Last week’s NEJM 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.
The 21 study participants all had chronic infection by HCV genotype 1, a strain that’s common in North America and relatively resistant to standard treatment. All subjects were between 18 and 70 years old, with a measurable level of HCV RNA in the blood, no evidence of cirrhosis, and no response to prior HCV treatment (according to criteria detailed in the paper). In the trial, 11 patients received a combination regimen of daclatasvir (60 mg once daily, by mouth) and asunaprevir (600 mg, twice daily by mouth) alone; the other 10 patients took the experimental drugs along with 2 older meds for HCV - Peginterferon (Pegasys, an injectible drug by Roche) and Ribavirin (Copegus, a pill, by Roche).
The main finding is that the 10 patients assigned to take 4 drugs all did strikingly well in terms of reducing detectable HCV in their blood over the course of 24 weeks. There was a dramatic response, also, in 4 of the 11 patients assigned to the new drugs only. An accompanying editorial highlighted the work as a Watershed Moment in the Treatment of Hepatitis C. The medical significance is that they’ve demonstrated proof of principle: by “hitting” a resistant HCV strain with multiple anti-viral drugs simultaneously, they could reduce it to undetectable levels.
The first question you have to ask about this report is why the NEJM – the most selective of medical journals — would publish findings of an exploratory analysis of two new pills paired with two older drugs for HCV. The best answer, probably, is that the virus infects some 4 million people in the U.S. and approximately 180 million people worldwide, according to the study authors. HCV can cause liver damage, cirrhosis, liver cancer (which is usually fatal) and, occasionally blood disorders.
The new drugs derive from some interesting science. This, maybe, also is a factor in why the article was published in the NEJM. Daclatasvir (BMS-790052) blocks a viral protein, NS5A, that’s essential for HCV replication. The second new drug, asunaprevir (BMS-650032) inhibits a viral protease, NS3.
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 6 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 3 times the normal limit.
Given all these limitations, you might wonder about BMS’s influence at the Journal or, more likely, the manuscript’s peer reviewers. The 17 study authors, and the editorialist, separately, disclose a host of industry ties.
What I’m thinking, as much as I’m critical of this research work, is that this is probably the way of the future – smaller, pharma-funded studies of targeted new drugs in complicated combinations. Many will be authored by academics with ties to industry, if not put forth directly by company-employed researchers. These quick-and-promising studies in select patient groups will be routine. And while advocates push for rapid publication of new clinical research in patients with resistant, disabling diseases, it’ll be hard for physicians and patients to interpret these kinds of data.
So these particular findings may turn out to be true and life-saving, or not. The bigger concern is this: It would be helpful if the journals would take a really tough stance on full disclosure of authors and editors ties to industry. As Merrill Goozner has emphasized, the Physician Payment Sunshine Act – a small component of the 2010 HCR legislation — has important implications for academic medicine and reporting of clinical research studies.