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HIV and Coverage of the
46th Annual Meeting of the European
Association for the Study of the Liver

March 30 - April 3, 2011, Berlin, Germany

Cyclophilin Inhibitor Alisporivir Active Against HCV in Phase 2b, HBV in Lab

SUMMARY: 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.

By Liz Highleyman

Cyclophilins 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.

Alisporivir, 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.

Alisporivir for HCV

At 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.

The 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 following regimens:

Alisporivir + pegylated interferon + ribavirin for a fixed 48 weeks;
The same 3 drugs for a fixed 24 weeks;
The 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;
Placebo + pegylated interferon + ribavirin for a fixed 48 weeks (standard therapy control arm).

In all but the control arm, the dose of alisporivir was 600 mg twice-daily during the first week, then 600 mg once-daily thereafter.

About 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).


In 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.
SVR24 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.
Alisporivir doubled the likelihood of SVR in people with the unfavorable IL28B TT gene pattern.
Rapid 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.
In the alisporivir 48-week and response-guided therapy arms, achieving RVR was 100% predictive of SVR24.
The virological breakthrough rate was 5% in all alisporivir arms (or 3% among those receiving full-dose alisporivir) vs 6% in the control arm.
Among patients taking alisporivir, 7 of 10 cases of viral breakthrough happened after treatment discontinuation or dose reduction.
Relapse 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.
Alisporivir was well-tolerated overall.
Frequency 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.
Rates of discontinuation due to adverse events were similar, at 5% in the alisporivir arms vs 4 % in the control arm.
33% 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 bilirubin).
3% 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.

"These 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."

They 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."

A 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.

Alisporivir for HBV

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 liver cells.

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."

Investigator affiliations:
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, Germany.
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 190.

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 3. Abstract 190.

Other Source
Novartis. 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.

























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