - and not just to Alisporivir, but to PEG/RBG as well  - is critical. This thinking should be applied to the current paradigm of DAA therapy with Boceprevir and Telaprevir as well to ensure successful outcomes.  

Subject: NATAP/APASL: Alisporivir Resistance/CC/TT Gt Phase 2b Study

Alisporivir, a Host-targeting Antiviral, in Combination with Peg-IFNα2a and Ribavirin Results in Superior SVR and No Viral Breakthrough in HCV Genotype 1 Treatment-naïve Patients of IL28B CC Genotype: Results from the Phase IIb ESSENTIAL Study

- see attached full poster report

Reported by Jules Levin

22nd Conference of the Asian Pacific Association for the Study of the Liver • February 16-19, 2012 • Taipei, Taiwan

Bin Li,1 Joke Snoeck,2 Yanhua Tang,1 Christopher T. Jones,1 Weibin Bao,3 Jing Yu,1 Yali Li,1 Anne-Mieke Vandamme,2 Gregoire Vuagniaux,4 Kai Lin1

1Novartis Institutes for BioMedical Research, Inc, Cambridge MA, USA; 2Rega Institute and KU Leuven, Leuven, Belgium; 3Novartis Pharmaceuticals, East Hanover NJ, USA; 4Debiopharm SA, Lausanne, Switzerland

SUMMARY

• Alisporivir (ALV)/Peg-IFN2α/RBV treatment achieved 100% SVR in patients of IL28B CC genotype in the RGT and ALV/48wks arms

• Nearly 70% of patients of CC genotype cleared virus within 4 wks of treatment and qualified for shortened therapy

• No VB was observed in any patient of CC genotype while on full dose of ALV treatment

• The rare occurrence of VB (patients of CT or TT genotype) was associated with frequent Peg/RBV dose adjustment or treatment stoppage, as well as suboptimal drug exposure

• Previously reported D320E (NS5A domain II) mutation emerged at the time of breakthrough in one patient (1/215), although phenotypic analysis revealed only ~3-fold change in susceptibility to ALV for clinical isolates harboring D320E

• Clinical data demonstrated virus harboring D320E was susceptible to ALV when exposed to sufficient drug level

• Unlike DAAs, VB in ALV triple therapy was not primarily driven by genotypic resistance; a combination o f suboptimal drug exposure, host factors and low-level of genotypic resistance may all contribute to VB

• Consistent with in vitro cross-resistance data, patients with preexisting resistance mutations to DAAs remained susceptible to ALV triple therapy, supporting combining ALV with DAA in IFN-free combination to treat HCV 

“No difference observed between GT1a and 1b: 1/43 GT1a and 5/172 GT1b patients had VB while on full dose of ALV”

A bit more info on Novartis' cyclophilin inhibitor...

An article appearing on Pharmiweb about the approval of Telaprevir and Boceprevir, but also comments on alisporivir, also known as DEB025 which Novartis licensed from fellow Swiss firm Debiopharm in February 2009.

THE Food and Drug Administration (FDA) has approved Vertex Pharmaceuticals Inc.'s (VRTX) hepatitis C drug telaprevir and Merck’s hepatitis C drug, boceprevir.

Both drugs are protease inhibitors (PIs) and are designed to block an enzyme that helps the hepatitis C virus replicate. Hepatitis C is a liver disease caused by infection with the hepatitis C virus, which is transmitted through contaminated blood. The infection can cause liver failure and liver cancer.

The move follows the presentation and publication of new data on the drugs at the recent annual meeting of the European Association for the Study of Liver Disease (EASL) held in Berlin. Also presented at the meeting was data on Novartis' novel investigational oral agent alisporivir. This data was described as “fantastic” by EASL vice secretary Mark Thursz, professor of hepatology at Imperial College, London, while Robert Flisiak from the Medical University of Bialystok, Poland, told the congress as he presented the data: “This novel agent has the potential to be an important component of future hepatitis C treatment.” The availability of novel agents such as alisporivir and the protease inhibitors marks a new era in the treatment of hepatitis C infection. More than 30 potential hepatitis C agents are currently in R&D pipelines. Professor Thursz said that the new PIs offered unprecedented levels of sustained virological response and would be used initially with the current standard of care, pegylated interferon-alpha plus ribavirin. However, with so many potential novel treatments for hepatitis C on the horizon, he envisaged a time when standard of care for hepatitis C would be an interferon-free regimen. Boehringer’s HCV polymerase inhibitor BI 207127 has been fast-tracked by the FDA in combination whilst Bristol-Myers Squibb is trialling its PI, BMS 650032, in combination with the NS5A inhibitor BMS 790052.

Novartis’ alisporivir shows significant promise if its phase II data from the ESSENTIAL study, presented at EASL, is repeated in a phase III trial, which is now underway. The ESSENTIAL study involved 300 previously untreated patients infected with genotype 1 HCV. Of those treated with alisporivir, plus standard of care (pegylated-interferon alfa 2a/ribavirin), 76% achieved superior viral cure compared to 55% of patients on standard care alone 24 weeks after stopping treatment.

The study’s principal investigator, Stefan Zeuzem from Goethe University Hospital in Frankfurt, said: “Hepatitis C is difficult to treat and current therapies are effective only in about half of patients with the most prevalent genotype. These results are exciting because a large majority of patients achieved sustained viral response with alisporivir.”

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. A Phase IIb 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; there are six variations of HCV.

An international Phase III study is evaluating the efficacy and safety of alisporivir combined with standard care in previously untreated HCV G1 patients. The Phase II study showed that serious adverse events occurred in 6.9% of patients treated with alispirovir and standard care compared to 5.5% of patients treated with standard care alone. Prof Flisiak reported a higher rate of bilirubin (32.9% versus 1.4% in the alisporivir-treated group compared to standard care alone) but this was transient and reversible and associated with the initial loading dose. Final data from the Phase III ESSENTIAL-2 is expected in March 2013.

Novartis medical director Nikolai Naoumov said: “The data is very encouraging because it has produced a significant response in the most common form of HCV which can be very difficult to treat and with a reasonable safety profile. If the results of Phase III and other studies are also encouraging, this agent could offer a paradigm shift in clinical practice by being able to treat a number of genotypes and patients who have not responded to standard care.” Novartis in-licensed alisporivir, also known as DEB025, from fellow Swiss firm Debiopharm in February 2009.

Read more: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=40176#ixzz1Lo0stbq3

Original article here: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=40176