Boosted Narlaprevir plus Pegylated Interferon and Ribavirin Leads to Rapid Viral Suppression in Genotype 1 Hepatitis C Patients

		SUMMARY: In the NEXT-1 study, presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) last week in Boston, the experimental HCV NS3 protease inhibitor narlaprevir (formerly SCH 900518), boosted with ritonavir, demonstrated potent antiviral activity in combination with pegylated interferon and ribavirin among treatment-naive patients with genotype 1 chronic hepatitis C. Across the doses tested, 53% to 87% of narlaprevir recipients achieved undetectable HCV RNA by week 4. Nalraprevir/ritonavir demonstrated no unique or treatment-limiting adverse effects.

The NEXT-1 study was conducted to identify the optimal treatment regimen of ritonavir-boosted narlaprevir/pegylated interferon/ribavirin combination therapy, and to compare outcomes against those using pegylated interferon/ribavirin alone. The inclusion of pegylated interferon and ribavirin is expected to reduce the emergence of resistance that can occur when directly-targeted antiviral agents are used as monotherapy.

The study included 111 previously untreated chronic hepatitis C patients treated in the U.S. About 60% were men, most (72% to 95% in the various treatment arms) were white, 13% were black, and the average age was about 45 years. About three-quarters (78%) had high baseline viral load (> 600,000 IU/mL) and 61% had genotype 1a.

Using a response-guided treatment strategy, participants received 12 weeks of narlaprevir at doses of 200 or 400 mg once-daily or 100 mg twice-daily, boosted with 100 mg ritonavir per dose, plus 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 600-1400 mg/day weight-adjusted ribavirin. Some participants received pegylated interferon/ribavirin for a 4-week lead-in period before starting narlaprevir. Based on response at week 4 of narlaprevir, study protocol called for 12 or 36 additional weeks of pegylated interferon/ribavirin. Narlaprevir regimens were compared with standard therapy using pegylated interferon/ribavirin.

The primary study endpoint was rapid virological response (RVR), or undetectable HCV-RNA at week 4, as well as response at week 12.

Results

	Through week 4, participants in the triple therapy lead-in arms had higher response rates that those who did not have a lead-in period.
	By week 12, however, there was no difference in the rates of patients who achieved undetectable HCV RNA in the lead-in and no lead-in arms.
	All null responders in the lead-in arms (<1 log10 drop in HCV RNA after 4 weeks of pegylated interferon/ribavirin) responded well to the addition of narlaprevir, achieving undetectable viral load at week 4.
	9 of these patients still had undetectable HCV RNA at week 12. 2 participants in the 200 mg once-daily narlaprevir arm experienced virological breakthrough by week 8.
	Narlaprevir combination therapy was well-tolerated overall.
	Adverse events included gastrointestinal symptoms, lethargy, elevated liver enzymes, and loss of appetite, and psychiatric symptoms.
	Adverse events generally occurred with similar frequency, except anemia and dizziness were more common in the narlaprevir arms.

	P/R	P/R NVR200QD	P/R NVR400QD	LI P/R NVR200QD	LI P/R NVR400QD	P/R NVR100BID
LI Wk 4	NA	NA	NA	6%	5%	NA
P/R/N Wk 1	ND	15%	0%	60%	50%	6%
P/R/N Wk 2	0%	35%	16%	80%	60%	29%
P/R/N Wk 4	0%	75%	58%	87%	85%	53%
P/R/N Wk 12	17%	85%	84%	87%	85%	65%

* Patients with at least 1 dose of narlaprevir, excluding P/R control arm

P/R = pegylated interferon/ribavirin; N = narlaprevir/ritonavir; NVR200QD = narlaprevir 200 mg once-daily; NVR400QD = narlaprevir 400 mg once-daily; NVR100BID = narlaprevir 100 mg twice-daily; LI = pegylated interferon/ribavirin lead-in; NA = not applicable; ND = not determined.

Based on these findings, the study investigators concluded that narlaprevir "has potent antiviral activity" against HCV, and the addition of once-daily narlaprevir "greatly improved viral clearance at week 4" compared with a standard-of-care pegylated interferon/ribavirin regimen in genotype 1 hepatitis C patients.

"These interim results, while preliminary, are very encouraging, and showed that narlaprevir has potent antiviral activity in hepatitis C," lead investigator John Vierling, MD, from Baylor College of Medicine said in a press release issued by Schering-Plough. "In this study, once-daily narlaprevir greatly improved viral clearance at week 4 of treatment in genotype 1 hepatitis C infection compared to the control group. We look forward to further results from this ongoing study."

11/10/09

Reference
JM Vierling, F Poordad, E Lawitz, and others. Once daily narlaprevir (SCH 900518) in combination with PegIntron (peginterferon alfa-2b)/ribavirin for treatment-naive subjects with genotype-1 CHC: interim results from NEXT-1, a phase 2a study. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract LB4.

Other source
Schering-Plough Corporation. Schering-Plough Reports Potent Antiviral Activity With Narlaprevir (SCH 900518), an Investigational, Once-Daily Protease Inhibitor for Hepatitis C. Press release. November 2, 2009.