By Michael Smith, North American Correspondent, MedPage Today
Published: April 28, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
AMSTERDAM -- An investigational protease inhibitor for hepatitis C (HCV) achieved high response rates in treatment-naive patients when given in what one expert called an "old-fashioned" regimen.
The drug (MK-5172) rendered the virus undetectable 24 weeks after the end of therapy in almost 90% of patients with the difficult-to-treat HCV genotype 1, according to Michael Manns, MD, of Hannover Medical School in Hannover, Germany.
In contrast, treatment with an approved protease inhibitor, boceprevir (Victrelis), led to an SVR24 in just 54%, Manns reported at the meeting of the European Association for the Study of the Liver (EASL).
But both drugs were combined with pegylated interferon and ribavirin, medications that are widely regarded as likely to fade from practice as a range of investigational direct-acting agents reaches the clinic.
The direct-acting agents, such as boceprevir and MK-5172, attack elements of the virus, in contrast to interferon and ribavirin, which respectively boost the immune system and target general viral replication.
Both have a range of unpleasant side effects and interferon in particular is seen as both difficult to tolerate and dangerous to use.
MK-5172 "is a very good drug," commented Alessio Aghemo, MD, of the University of Milan in Italy, who was not involved with the study but who moderated the EASL session at which it was presented.
But he told MedPage Today that clinicians and researchers are withholding judgment until it is tested without interferon and perhaps without ribavirin.
"The SVR rates are high with (interferon and ribavirin) but it's an old-fashioned regimen," he said. "It needs to go into an interferon-free regimen."
The study, Manns reported, included 332 treatment-naïve patients with genotype 1 virus and without cirrhosis. They were randomly assigned to one of four doses (100, 200, 400, or 800 mg) of MK-5172 or to boceprevir as a control. All patients also received pegylated interferon, and ribavirin for durations that varied according to early treatment response.
Manns presented data on the proportion of patients in each arm who reached SVR24 or who had undetectable virus at their last visit if that occurred before they completed 24 weeks after the end of therapy.
When the data were compiled in March, 311 patients had either reached the 24-week mark or had dropped out of the study before then, but all patients had completed treatment.
Analysis showed that the SVR24 rates in the MK-5172 arms ranged from 86% to 92%, compared with 54% in the boceprevir arm.
When the researcher added those who had not reached the 24-week mark, but who had undetectable virus at their last study visit, the rates ranged from 92% to 99% for MK-5172 and rose to 67% in the boceprevir arm.
Interestingly, there was little variation when the researchers stratified patients by polymorphisms of the IL28B gene, which predicts response to interferon, although the favorable CC allele tended to yield slightly better response rates numerically.
Manns noted that some patients getting higher doses of MK-5172 (400 and 800 mg ) were "down-dosed" to 100 mg daily, which will be the dose used in future studies.
There were no deaths on the study and the rates of serious adverse events were similar – 9% in the combined MK-5172 arms and 8% in the boceprevir arm, Manns said. Adverse events included gastrointestinal problems, rash, and anemia.
Only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.
A total of 26 patients had bilirubin elevations, possibly because MK-5172 inhibitors some transporter molecules and enzymes, he said. The elevations mostly occurred early and were not associated with decreases in hemoglobin.
In general, the drug was well tolerated but the investigators noted dose-related elevations in liver enzymes, he said.
The study was supported by Merck. Manns reported financial links with the company, as well as with Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche, Idenix, and Valeant.
Aghemo reported financial links with Roche, Gilead, Jannsen, and Merck.
Primary source: EASL 2013
Source reference:
Manns M, et al. "High Sustained Viral Response at 12- and 24-Week Follow-Up of MK-5172 with Pegylated Interferon Alfa-2B and Ribavirin (PR) in HCV Genotype Treatment-Naive Non-Cirrhotic Patients" EASL 2013;abstract 66.
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