HCV Protease Inhibitor SCH 900518, with or without Pegylated Interferon, Appears
Safe and Exhibits Good Antiviral Activity
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.
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.
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
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.
Both dose regimens resulted in SCH 900518 plasma trough (lowest) concentrations
above the 90% effective concentration (EC90) as determined by previous laboratory
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
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).
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.
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,
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.
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.
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.
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.
2009 MAIN PAGE
2009 Conference Coverage
HIV and Hepatitis.com Highlights from EASL 2009
Conference on Retroviruses and Opportunistic Infections (CROI 2009)
by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
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