The clear conclusion from a clinical trial of alisporivir (DEB025, from Swiss drug major Novartis [NOVN: VX]), an oral host-targeting cyclophilin inhibitor, is that treatment based on it may be an effective, interferon (IFN)-free alternative for individuals with genotype 2 or 3 (G2/G3) hepatitis C virus (HCV) infections. The finding was presented by Jean-Michel Pawlotsky, a professor at the Henri Mondor Hospital, University of Paris-Est, Creteil, France, at a late-breaking poster session on November 7, 2011 at the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) held last week in San Francisco.
Novartis in-licensed DEB025 from Debiopharm, an independent biopharmaceuticals company based in Switzerland, under an agreement which gives Novartis exclusive worldwide development, manufacturing and marketing rights (excluding Japan; The Pharma Letter February 9, 2010).
IFN therapy is associated with significant adverse events, including flu-like symptoms, fatigue and nausea, all of which can significantly impact treatment adherence, and therefore also response rates and disease control. HCV G2/G3 represents the second most prevalent variant of HCV infection. While an effective and well-tolerated oral IFN-free HCV treatment would likely be widely embraced, because registrations trials are not yet completed, investigators and Novartis representatives were unwilling to speculate on the impact of an ultimate alisporivir approval.
Attraction of an oral agent
Dr Pawlotsky noted that alisporivir is attractive as an HCV treatment because it is an oral agent, it has potent activity across the HCV genotypes, and it has demonstrated a high barrier to viral resistance.
The international, multicenter, open-label study led by Dr Pawlotsky and colleagues included 334 G2/3 patients (ratio 3:7) who had not been treated previously for HCV infection. They were randomized to five treatment arms:
• alisporivir 1,000mg daily monotherapy (ALV1000) (n=82),
• alisporivir 600mg daily plus ribavirin (R) (ALV600R) ( n=84],
• alisporivir 800mg daily plus R (ALV800R) (n=94),
• alisporivir 600mg daily plus pegylated interferon (P) (ALV+P) (n=39), or
• P plus R (P+R) (n=35).
In week one, all alisporivir-treated patients received ALV 600mg twice daily. Patients receiving alisporivir as IFN-free treatment who achieved undetectable HCVRNA (<25 IU/mL) at week four remained on initial treatment, while those with detectable HCVRNA had add-on IFN and continued with ALV+PR triple therapy from week six to week 24.
Dr Pawlotsky reported a greater than 3 log reduction in mean HCV-RNA levels over the first four weeks of treatment with alisporivir-based IFN-free therapy. Also, rapid virologic responses (RVRs) were achieved by 28%, 37% and 42% of patients in the AlV1000, ALV600R and ALV800R groups, respectively. RVR patients on IFN-free treatment maintained responses to week 12, with minimal incidence of viral rebound.
From week four to six, the proportion of patients with undetectable HCV RNA with alisporivir-based, IFN-free therapy increased further to 32%, 49% and 46% in the AlV1000, ALV600R and ALV800R groups, respectively.
The proportion of patients with undetectable HCV-RNA levels was higher with alisporivir plus R than with alisporivir monotherapy. The RVR rate was about 60% higher for patients with lower baseline HCV RNA (less then 800,000 IU/mL) than for the overall group. However, for those alisporivir patients who did not achieve RVR by week four, add-on IFN as triple therapy (alisporivir 600mg daily plus PR plus IFN) from week six resulted in rapid HCV clearance with more than 90% of patients having undetectable HCV-RNA levels at week 12.
Fewer adverse events
Markedly lower rates of flu-like symptoms (fatigue, pyrexia, myalgia and arthralgia) were reported for alisporivir-based IFN-free as compared with IFN-containing treatment. For example, fatigue, headache and pyrexia were reported at percent rates of around13, 12 and 3, respectively, in the IFN-free arms and at about 27,27 and 23, respectively, in the add-on IFN arms. Overall, fewer adverse events were reported in the alisporivir arm of the trial. Transient increase in serum bilirubin (>5xULN) was observed in five (2%) of alisporivir-treated patients. Serum ALT levels remained normal. Grade 1&2 anemia reported in 19% to 27% of patients receiving alisporivir-regimens was attributable to ribavirin (anemia occurred in 27 percent of the standard of care PR arm). There were no reports of grade 3&4 anemia. Also, neutropenia, found in 17% of patients in the PR arm, was not observed in the alisporivir-based IFN-free arms. Only two patients discontinued treatment on account of adverse events.
Dr Pawlotsky commented: “Alisporivir once daily shows promise to become the first interferon-free oral treatment for a substantial proportion of treatment-naïve HCV G2/G3 patients.”
HVC affects more than 170 million people worldwide. Alisporivir, with potential to address an unmet need in this population, was been granted fast track review by the US Food and Drug Administration.
An ongoing pivotal Phase III study with DEB025 is evaluating the efficacy and safety of DEB025 plus interferon and ribavirin in previously untreated HCV genotype 1 patients.
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