Inhibitor Alisporivir Active Against HCV in Phase 2b, HBV in
Cyclophilin inhibitor alisporivir (Debio 025) plus pegylated
interferon/ribavirin boosted sustained response in treatment-naive
genotype 1 hepatitis C patients, and also demonstrated antiviral
activity against hepatitis B in a laboratory study, researchers
reported at EASL 2011.
are intracellular enzymes that play a role in folding and transporting
cellular proteins. Cyclophilin inhibitors can affect viral infection
by interfering with proteins viruses need for replication.
being developed by Novartis (under license from Debiopharm),
is a cyclophilin inhibitor without immunosuppressive activity
(unlike the related compound cyclosporin A). In preclinical
and early clinical studies it demonstrated activity against
hepatitis C virus (HCV) and HIV,
and was among the first direct-acting antivirals to be tested
in HIV/HCV coinfected
patients. Its advantages include a high barrier to resistance
and little potential for cross-resistance with direct-acting
antivirals targeting the HCV lifecycle.
the European Association for the Study of the Liver's International
Liver Congress (EASL 2011) last week
in Berlin, Robert Flisiak presented data from a Phase 2b study
evaluating the safety and efficacy of alisporivir combination
therapy in previously untreated patients with hard-to-treat
HCV genotype 1.
ESSENTIAL study was a multinational placebo-controlled trial
that included 288 participants in 36 European countries who
were randomly assigned to receive alisporivir or placebo in
combination with pegylated
interferon alfa-2a (Pegasys) and ribavirin in one of the
Alisporivir + pegylated interferon + ribavirin for a fixed
The same 3 drugs for a fixed 24 weeks;
same 3 drugs using a response-guided therapy in which people
with undetectable HCV RNA at week 4 stopped treatment at
24 weeks and the rest continued for 48 weeks;
+ pegylated interferon + ribavirin for a fixed 48 weeks
(standard therapy control arm).
all but the control arm, the dose of alisporivir was 600 mg
twice-daily during the first week, then 600 mg once-daily thereafter.
half the participants were men, almost all were Caucasian, and
the average age was about 41 years. Baseline characteristics
were similar overall, except compared with the control arm,
fewer people taking alisporivir for 48 weeks had the favorable
IL28B CC gene pattern, which predicts better response to interferon
(33% vs 19%, respectively).
an intent-to-treat analysis 24 weeks after completion of
therapy, 76% of participants receiving alisporivir triple
therapy for 48 weeks achieved sustained virological response
(SVR24), compared with 55% in the 48-week control arm.
rates were 53% in the fixed 24-week alisporivir triple therapy
arm -- similar to standard therapy for 48 weeks -- and 69%
in the alisporivir response-guided therapy arm.
doubled the likelihood of SVR in people with the unfavorable
IL28B TT gene pattern.
virological response (RVR; HCV RNA < 10 IU/mL at week
4) rates were 24%, 28%, and 23%, respectively, in the alisporivir
48-week, 24-week, and response-guided arms, compared with
8% in the standard therapy arm.
the alisporivir 48-week and response-guided therapy arms,
achieving RVR was 100% predictive of SVR24.
virological breakthrough rate was 5% in all alisporivir
arms (or 3% among those receiving full-dose alisporivir)
vs 6% in the control arm.
patients taking alisporivir, 7 of 10 cases of viral breakthrough
happened after treatment discontinuation or dose reduction.
rates were 15%, 39%, and 16%, respectively, in the alisporivir
48-week, 24-week, and response-guided arms, compared with
24% in the standard therapy arm.
was well-tolerated overall.
of serious adverse events was 7% in the alisporivir 24-week
and 48-week arms and 10% in the response-guided arm, compared
with 6% in the control arm.
of discontinuation due to adverse events were similar, at
5% in the alisporivir arms vs 4 % in the control arm.
of alisporivir recipients in the 48-week arm, 42% in the
24-week arm, and 25% in the response-guided arm, vs 1% in
the control arm, developed hyperbilirubinemia (elevated
of alisporivir recipients in the 24-week and response-guided
arms and 7% in the 48-week arm had severe hyperbilirubinemia
(> 5 x upper limit of normal); this was reversible and
not associated with elevated ALT.
results demonstrate the superiority of alisporivir combined
with [pegylated interferon/ribavirin] in achieving SVR24 in
genotype 1 treatment-naive patients," the investigators
concluded. Alisporivir "has the potential to be an important
component of future HCV treatment."
added that, "24 weeks of treatment is sufficient for those
patients who achieve RVR, and "[t]reatment with alisporivir
was well tolerated and associated with low viral breakthrough."
recently started Phase 3 trial is testing alisporivir in previously
untreated HCV genotype 1 patients. The drug is also currently
being tested in Phase 2 studies of treatment-naive people with
HCV genotypes 2 and 3, and treatment-experienced prior non-responders
with genotype 1.
Further back in the development pipeline, investigators assessed
the activity of alisporivir and another cyclophilin inhibitor,
NIM811, against hepatitis B virus (HBV).
Changes in mitochondrial calcium flow and calcium signaling,
both affected by cyclophilin inhibitors, affect HBV replication,
the researchers noted as background. Furthermore, hepatitis
B surface antigen (HBsAg) can interact with cyclophilin A in
In this study the investigators looked at HBV replication and
virus particle release in a panel of liver cell lines exposed
to alisporivir and NIM811. Stably transfected HepG2215 cells
were cultured for 7 days and then treated with 0.25, 1.0, and
5.0 mcg/mL of alisporivir or NIM811. They were analyzed at baseline
and at 6, 24, 48, and 72 hours after adding of the drugs. Similar
experiments were repeated with Huh-7 cells and PLC/PRF/5 cells.
Both cyclophilin inhibitors significantly reduced core-particle-associated
HBV DNA levels in cells by 2-fold to 10-fold compared with control
cells. The most pronounced reduction in intracellular HBV DNA
levels -- by 10-fold at 72 hours -- was seen after exposure
to 5.0 mcg/mL alisporivir. Alisporivir at both 1.0 and 5.0 mcg/mL
doses reduced HBV virion production more than NIM811. Both compounds
significantly reduced HBsAg secretion from cells by about 50%
compared with controls.
"Cyclophilin inhibition interferes with HBV replication
within liver cell lines, and in addition, it significantly reduces
the secretion of virions and HBsAg particles from the cells,"
the investigators concluded. "A combination of cyclophilin
inhibitor and [nucleoside/nucleotide] anti-HBV agent may be
useful for treatment of chronic hepatitis B."
Abstract 190: Medical University of Bialystok, Bialystok, Poland;
Hôpital Henri Mondor, Créteil, France; Debiopharm,
Lausanne, Switzerland; Centrul de Diagnostic si Tratament Dr.
Viktor Babes, Bucharest, Romania; Department of Infectious Diseases,
Provincial Hospital, Kielce, Poland; Universitätsklinikum,
Düsseldorf, Germany; Department of Internal Medicine and
Gastroenterology, University of Bologna, Bologna, Italy; UCM
Digestive Diseases and Ciberehd, Hospital Universitario de Valme,
Sevilla, Spain; Novartis, Basel, Switzerland; Department of
Internal Medicine I, J.W. Goethe University Hospital, Frankfurt/Main,
Abstract 928: Institute of Hepatology, Foundation for Liver
Research, London, UK; Novartis Pharma AG, Basel, Switzerland.
R Flisiak, J-M Pawlotsky, R Crabbé, et al. Once daily
alisporivir (DEB025) plus PegIFNalfa2a/ribavirin results in
superior sustained virologic response (SVR24) in chronic hepatitis
C genotype 1 treatment naive patients. 46th Annual Meeting of
the European Association for the Study of the Liver (EASL 2011).
Berlin. March 30-April 3. Abstract
S Chokshi, S Phillips, A Riva, and N Naoumov. Characterization
of antiviral activities of cyclophilin inhibitors DEB025 (alisporivir)
and NIM811 on hepatitis B virus (HBV) replication and HBsAg
secretion in vitro. 46th Annual Meeting of the European Association
for the Study of the Liver (EASL 2011). Berlin. March 30-April
Novartis first-in-class antiviral DEB025 achieved sustained
viral response in 76% of patients with chronic hepatitis C,
new phase II study shows. Press release. March 31, 2011.