Simeprevir regimens for HCV effective, less complicated: studies

By Megan Brooks

NEW YORK (Reuters Health) - Results of two of the three pivotal clinical trials that led to approval of simeprevir for chronic hepatitis C in the U.S. and elsewhere - QUEST 1 and QUEST 2 - are now published.

Simeprevir (Olysio, Janssen) is the third protease inhibitor to be approved in the U.S. for treating hepatitis C virus (HCV). It belongs to the same class as its predecessors, boceprevir and telaprevir, but has the advantage of once-daily dosing.

Simeprevir "clearly represents an improvement over first-generation protease-based treatment in that it is less complicated, seems to be well tolerated, and has high efficacy," write the authors of a Comment published with the QUEST trials online June 4 in The Lancet.

Both QUEST 1 and 2 used the same study design, collectively enrolling 785 treatment-naive patients with chronic HCV-1 infection and testing simeprevir 150 mg once daily (vs placebo) with standard pegylated interferon alfa 2a or 2b and ribavirin.

"The results of the studies are remarkably similar," Marc Ghany of the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland and Naveen Gara of Washington Hospital Center, Washington, DC, note in their Comment.

In both studies, the primary endpoint was a sustained virological response at 12 weeks after the planned end of treatment (SVR12). Treatment duration was response-guided. Total treatment was 24 or 48 weeks.

In both studies, rates of SVR12 were significantly higher with simeprevir than placebo and the vast majority of patients who received simeprevir qualified for the shorter treatment.

Rates of on-treatment virological failure were low (9% in QUEST-1 and 7% in QUEST-2) and those who did fail simeprevir-containing treatment developed mutations that conferred resistance to the drug.

Simeprevir was generally well tolerated; the incidence and severity of adverse events were similar to the peginterferon plus ribavirin group. Adverse events that were higher with simeprevir were mostly skin-related and included pruritus, rash, photosensitivity and raised bilirubin concentration.

Ghany and Gara note that the simeprevir regimen appears to have no advantage for patients with HCV genotype 1a with baseline Q80K polymorphism. This is a particular issue in the U.S. where the prevalence is 48% but less of an issue in Europe with 19% prevalence, they point out.

Another regimen made up of sofosbuvir with peginterferon and ribavirin was approved in the U.S. about the same time as simeprevir. This regimen has similar safety and efficacy but with shorter treatment of only 12 weeks. "Which of these interferon-sparing regimens to recommend for patients with HCV genotype 1 should be left to the discretion of the healthcare provider and patient to decide after a thorough discussion of risks and benefits," Ghany and Gara advise.

They also note that recent advances in drug therapy for HCV genotype 1 are "overshadowed" by the rapid development of interferon-free and ribavirin-free regimens. These regimens have virological cure rates topping 90% for most HCV genotypes, regardless of which combinations of agents are used or the baseline characteristics of the patients and should reach the clinic by the end of this year or early next year, they predict.

The advantages of these regimens are "much simpler schedules with once-daily dosing, without the need for complicated monitoring or response-guided treatment, shorter treatment, and fewer side-effects, and will undoubtedly replace currently approved treatments," Ghany and Gara say.

Dr. Ira Jacobson of Weill Cornell Medical College in New York, who worked on the QUEST 1 study, told Reuters Health, "There are two trials underway called OPTIMIST-1 and OPTIMIST-2 evaluating simeprevir and sofosbuvir for noncirrhotic and cirrhotic patients."

SOURCES: http://bit.ly/1kYP0zy, http://bit.ly/1mEyFLW, and http://bit.ly/1llBODn

Lancet 2014.