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Boceprevir for Untreated Chronic HCV Genotype 1 Infection

N Engl J Med 2011; 364:1195-1206March 31, 2011
http://www.nejm.org/doi/full/10.1056/NEJMoa1010494?query=TOC

Fred Poordad, M.D., Jonathan McCone, Jr., M.D., Bruce R. Bacon, M.D., Savino Bruno, M.D., Michael P. Manns, M.D., Mark S. Sulkowski, M.D., Ira M. Jacobson, M.D., K. Rajender Reddy, M.D., Zachary D. Goodman, M.D., Ph.D., Navdeep Boparai, M.S., Mark J. DiNubile, M.D., Vilma Sniukiene, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Jean-Pierre Bronowicki, M.D., Ph.D. for the SPRINT-2 Investigators

Background
Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.

Methods
We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon–ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon–ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.

Results
A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon–ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.

Conclusions
The addition of boceprevir to standard therapy with peginterferon–ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.)

The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.

Supported by Schering-Plough (now Merck).

Dr. Poordad reports receiving consulting fees from Merck, Vertex, Abbott, Gilead, Achillion, Genentech, and Tibotec; grant support from Merck; and payment for development of educational presentations from Merck. Dr. McCone reports receiving lecture fees and speaker's fees from Schering-Plough (now part of Merck). Dr. Bacon reports receiving consulting fees from Gilead, Three Rivers Pharmaceuticals, Valeant, Vertex, and Human Genome Sciences; grant support from Roche, Gilead, Bristol-Myers Squibb, Three Rivers Pharmaceuticals, Valeant, Vertex, Human Genome Sciences, Wyeth, and Romark Laboratories; and lecture or speaker's fees from Three Rivers Pharmaceuticals, Gilead, and Schering-Plough (now part of Merck); as well as having served on data and safety monitoring boards for Novartis, Isis, Vertex, and Gilead. Dr. Manns reports receiving consulting fees from Schering-Plough (now part of Merck), Roche, Bristol-Myers Squibb, Gilead, Valeant, Boehringer Ingelheim, Novartis, Idenix, Tibotec, Vertex, GlaxoSmithKline, and Merck; grant support from Schering-Plough (now part of Merck), Roche, Gilead, Novartis, Boehringer Ingelheim, and Bristol-Myers Squibb; and payment for development of educational presentations from Schering-Plough (now part of Merck), Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Gilead. Dr. Sulkowski reports receiving consulting fees from Vertex, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Pharmasset, Abbott, Tibotec, Roche, and Gilead; fees for expert testimony from Abbott; and grant support from Vertex, Abbott, Boehringer Ingelheim, Tibotic, Gilead, Pharmasset, Zymogenetics, Bristol-Myers Squibb, Orasure, Achillion, and Roche. Dr. Jacobson reports receiving consulting fees from Bristol-Myers Squibb, Novartis, Gilead, Schering-Plough (now part of Merck), Pfizer, Vertex, GlobeImmune, Human Genome Sciences, Boehringer Ingelheim, Pharmasset, Zymogenetics, Tibotec, Abbott, Roche–Genentech, Anadys, Sanofi-Aventis, Achillion, GlaxoSmithKline, and Biolex; grant support from Schering-Plough (now part of Merck), Tibotec, Roche–Genentech, Pharmasset, Anadys, Boehringer Ingelheim, Novartis, Gilead, Vertex, GlobeImmune, Human Genome Sciences, Pfizer, Bristol-Myers Squibb, and Zymogenetics; lecture or speaker's fees from Schering-Plough (now part of Merck), Gilead, Bristol-Myers Squibb, and Roche–Genentech; and payment for development of educational presentations from Bristol-Myers Squibb, Gilead, and Vertex. Dr. Reddy reports receiving consulting fees from Roche, Merck, Salix, Vertex, Tibotec, and Human Genome Sciences; grant support from Roche, Vertex, Tibotec, Bristol-Myers Squibb, and Gilead; and payment for development of educational presentations from ViralEd. Dr. Goodman reports receiving consulting fees from Merck and Gilead Sciences; grant support from Schering-Plough (now part of Merck), GlaxoSmithKline, Bristol-Myers Squibb, Novartis, GlobeImmune, Gilead Sciences; and lecture or speaker's fees from Bristol-Myers Squibb. Ms. Boparai and Drs. DiNubile, Sniukiene, Brass, and Albrecht report being employees of Merck and owning stock or stock options in the company. Dr. Bronowicki reports receiving fees for board membership from Schering-Plough (now part of Merck), Roche, Gilead, Bristol-Myers Squibb, Janssen, and Bayer; consulting fees from Merck, Boehringer Ingelheim, and Novartis; lecture or speaker's fees from Schering-Plough (now part of Merck), Roche, Bayer and Bristol-Myers Squibb; and reimbursement for travel expenses from Roche. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.