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 at 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 that 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
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.
About two-thirds of participants were men, about half
were white and half were Asian, and the average age was about 42 years. One-third
had genotype 2, the remainder genotype 3.
Participants in this open-label phase IIb trial were
randomly assigned to one of five treatment arms: 1000mg once-daily alisporivir
monotherapy, 600mg once-daily alisporivir plus ribavirin, 800mg once-daily
alisporivir plus ribavirin, 600mg once-daily alisporivir plus pegylated
interferon or standard therapy using pegylated interferon/ribavirin.
All alisporivir recipients started with a 'loading
dose' of 600mg 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 achieve a rapid virological response switched to 600mg alisporivir plus pegylated
interferon/ribavirin and continued treatment for the same duration.
Across all alisporivir arms, participants experienced
rapid viral load reduction during the first week while taking alisporivir
alone. RVR rates were 29% in the 1000mg alisporivir monotherapy group, 37% with
600mg alisporivir/ribavirin and 42% with 800mg alisporivir/ribavirin. In these
three groups 12%, 17% and 10%, respectively, experienced 'primary
non-response', defined as < 1 log10 reduction from baseline
In an intention-to-treat analysis, 81% of people taking
1000mg alisporivir alone, 83% and 81%, respectively, taking 600mg or 800mg
alisporivir plus ribavirin and 77% taking alisporivir plus pegylated interferon
achieved sustained virological response (< 25 IU/mL) at 12 weeks after
completing treatment (known as SVR12), compared with 58% of those receiving
pegylated interferon/ribavirin. (The cure rate in the latter group was rather
low, as interferon-based therapy typically produces SVR rates in the range of
70 to 80% for genotype 2/3 patients.)
Cure rates were higher in a per-protocol analysis that
only included participants who remained on their assigned regimen for the full
24 weeks; the corresponding SVR12 rates were 91%, 91%, 94%, 86% and 74%,
respectively. RVR was a good predictor of SVR.
In the per-protocol analysis no patients receiving
800mg or 1000mg alisporivir experienced viral breakthrough during treatment,
but 3% did so in the 600mg arm. Relapse rates after treatment were 4% in the
600mg alisporivir/ribavirin arm and 9% in the 800mg alisporivir/ribavirin arm,
but twice as high
– in the alisporivir monotherapy group, leading
Pawlotsky to note that "ribavirin matters" in this regimen. Several
resistance mutations were identified in people with viral breakthrough.
"Ribavirin matters in this regimen", Jean-Michel Pawlotsky, Hôpital Henri Mondor, Paris
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%). Flu-like
symptoms were substantially less common among people who did not take interferon.
Rates of serious adverse events in the alisporivir
arms ranged from 1% to 11%, vs 5% in the pegylated 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
Pawlotsky explained was due to the drug's effect on bilirubin transporters
but severe elevations were uncommon.
Importantly, Pawlotsky reported that no participants
in this phase IIb trial developed pancreatitis. At the opening press
conference of the congress, it was noted that the US Food and Drug Administration (FDA) had recently put a
hold on further development of alisporivir after a small number of patients
six out of approximately 1800 people who have received the drug in various
– experienced pancreatitis (inflammation of the pancreas), leading to
VITAL-1 principal investigator
Nikolai Naoumov from Novartis (who attended the presentation 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 if alisporivir raises the risk.
Despite this setback, the researchers concluded,
"Cyclophilin inhibition plus ribavirin represents an effective
interferon-free option and achieves high SVR rates in patients with HCV genotypes
2 or 3 with RVR" and "in this study, alisporivir was associated with
low and similar rates of discontinuation due to adverse events across treatment