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”