Wednesday 29 June, 2016 13.00 EDT
The changing role of SVR12 in clinical trials of HCV drugs
In clinical trials of therapy for hepatitis C virus (HCV) infection, the standard to assess the effectiveness of treatment has been the decline of HCV RNA (viral load) during therapy such that it becomes very low followed by undetectable viral load for 24 consecutive weeks after therapy has ended. Such a response in the 24 weeks after the cessation of therapy is called a sustained virologic response, written as SVR24.
The previous regimen
Over much of the past decade in high-income countries such as Canada, Australia and the U.S. and in regions such as Western Europe, standard therapy for HCV has been a combination of long-lasting interferon called peginterferon, injected once weekly, combined with twice-daily doses of the drug ribavirin. Interferon activates genes that help control viral infections and ribavirin is a broad-spectrum antiviral agent. Both drugs have indirect effects on HCV-infected cells.
In the past several years, researchers have developed drugs specifically designed to target key proteins of HCV. Due to the highly specific way that they work, these drugs are called DAAs—direct-acting antivirals. Two currently licensed DAAs are boceprevir (Victrelis) and telaprevir (Incivek, Incivo). These two drugs are used in combination with peginterferon and ribavirin for the treatment of HCV genotype 1. Expect additional DAAs to be licensed over the next several years. Most of these additional DAAs will be multi-genotypic, meaning that they will have anti-HCV activity against different genotypes, or strains, of HCV.
An FDA review
Researchers at the U.S. Food and Drug Administration (FDA) have reviewed results from clinical trials of HCV treatment in nearly 13,600 adult participants. Some of these studies have included the use of boceprevir and telaprevir. In doing the review, the FDA researchers found that 51.8% of participants had an undetectable viral load 12 weeks after cessation of therapy; this is written as SVR12. Overall, 50.6% of participants also had the same result at week 24 after cessation of therapy—an SVR24. This means that the vast majority (more than 98%) of participants who had an SVR12 also had an SVR24. This suggests than an SVR12 may be a very important result or end-point in HCV clinical trials. Expect more pharmaceutical companies to focus on SVR12 in the future.
Overall, there were 388 participants who achieved an SVR12 but who did not achieve an SVR24. The majority of these participants did not return to the study clinic for assessment at week 24, so blood could not be drawn to measure their viral load. Researchers, in making a strict interpretation of the dataset, decided that these missing values would be considered to be detectable.
Most participants in the FDA dataset had the genotype of HCV that is commonly found in North America and Western Europe—genotype 1, written as GT 1.
Results by genotypes
The close relationship between SVR12 and SVR24 was also seen for participants who had genotypes 1, 2 and 3. Specifically, people with these three genotypes who achieved an SVR12 were extremely likely to also develop an SVR24.
The most common reasons for having a detectable viral load at the 24th week after treatment cessation were listed by the FDA researchers as follows:
- other (undisclosed) reasons
New therapies and subgroups
When the analysis was restricted to clinical trials with boceprevir and telaprevir, the association between having an SVR12 and subsequently an SVR24 was similar to the other analyses.
Not a major factor
Furthermore, when the researchers analysed people with the following characteristics, trends between SVR12 and SVR24 were similar:
- having been treated more than once
- GT 1a vs. GT 1b
- severe liver damage
Using these analyses
Based on the findings of a close link between SVR12 and SVR24, the FDA has instructed pharmaceutical companies that they can use SVR12 as a primary endpoint, or goal, in clinical trials. This will speed up clinical trial development—an important effect, as there are many drugs and combinations of drugs that require testing in the race to find the perfect combination.
For interferon-free regimens of DAAs, the FDA requires that companies continue to collect both SVR12 and SVR24 data so that the relationship between these two time points can be confirmed. The equivalent to the FDA in Europe—the European Medicines Agency (EMA)—also agrees with the FDA analysis and has given similar guidance to companies.
Previous mathematical analyses have suggested that with regimens containing peginterferon + ribavirin, 70% of relapses are forecast to occur within the first four weeks of treatment cessation. Furthermore, the same mathematical analyses have predicted that 95% of relapses of HCV treatment should occur within the first 12 weeks of treatment cessation.
In analyzing the SVR4 data (the fourth week after treatment cessation to observe an undetectable viral load), the FDA researchers in the present study found that 65% of participants who did not have an SVR24 also did not have an SVR4. In the future, SVR4 may be an endpoint worth observing, if only for its ability to predict future trends.
Bear in mind
The present FDA analysis was based upon previously collected data from clinical trials and this data was subjected to a reanalysis. Such analyses that look back upon previously collected data can find associations and trends but cannot produce definitive results. That is why the FDA is requiring the developers of interferon-free regimens to collect SVR24 outcomes in the early phase clinical trials (such as phase I/II or phase II). Results from these studies can be used to guide the design of phase III clinical trials with DAAs and their choice of endpoints (SVR12 or SVR24).
When it comes to outcomes of HCV-positive people who have initiated treatment, the FDA warns that doctors should exercise “caution” in using its analysis at the individual level. The agency encourages doctors to follow clinical guidelines. In such guidelines SVR24 is the goal of therapy.
—Sean R. Hosein
Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 2013 Jun;144(7):1450-1455.