Researchers Present Data on Investigational Cyclophilin Inhibitors Debio 025 and SCY-635

At the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen, researchers presented promising data from studies of a new class of agents for HCV therapy, cyclophilin inhibitors.

While most investigational therapies for chronic hepatitis C virus (HCV) infection are either new forms of interferon or ribavirin, or directly targeted agents that interfere with various steps of the viral lifecycle (e.g., HCV protease and polymerase inhibitors), other approaches are also under study. 

Cyclophilins are a family of enzymes that assist in the folding and transport of proteins synthesized within a cell; they also play a role in chronic viral infection and appear to facilitate HCV replication. Some cyclophilin inhibitors (such as cyclosporine A) have long been used to prevent organ rejection in transplant patients, but non-immunosuppressive cyclophilin inhibitor analogs may have therapeutic applications for a wide variety of diseases.

Debio 025

D.R. Nelson from the University of Florida and colleagues presented findings from a study of Debio 025, a first-in-class synthetic selective cyclophilin inhibitor being developed by Debiopharm Group in Switzerland. In previous studies, Debio 025 exhibited potent anti-HCV activity in treatment-naive hepatitis C patients and individuals with HIV-HCV coinfection.

In the present study, researchers evaluated different dosing regimens of Debio 025 in combination with pegylated interferon and ribavirin in genotype 1 chronic hepatitis C patients who were previously null responders, that is, experienced < 2 log₁₀ drop in HCV RNA after 12 weeks of standard therapy with pegylated interferon plus ribavirin.

In this Phase 2a trial, 50 patients were randomly assigned to receive Debio 025 plus 180 mcg/week pegylated interferon alfa-2a (Pegasys) with or without 1000/1200 mg/day weight-adjusted ribavirin in the following combinations for 29 days:

• Group A: pegylated interferon + ribavirin + 400 mg once-daily Debio 025;
• Group B: 400 mg once-daily Debio 025 monotherapy;
• Group C: pegylated interferon + 400 mg once-daily Debio 025 (without ribavirin);
• Group D: pegylated interferon + ribavirin + 800 mg once-daily Debio 025;
• Group E: pegylated interferon + ribavirin + 400 mg once-daily Debio 025 with initial loading dose (400 mg twice-daily for 7 days).

After the initial month of randomized therapy, all participants continued on pegylated interferon plus ribavirin for the standard duration.

Results

• Debio 25 monotherapy at a dose of 400 mg did not demonstrate antiviral activity in this population.
• The triple regimen of Debio 025 plus pegylated interferon and ribavirin demonstrated significant antiviral activity in previous null responders.
• Participants who received either 800 mg Debio 25 (Group D) or an initial loading dose (Group E) had a significant decrease in HCV RNA from baseline:

o   Group A: +0.88 log₁₀;

o   Group B: +0.29 log₁₀;

o   Group C: -0.61 log₁₀;

o   Group D: -2.38 log₁₀ (-99.5%);

o   Group E: -1.96 log₁₀ (-98.9%).

• The addition of a loading dose of Debio 025 in Group E produced antiviral activity that was 1.08 log₁₀ greater than that seen in Group A, which received the same combination without the loading dose (P = 0.033).
• Treatment with Debio 25 was generally well tolerated.
• 3 of 50 patients developed reversible bilirubin increases resulting in hyperbilirubinemia (total bilirubin > 3 mg/dL).

Based on these findings, the researchers concluded, "Debio 025 at doses of 400 mg (with initial loading) and 800 mg daily for 29 days shows a significant reduction of HCV RNA when co-administered with [pegylated interferon alfa-2a] and ribavirin in previous null responders. A loading dose of Debio 025 at the start of treatment accelerates the onset of action and enhances efficacy in the early stage of treatment."

"These results in patients who are highly unlikely to respond to re-treatment with an interferon-based regimen are very important to us, as they confirm that Debio 025 is a potent anti-HCV agent," said Debiopharm group president and founder Rolland-Yves Mauvernay in a press release issued by the company.

University of Florida, Gainesville, FL; Methodist Transplant Physicians, Dallas, TX; Johns Hopkins University School of Medicine, Baltimore, MD; University of Miami Center for Liver Diseases, Miami, FL; Metropolitan Research, Fairfax, VA; Scripps Clinic, La Jolla, CA; Virginia Mason Medical Center, Seattle, WA; Debiopharm SA, Lausanne, Switzerland.

SCY-635

S. Hopkinsand colleagues from SCYNEXIS presented data on SCY-635, a non-immunosuppressive analog of cyclosporine A that exhibits potent suppression of HCV RNA replication in vitro.

The present Phase 1b randomized, double-blind, placebo-controlled trial aimed to determine if SCY-635 monotherapy could suppress HCV viral load. The small study included 20 men (15 of them African-American, average age 53 years) with genotype 1 chronic hepatitis C and baseline plasma HCV RNA levels exceeding 100,000 IU/mL (average 5,600,000 IU/mL). Just over half (55%) were treatment-naive. Individuals with HIV coinfection, hepatitis B virus (HBV), decompensated liver function, or ALT values 2.5 times greater than the upper limit of normal were excluded.

Participants were sequentially enrolled into one of 3 ascending-dose cohorts, receiving total daily doses of 300, 600, or 900 mg SCY-635 administered orally in divided doses 3 times daily for 15 days. Within each cohort, patients were randomized to receive SCY-635 or placebo in a 6:1 ratio. Pharmacokinetic assessments and viral load monitoring were performed throughout the treatment period.

Results

• Greater than proportional increases in plasma exposure to SCY-635 were observed with increasing doses.
• Steady-state was achieved on day 3.
• In the 900 mg cohort, mean trough plasma concentrations of SCY-635 remained above the replicon-derived EC₉₀ value (90% effective concentration) from day 3 through day 15.
• Consistent decreases in HCV RNA were observed only in the 900 mg cohort.
• In the 900 mg cohort, all treated patients experienced a reduction in HCV viral load, with a group mean maximum decrease of 2.2 log₁₀ on day 15 (P < 0.05).
• 1 participant achieved undetectable HCV viral load on day 15.
• SCY-635 was generally well tolerated, with no serious adverse events or premature treatment discontinuations.
• Adverse events were similar across all dose cohorts.
• There were no trends in adverse events indicating potential dose-limiting toxicity.

These results led the investigators to conclude, "The demonstration of clinically relevant suppression of plasma [HCV] RNA in the absence of dose-limiting toxicity establishes proof of concept for SCY-635 as a new anti-viral agent for treating individuals with chronic hepatitis C infection."

“In this single-agent study SCY-635 demonstrated highly potent antiviral activity that was sustained throughout treatment with the nadir occurring on the last day of the study, suggesting that with a longer treatment period we may see even greater reductions in viral load,” said SCYNEXIS chief scientific officer Sam Hopkins in a company press release. “These clinical results combined with earlier preclinical work demonstrating additive or synergistic activity with both approved and investigational agents suggest that in a combination regimen, SCY-635 may improve rates of sustained virological response.”

Research, Scynexis Inc, Durham, NC; Hepatology, McGuire VA Medical Center, Richmond, VA; Clinical Development, Quest Clinical Research, San Francisco, CA.

5/15/09

References

DR Nelson, RH Ghalib, M Sulkowski, and others. Efficacy and Safety of the Cyclophilin Inhibitor Debio 025 in Combination with Pegylated Interferon Alpha-2a and Ribavirin in Previously Null-Responder Genotype 1 HCV Patients. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

S Hopkins, D Heuman, E Gavis, and others. Safety, Plasma Pharmacokinetics, and Anti-viral Activity of SCY-635 in Adult Patients with Chronic Hepatitis C Virus Infection. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

Other Sources

Debiopharm Group. Clinical Update -- Debio 025 in Hepatitis C Debiopharm Presents Promising Phase IIa Results Showing Potent Antiviral Activity. Press release. April 28, 2009.

SCYNEXIS. SCYNEXIS’ SCY-635 Demonstrates Clinically Relevant Single-Agent Results in a Phase 1b Study in Adults with HCV. Press release. April 27, 2009.