Experimental HCV Protease Inhibitor SCH 900518, with or without Pegylated Interferon, Appears Safe and Exhibits Good Antiviral Activity

By Liz Highleyman

In an effort to improve upon the effectiveness of standard treatment for chronic hepatitis C virus (HCV) infection using pegylated interferon plus ribavirin, researchers have explored agents that directly target various steps of the viral lifecycle, an approach known as STAT-C.

One such agent is SCH 900518, Schering-Plough's novel HCV NS3 protease inhibitor, a successor to boceprevir. Data from 4 preclinical and early clinical studies of SCH 900518 were presented last week at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) in Copenhagen.

The early clinical study included 40 genotype 1 chronic hepatitis C patients, some who were treatment-naive and some who did not achieve sustained response to prior interferon-based therapy.

In this 2-period proof-of-concept study, participants first received SCH 900518 as a suspension for 7 days, at doses of 800 mg 3 times per day or 400 mg twice-daily with ritonavir (as is the case with HIV protease inhibitors, ritonavir can "boost" levels of telaprevir by slowing its processing in the body). After a 4 week washout period, SCH 900518 was administered at the same dose in combination with pegylated interferon alfa-2b (PegIntron) for 14 more days.

Results

Both dose regimens resulted in SCH 900518 plasma trough (lowest) concentrations above the 90% effective concentration (EC90) as determined by previous laboratory studies.

The estimated SCH 900518 half-life was found to be 5 hours when administered alone and 16 hours when administered with ritonavir.

Treatment-naive and previously treated patients both experienced rapid and continuous declines in plasma HCV RNA during 7 days of SCH 900518 monotherapy (with or without ritonavir).

At day 8, HCV RNA levels were 4.0-4.5 log10 lower than baseline.

A majority of both treatment-naive and experienced patients achieved undetectable HCV RNA (< 25 IU/mL) by day 15 of the combination therapy period:

Treatment-naive 800 mg SCH 90015: 75%;

Treatment-naive 400 mg SCH 90015 + ritonavir: 63%;

Treatment-experienced 800 mg SCH 90015: 50%;

Treatment-experienced 400 mg SCH 90015 + ritonavir: 50%.

Overall, SCH 900518 was well-tolerated, with no drug related serious adverse events considered related to the drug (1 patient had a high fever during follow-up treatment with pegylated interferon/ribavirin).

No clinically significant changes from baseline in vital signs, laboratory values, or ECG were observed.

Resistance mutations were detected in 2 treatment-experienced non-responders receiving SCH 900518 plus ribavirin (V36, R155, and A156).

Based on these findings, the investigators concluded, "SCH 900518 administered alone or in combination with PegIntron was safe and well tolerated. Robust reductions in plasma HCV RNA levels were achieved in both treatment-experienced and naive HCV genotype 1-infected patients."

According to a press release from Schering-Plough, pharmacokinetic data from this trial were used to design an ongoing Phase 2a dose-finding study of SCH 900518 plus ritonavir in combination with PegIntron and ribavirin, known as NEXT-1.

Preliminary results from the Phase 2 study indicate that among treatment-naive patients receiving 200 mg twice-daily SCH 900518 plus 100 mg ritonavir with PegIntron and ribavirin, 95% achieved rapid virological response (RVR), or undetectable HCV RNA (< 25 IU/mL) at week 4 of therapy.

Hepatology, Academic Medical Center, Amsterdam, Netherlands; Hepatology, Erasmus MC University Hospital, Rotterdam, Netherlands; PRA International, Zuidlaren, Netherlands, SPRI, Schering-Plough, Kenilworth, NJ.

5/01/09

References

H Reesink, J Bergmann, J de Bruijne, and others. Safety and antiviral activity of SCH 900518 administered as monotherapy and in combination with peginterferon alfa-2b to naive and treatment-experienced HCV infected patients. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Abstract 86.

X Tong, A Arasappan, F Bennett, and others. Preclinical characterization of SCH 900518, a novel mechanism-based inhibitor of HCV NS3 protease. EASL 2009. Copenhagen, Denmark. April 22-26, 2009. Abstract 967.

E Hughes, Y Wan, MA Treitel, and others. A regional gastrointestinal absorption study of the HCV NS3 protease inhibitor SCH 900518 in healthy volunteers. EASL 2009. Copenhagen, Denmark. April 22-26, 2009. Abstract 948.

E Hughes, M Treitel, S Gupta, and others. A single- and multiple-dose assessment of the safety and pharmacokinetics of SCH 900518 and its effect on the pharmacokinetics of midazolam in healthy subjects. EASL 2009. Copenhagen, Denmark. April 22-26, 2009. Abstract 949.

Other Source

Schering-Plough. Final Results of Boceprevir Phase II HCV SPRINT-1 Study Showed Significantly Higher SVR Rates Compared to Standard of Care in Treatment-Naive Genotype 1 Hepatitis C Patients. Press release. April 23, 2009.

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15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
Coverage by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
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