Published: Apr 10, 2014
By Michael Smith, North American Correspondent, MedPage Today
Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Note that this nonrandomized trial demonstrated good efficacy of the novel agent ledipasvir when combined with sofusbuvir and ribavirin for the treatment of hepatitis C.
- Be aware that larger studies in more diverse groups of patients will be needed to further characterize the appropriate use of this agent.
LONDON -- An investigational drug combination for hepatitis C virus (HCV) was efficacious in three groups of hard-to-treat patients, a researcher said here.
The fixed-dose, once-daily combination of sofosbuvir (Sovaldi) and ledipasvir, given for 12 weeks, yielded cure rates of between 64% and 100%, according to Edward Gane, MD, of Auckland Clinical Studies in New Zealand, and colleagues.
But the combination appears to need the help of an old HCV therapeutic standby, ribavirin, to achieve its highest cure rates, Gane told MedPage Today at the annual meeting of the European Association for the Study of the Liver.
But with ribavirin, he said, "you can cure genotype 3 ... remarkable!"
For several years, genotypes 2 and 3 of the virus had been regarded as easier to treat than genotype 1, but recent evidence suggests that genotype 3 is actually more difficult. When sofosbuvir, a nucleotide analog polymerase inhibitor, was approved in the U.S., the treatment duration was set at 24 weeks for genotype 3 patients and 12 weeks for those with genotype 2, reflecting that realization.
Ledipasvir, an NS5A inhibitor, remains investigational, but a New Drug Application for the combination has been given priority review by the FDA.
The drugs are part of a new wave of so-called direct-acting agents which attack the virus itself, in contrast to earlier therapies. The first to be approved in 2011 were the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis), followed in 2013 by sofosbuvir and the protease inhibitor simeprevir (Olysio).
But for years, the only therapy was pegylated interferon-alfa combined with ribavirin, which was regarded as both dangerously toxic and difficult to tolerate.
As a result, many patients with HCV have been waiting for treatment with the new agents, largely because they want to avoid peginterferon, commented Andrew Talal, MD, of the University at Buffalo in New York, who was not part of the trial.
"We've been treating people who need treatment or desperately want treatment," Talal told MedPage Today. But his institution, like many others, has "a significant number of people who self-select not to be treated at this time, who are waiting for the elimination of interferon from the therapeutic armamentarium."
The sofosbuvir/ledipasvir combination, he said, "is very promising, particularly in the populations that were studied," even though it might not completely eliminate the use of ribavirin.
But the role the combination will play in clinical practice is likely to depend, not on its efficacy, Talal said, but on its cost. "The major factor that determines, at this point, which drug or which combination of compounds will be the front-runner is price," he said.
He said he has been asked regularly about the cost of the new agents, including that of sofosbuvir, which has been set at $84,000 for a course of treatment in the U.S.
Gane reported on the so-called ELECTRON-2 study, which enrolled three cohorts -- 51 treatment-naive genotype 3 patients, 19 genotype 1 patients who had been treated previously with sofosbuvir in various studies but who had relapsed, and 20 genotype 1 patients with decompensated cirrhosis (Child Pugh Turcotte B).
All patients were treated with the single-pill combination for 12 weeks but some -- including all of the relapsed patients and half of the genotype 3 volunteers -- were also given ribavirin, Gane reported.
The primary endpoint was a sustained virologic response 12 weeks after the end of therapy (SVR12), defined as no detectable HCV RNA. An SVR12 is currently regarded as tantamount to a cure, since relapses among people who reach that landmark are rare.
The researchers found:
- Among the 26 treatment-naive genotype 3 patients given ribavirin, the SVR12 rate was 100%.
- Among the 25 patients in the group who did not get ribavirin, it was 64%.
- Among the 20 patients with cirrhosis (who did not get ribavirin), seven relapsed, yielding an SVR12 rate of 65%.
- Among the 19 previous relapsers (all given ribavirin), the SVR12 rate was 100%.
Almost all patients reported some adverse events, but there were no new toxicity signals, Gane told the opening plenary session of the meeting. There were only four grades 3 or 4 adverse events and only six serious adverse events.
Only one patient stopped therapy owing to an adverse event -- a patient who developed perforated sigmoid diverticulitis on the seventh day of participation and did not resume therapy after it was treated, Gane said.
The most common adverse events included headache, upper respiratory tract infection, nausea, and fatigue, he said.
Grades 3 and 4 lab abnormalities affected 13 patients, with seven of those among the genotype 3 patients getting ribavirin, Gane said. On the other hand, only seven patients (all but one on ribavirin) had hemoglobin below 10 g/dL, and none fell below 8.5.
The ELECTRON-2 study is just the first of several to be presented here that showcase the fixed-dose combination in various patient groups.
The study was supported by Gilead. Gane disclosed relevant relationships with the company, as well as with AbbVie, Janssen, Idenix, Novartis, Merck, Roche, and Vertex.
Talal disclosed relevant relationships with Gilead and AbbVie.
Primary source: European Association for the Study of the Liver
Gane EJ, et al "Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and genotype-1 patients with prior sofosbuvir treatment experience" EASL 2014; Abstract 06.