EASL 2012: Alisporivir + Ribavirin Is Effective for Hepatitis C, but Pancreatitis Remains a Concern

Alisporivir (formerly Debio 025) in interferon-free combinations cured more than 80% of patients with hepatitis C virus (HCV) genotype 2 or 3, researchers reported the 47th International Liver Congress (EASL 2012) last week in Barcelona. The drug has been put on hold, however, due to a small number of recipients developing life-threatening pancreas inflammation.

The advent of direct-acting antiviral agents for hepatitis C has brought about a new era of treatment, but many patients and clinicians are eager to see all-oral regimens that do not include interferon and its difficult side-effects.

Alisporivir is a cyclophilin blocker than stops HCV from replicating in cells. Unlike many of the new drugs in development, it targets a component in host cells rather than the virus itself. Previous small studies showed that it is active across HCV genotypes and has a high barrier to resistance.

Jean-Michel Pawlotsky from Hôpital Henri Mondor in Paris and colleagues evaluated alisporivir in an international exploratory study (VITAL-1) that included 340 previously untreated people with hepatitis C genotype 2 or 3, types considered easier to treat than genotype 1.

Two-thirds of participants were men, about half were white and half Asian, and the average age was about 42 years. One-third had genotype 2, the remainder genotype 3.

Participants in this open-label Phase 2b trial were randomly assigned to 1 of 5 treatment arms: 1000 mg once-daily alisporivir monotherapy, 600 mg once-daily alisporivir plus ribavirin, 800 mg once-daily alisporivir plus ribavirin, 600 mg once-daily alisporivir plus pegylated interferon, or standard therapy using pegylated interferon/ribavirin.

All alisporivir recipients started with a "loading dose" of 600 mg twice-daily before beginning their assigned regimen. Those who achieved rapid virological response (RVR) -- or HCV viral load below the limit of quantification (< 25 IU/mL) at week 4 -- stayed on the assigned regimen through week 24. Those who did not switched to 600 mg alisporivir plus pegylated interferon/ribavirin and continued for the same duration.

Results

• Across all alisporivir arms, participants experienced rapid viral load reduction during the first week while taking alisporivir alone.
• RVR rates were as follows:
  • 29% in the 1000 mg alisporivir monotherapy group;
  • 37% with 600 mg alisporivir/ribavirin;
  • 42% with 800 mg alisporivir/ribavirin.
• In these 3 groups 12%, 17%, and 10%, respectively, experienced primary non-response, defined as < 1 log reduction from baseline levels.
• In an intention-to-treat analysis, rates of sustained virological response (< 25 IU/mL) at 12 weeks after completing treatment (SVR12) were:
  • 81% in the 1000 mg alisporivir monotherapy group;
  • 83% with 600 mg alisporivir/ribavirin;
  • 81% with 800 mg alisporivir/ribavirin;
  • 77% with alisporivir plus pegylated interferon;
  • 58% with pegylated interferon/ribavirin (lower than the typical genotype 2/3 SVR range of 70% to 80%).
• Cure rates were higher in a per-protocol analysis that only included participants who remained on their assigned regimen for the full 24 weeks:
  • 91% in the 1000 mg alisporivir monotherapy group;
  • 91% with 600 mg alisporivir/ribavirin;
  • 94% with 800 mg alisporivir/ribavirin;
  • 86% with alisporivir plus pegylated interferon;
  • 74% with pegylated interferon/ribavirin.
• RVR was a good predictor of SVR.
• No patients receiving 800 mg or 1000 mg alisporivir experienced viral breakthrough during treatment, but 3% did so in the 600 mg arm.
• Relapse rates after treatment were 4% in the 600 mg alisporivir/ribavirin arm and 9% in the 800 mg alisporivir/ribavirin arm, but twice as high -- 18% -- in the alisporivir monotherapy group.
• Overall, alisporivir was generally well-tolerated.
• The most common side effects among people not taking interferon were psychiatric disorders (24%), nausea (18%), and fatigue and headache (both 13%).
• Rates of serious adverse events in the alisporivir arms ranged from 1% to 11%, vs 5% in the pegyalted interferon/ribavirin arm.
• Rates of discontinuation due to adverse events among alisporivir recipients ranged from 2% to 8%, with none in the control arm.
• Up to 12% of people taking alisporivir with ribavirin developed moderate bilirubin elevation -- which Pawlotsky explained was due to the drug's effect on bilirubin transporters -- but severe elevations (> 5 times the upper limit of normal) were uncommon.

Importantly, Pawlotsky reported that no participants in this Phase 2b trial developed pancreatitis. At the congress' opening press conference prior to this late-breaker presentation it was noted that the US Food and Drug Administration recently put a hold on further development of alisporivir after a small number of patients -- 6 out of approximately 1800 people who have received the drug in various studies -- experienced pancreatitis (inflammation of the pancreas), leading to 1 death.

VITAL-1 principle investigator Nikolai Naoumov from Novartis -- who attended the presser but was not a presenter -- explained that these cases occurred among patients taking alisporivir in combination with pegylated interferon/ribavirin. Since pancreatitis has been reported as a rare side effect of interferon, the study team is conducting further testing to determine ifalisporivir raises the risk.

Despite this setback, the investigators concluded, "Cyclophilin inhibition plus ribavirin represents and effective interferon-free option and achieves high SVR rates in patients with HCV genotypes 2 or 3 with RVR."

"In this study, alisporivir was associated with low and similar rates of discontinuation due to adverse events across treatment groups," they added.

4/23/12

Reference

JM Pawlotsky, SK Sarin, G Foster, NV Naoumov, et al. Alisporivir plus Ribavirin is Highly Effective as Interferon-free or Interferon-add-on Regimen in Previously Untreated HCV-GT2 or GT3 Patients: SVR12 Results from VITAL-1 Phase 2b Study. 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012). Barcelona, April 18-22, 2012. Abstract 1405.

Other Source

Associated Press. Novartis Halts Hepatitis Drug Trial after Death. April 19, 2012.