SUMMARY: Final results from 2 pivotal Phase 3 clinical trials presented at the American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) this week in Boston showed that adding Merck's experimental hepatitis C virus (HCV) NS3 protease inhibitor boceprevir to standard therapy increased the likelihood of sustained virological response for both previously untreated and treatment-experienced genotype 1 chronic hepatitis C patients.

By Liz Highleyman

Current standard therapy for chronic hepatitis C consists of pegylated interferon plus ribavirin for 24 weeks (HCV genotypes 2 and 3) or 48 weeks (genotypes 1 or 4). Interferon-based therapy can cause difficult side effects, however, and only about half of people with hard-to-treat HCV genotype 1 achieve a cure.

The first novel oral drugs that directly target steps of the viral lifecycle -- such as HCV protease and polymerase inhibitors -- are in the final stages of development. Most studies to date have looked at these agents in combination with pegylated interferon plus ribavirin. These direct-acting agents are often tested in genotype 1 prior non-responders who did not achieved a cure with previous interferon-based therapy, since they are most difficult to treat and stand to benefit most from new treatment options.

A pair of HCV protease inhibitors -- Merck's boceprevir and Vertex's telaprevir -- are furthest along in the development pipeline, and many experts expect that they will be approved next year.

RESPOND-2

The Phase 3 RESPOND-2 study included 403 treatment-experienced genotype 1 patients in the U.S., Canada, and Europe. Participants included prior null responders (no notable decrease in HCV viral load), non-responders (some decrease, but not undetectable), and relapsers (undetectable at the end of treatment followed by viral rebound). About two-thirds were men, 12% were black -- a group that responds more poorly to interferon -- and 12% had liver cirrhosis (another predictor of poor response).

All participants initially took a standard therapy regimen of 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron) plus 600-1400 mg/day weight-adjusted ribavirin for a 4-week lead-in period. After this, they were randomly assigned to continue on pegylated interferon/ribavirin, either alone or in combination with 800 mg 3-times-daily boceprevir.

Boceprevir recipients were assigned to either receive triple combination therapy for a fixed duration of 44 more weeks of (total 48 weeks), or to use a response-guided therapy strategy in which the total duration was determined based on early response. Patients with undetectable HCV RNA viral load at weeks 8 and thereafter were eligible to stop all treatment at week 36. Those with detectable viral load at week 8 but not at week 12 also stopped boceprevir at week 36, but continued on pegylated interferon/ribavirin through week 48. Anyone who still had detectable HCV RNA at week 12 discontinued all therapy due to the likely futility of further treatment.

Results

	In an intent-to-treat analysis, patients using boceprevir had a significantly higher rate of sustained virological response (SVR), or continued undetectable HCV RNA at 24 weeks after completion of treatment:
	Standard therapy without boceprevir: SVR 21%; Response-guided therapy with boceprevir: 59% (37% improvement); Fixed-duration therapy with boceprevir: 67% (45% improvement).
	In all arms, previous relapsers and non-responders had higher SVR rates than prior null responders:
	Standard therapy without boceprevir: 29%, 7%, and 0%, respectively; Response-guided therapy with boceprevir: 69%, 40%, and 33%, respectively; Fixed-duration therapy with boceprevir: 75%, 52%, and 34%, respectively.
	Prior null responders in both response-guided and fixed-duration boceprevir arms had significantly higher SVR rates than those receiving standard therapy.
	46% of patients in the response-guided therapy arm met the early response criteria and were eligible to stop all treatment at 36 weeks; the SVR rate for this subgroup was 86% (versus 88% with fixed-duration boceprevir).
	The highest SVR rate -- 80% -- was seen among patients who had at least a 1 log drop in HCV RNA at week 4 following the lead-in and received boceprevir for 44 weeks.
	Relapse rates were 32% in the standard therapy arm, 15% in the boceprevir response-guided therapy arm, and 12% in the boceprevir fixed-duration arm.
	Rates of discontinuation due to adverse events were 3% in the standard therapy arm, 8% in the boceprevir response-guided arm, and 12% in the boceprevir fixed-duration arm.
	The most common treatment-related adverse events were fatigue, headache, nausea, chills, and flu-like illness -- all symptoms of interferon -- occurring at similar rates in all arms.
	Anemia, however, was more common in the response-guided and fixed-duration boceprevir arms (43% and 46%) than in the standard therapy arm (20%); 41%, 46%, and 21%, respectively, used erythropoietin to manage anemia.
	There were no discontinuations due to skin rash, a potential boceprevir side effect.

"Boceprevir added to [pegylated interferon/ribavirin] leads to high SVR rates in genotype 1 previous non-responders and relapsers to [pegylated interferon/ribavirin] therapy, with significant but lower response rates in 'null' responders," the RESPOND-2 investigators concluded. "This therapy was generally well tolerated, and offers substantial benefit to patients who failed prior [pegylated interferon/ribavirin] therapy."

"In the study of patients who failed prior treatment, boceprevir combination therapy helped the majority of patients achieve sustained virologic response, the goal of treatment," co-principal investigator Bruce Bacon from Saint Louis University School of Medicine said in a press release issued by Merck. "We observed that many patients in the boceprevir response-guided therapy arm were able to have their treatment duration reduced by 3 months compared to current standard duration of treatment."

SPRINT-2

The Phase 3 SPRINT-2 study included 1097 treatment-naive genotype 1 patients. Participants were divided into cohorts according to race, since people of African descent do not respond as well to interferon. One cohort included 159 African-American/black patients (about 15%), while the other included 938 people of other racial/ethnic groups ("non-black"). More than 90% had high HCV viral load (> 400,000 IU/mL) and 9% had advanced (stage F3-F4) liver fibrosis.

As with RESPOND-2, participants in SPRINT-2 were randomly assigned to receive the same doses of pegylated interferon alfa-2b plus ribavirin either alone or with boceprevir. This study also assigned some patients to a fixed-duration 48-week course of treatment and others to response-guided therapy; in this study, however, people with undetectable HCV viral load at week 8 were eligible to stop all treatment at 28 weeks. Patients with detectable HCV RNA at week 24 discontinued due to likely futility.

Results

	In an intent-to-treat analysis, SVR rates were again significantly higher in the boceprevir arms:
	Standard therapy without boceprevir: 38% (40% for non-blacks and 23% for blacks); Response-guided therapy with boceprevir: 63% (67% and 42%, respectively); Fixed duration therapy with boceprevir: 66% (69% and 53%, respectively).
	44% of patients in the response-guided therapy arm met the early response criteria and were eligible to stop all treatment at 28 weeks; SVR rates in this subgroup were 97% for non-blacks and 87% for blacks (versus 96% and 95%, respectively, with fixed-dose boceprevir).
	Relapse rates were as follows:
	Standard therapy without boceprevir: 23% for non-blacks and 14% for blacks; Response-guided therapy with boceprevir: 9% and 12%, respectively; Fixed duration therapy with boceprevir: 8% and 17%, respectively.
	Rates of discontinuation due to adverse events were 16% in the standard therapy arm, 12% in the boceprevir response-guided arm, and 16% in the boceprevir fixed-duration arm.
	The most common side effects were similar to those reported by treatment-experienced patients, again affecting similar proportions of participants in all arms.
	Again, anemia was more common in the boceprevir arms (49% for both) than in the standard therapy arm (29%); 13% and 21%, respectively, reduced drug doses, and 1% and 2%, respectively, discontinued therapy early for this reason.

"[Boceprevir/pegylated interferon/ribavirin] significantly increased SVR in both the [response-guided therapy] and 48-week treatment arms over standard of care by ~70%," the SPRINT-2 team concluded. "Compared to 44 weeks of triple therapy after the lead-in period, [response-guided therapy] produced comparable SVR [rates]."

"Boceprevir was well tolerated," they added. "[A]lthough reported more often in boceprevir recipients, anemia rarely led to treatment discontinuation."

"In these studies, boceprevir response-guided therapy provided physicians flexibility in the management of their patients' HCV therapy, which enabled them to adapt treatment duration based on individual patient response," said co-principal investigator Fred Poordad from Cedars-Sinai Medical Center in a Merck press release. "These studies were designed with a 4-week lead-in strategy that was intended to help physicians identify their patients' responsiveness to interferon prior to the addition of a protease inhibitor, which provided an early indication of the likelihood of treatment success."

"We are excited by the results of these pivotal studies," Peter Kim, President of Merck Research Laboratories, said in the company press release. "In these studies, boceprevir substantially increased success rates compared to standard therapy, both for patients who received 48 weeks of treatment and for patients treated with the response-guided therapy approach, many of whom were able to be treated for 28 to 36 weeks."

Based on these data, he added, Merck has initiated a rolling submission of a New Drug Application (NDA) for boceprevir to the U.S. Food and Drug Administration (FDA), with completion expected by the end of 2010.

Investigator affiliations:

Bacon study (RESPOND-2): Saint Louis University School of Medicine, St. Louis, MO; Henry Ford Hospital, Detroit, MI; Alamo Medical Research, San Antonio, TX; University Paris 7-Hôpital Beaujon, Clichy, France; Baylor College of Medicine, Houston, TX; Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; Cedars-Sinai Medical Center, Los Angeles, CA; Merck, Whitehouse Station, NJ; Hospital General Universitario Vall d'Hebron, Barcelona, Spain. Poordad and Bronowicki studies (SPRINT-2): Cedars-Sinai Medical Center, Los Angeles, CA; Gastroenterology/Hepatology Certified Endoscopy Centers, Alexandria, VA; St. Louis University School of Medicine, St. Louis, MO; University of Milan, Milan, Italy; Medical School of Hannover, Hannover, Germany; Johns Hopkins School of Medicine, Baltimore, MD; Joan Sanford I. Weill Medical College of Cornell University, New York, NY; University of Pennsylvania, Philadelphia, PA; Merck, North Wales, PA; Centre Hospitalier Universitaire de Nancy-Brabois, Vandoeuvre-lès-Nancy, France.

11/2/10

References

BR Bacon, SC Gordon, E Lawitz, and others. HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PegIntron (Peginterferon alfa-2b)/Ribavirin. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 216.

F Poordad, J McCone, BR Bacon, and others. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naive Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-4.

J Bronowicki, J McCone, BR Bacon, and others. Response-Guided Therapy (RGT) with Boceprevir (BOC) + Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1 Was Similar to a 48-Wk Fixed-Duration Regimen with BOC + P/R in SPRINT-2. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-15.

Other Source
Merck. Merck's Investigational Medicine Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure and Treatment-Naive Adult Patients with Chronic Hepatitis C Genotype 1 Compared to Control. Press release. October 30, 2010.