Zepatier Clinical Trials: Why They Matter
This is not a scientific report. It is a layperson’s explanation of the importance of how Merck conducted its Zepatier clinical trials. It is meant to contrast Merck’s approach to research with that of other recently approved HCV DAA drugs. It contains no statistics, although overall cure rates in each cohort was 90+%. It is a report on how this company worked to include as many difficult-to-treat patients as possible. On the Zepatier website, Merck states its “unwavering commitment to the eradication” of the hepatitis C virus.
The world of late-phase HCV clinical trials is a tightly controlled one. To qualify, the patient must meet rigorous lab requirements. If the patient’s labs are off either way by as little as a decimel, it means disqualification. There is a well thought-out reason for this approach: good numbers are a necessary step down the road to FDA approval. Admit only patients with the highest probability for success; avoid the risky ones. This paradigm produces the lowest number of failures, and the highest number of cures.
This trial paradigm has remained in place over the years. That is, until Merck began testing the drug that would become Zepatier. Confident of the drug’s saftey and side-effect profile, Merck created trials for cohorts of patients most companies had previously avoided – most notably, injection drug users (IDUs). Instead of avoiding these folks, Merck recruited them. The first arm was the most general, and common to all experimental HCV drugs: treatment experienced (IFN/RBV), and treatment-naive.
Injection Drug Users (IDUs)
Other clinical trials, and current restrictions (due to cost) require that IDUs prove they’ve been “clean” of all opioid use for a period of at least 6 months – a burden that has proven nearly impossible for these patients to achieve. Merck allowed them to participate in opioid replacement therapy – a supervised methadone program. This practice greatly improved success rates in treatment, as well as assisting addicts in employing a drug that offers little or no euphoria, removing that element as an incentive to use. This protocol also served as a means toward improving daily functionality, with the goal of transitioning the patient from injecting their drugs, to a safer, measured oral dose. Of course, the IDU community will always be at risk for re-infection.
Some of the hardest-to-treat patients, those who were both co-infected and treatment-experienced, showed a response rate of 100%, in a study of 16 weeks of Zepatier with ribavirin. Why these patients are more resistant to treatment is unknown, but resolution appears to be dose-related. This research arm included genotypes 1, 4, and 6. Zepatier has been approved for two genotypes: 1 and 4.
Experience With First Generation HCV Protease Inhibitor
The primary concern was that this population may have developed long-term resistance to stronger PIs. Possible resistance was evaluated at the beginning of this study by identifying mutations in the NS3 region of the virus. Patients in this group had previously failed treatment with telaprevir (Incivek), boceprevir (Victrellis), and simeprevir (Olysio). 95% of these patients achieved a cure (SVR 12).
Chronic Kidney Disease (ERSD)
These patients are often excluded because the drug being tested is metabolized fully or partially by the kidneys. This includes Sovaldi, a new generation PI. It is known that infection with hepatitis C can cause eventual kidney failure. Development of diabetes may soon follow. Patients with HCV who go on to receive kidney transplant run a higher risk of rejection of the transplanted organ. Patients with chronic kidney disease have often been overlooked because they are so difficult to treat. Merck lowered the dose to 50Mg in this group, even though Zepatier is metabolized by the liver.
Advanced Liver Disease
The trial with the most interesting outcome. As of today, Zepatier is not recommended for advanced liver disease, even though trials with this cohort were remarkably successful. Here’s the rub: patients in this arm were treated with a lower dose – 50Mg, instead of the usual 100Mg. The dose was lowered to guard against accumulation of the drug in the liver. At the present time, Zepatier is manufactured only in the 100Mg dose. It seems possible, however, that once Merck establishes its revenue stream, and manufacturing capability the company may offer the lower dose for those with Child-Pugh B disease. This is an educated guess, not written in stone, but given Merck’s goal of eradicating HCV, one would hope their purview would expand to include the neediest of patients.
Merck’s commitment to treat as many patients as possible, even those who are considered problematic, seems clear from the way in which these trials were conducted. Although no drug can cure everyone, it is hoped that the market will eventually become populated with enough treatment options to cover the majority of HCV patients. Perhaps in the near future, financially challenged patients will have an easier time of it as well. It depends on what kind of society we want to become.