Today on the blog is an abstract from Medscape showing data on a small phase II study using the interferon free combo BMS-790052-Daclatasvir/BMS-650032-Asunaprevir. Last month an interesting article discussing concerns about the study appeared at Medical Lessons. The author Elaine Schattner, MD., points us to the phase II study published at New England Journal of Medicine, the author writes:
A recent New England Journal of Medicine delivered an intriguing, imperfect article on a new approach to treating hepatitis C (HCV). The paper's careful title, Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1, seems right. The analysis, with 17 authors listed, traces the response of 21 people with hepatitis C (HCV) who got two new anti-viral agents, with or without older drugs, in a clinical trial sponsored by Bristol-Meyers Squibb.
I have several concerns about this report. One is that the researchers screened 56 patients for possible registration but enrolled only 21 on the trial; according to a supplementary Figure 1, 35 potential subjects (over half) didn't meet criteria for eligibility. This disparity makes any once-researcher wonder about bias in selecting patients for enrollment. If you're a pharmaceutical company and want to show a new drug or combo is safe, you're going to pick patients for a trial who are least likely to experience or display significant toxicity.
Toxicity seems like it could be problematic. Diarrhea, fatigue and headaches were common among the study subjects. Worrisome is that six patients (of 21, that would be 28.5% of those on the trial) had liver problems manifest by at least one enzyme (the ALT) rising over three times the normal limit.
If you're interested today the article was posted at ACP Internist.
From Journal Watch > Journal Watch Gastroenterology
New Antivirals Show Promise for an Interferon-free Hepatitis C Treatment
Atif Zaman, MD, MPH
Posted: 02/28/2012; Journal Watch © 2012 Massachusetts Medical Society
Patients with HCV genotype 1 and previous null response achieved a 36% sustained virologic response at 24 weeks of therapy with daclatasvir and asunaprevir alone.
The current generation of direct acting antivirals (DAAs), telaprevir and boceprevir, in combination with peginterferon and ribavirin (PEG/RBV) have demonstrated limited efficacy in patients with hepatitis C virus (HCV) genotype 1 infection who have experienced a previous null response to PEG/RBV. Sustained virologic response (SVR) has been approximately 30%, with associated high rates of resistance. Now, researchers have explored the efficacy of two next-generation DAAs with and without PEG/RBV in this patient population.
This phase IIa, industry-sponsored, randomized study involved 21 patients with previous null response to PEG/RBV (defined as <2 log HCV RNA drop from baseline at 12 weeks).
Eleven patients received 60 mg daily of daclatasvir (an NS5A replication complex inhibitor) and 600 mg twice daily of asunaprevir (an NS3 protease inhibitor) for 24 weeks (DAA-only group).
Ten patients received both DAAs and PEG/RBV for 24 weeks (DAA+PEG/RBV group). Of note, 90% of the study cohort had IL28B genotypes CT or TT, which respond poorly to PEG/RBV. The primary endpoint was SVR at 12 weeks after stopping therapy.
The SVR in the DAA-only group was 36% (2 of 9 with genotype 1a and 2 of 2 with genotype 1b). Six patients, all with genotype 1a, had viral breakthrough that was associated with viral resistance mutations to both DAAs.
Alternately, the SVR in the DAA+PEG/RBV group was 100% (90% with genotype 1a) at 12 weeks after therapy and 90% at 24 weeks. Most adverse events were mild to moderate and included diarrhea, fatigue, headache, and nausea.
These findings provide early evidence that the next generation of DAAs is more potent than the current generation in treating HCV genotype 1 infection.
In this cohort of the most difficult-to-treat HCV patients — previous null responders with genotype 1 infection — a 24-week SVR of 90% was achieved after 24 weeks of quadruple therapy (2 DAAs and PEG/RBV). Even an interferon-free regimen of the 2 DAAs resulted in an SVR of 36%.
Results are eagerly anticipated from the phase III trial currently under way.