By Michael Smith, North American Correspondent, MedPage Today
Published: April 23, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse
AMSTERDAM – An investigational drug that acts directly against the hepatitis C virus (HCV) works quickly and effectively, according to new reports.
Each report on the oral nucleotide analogue sofosbuvir, appearing in the New England Journal of Medicine, focuses on different patient populations, but, with one exception, they suggest that the drug can deliver high cure rates and an acceptable safety profile with 12 weeks of therapy.
In contrast, the current standard of care – involving pegylated interferon and ribavirin -- can take up to 48 weeks.
All of the findings will be presented this week at the Internal Liver Congress sponsored by the European Association for the Study of the Liver.
The data suggest that "a radical change in clinical practice is imminent," according to Joost P.H. Drenth, MD, PhD, of Radboud University Nijmegen Medical Center in Nijmegen, the Netherlands.
In an accompanying NEJM editorial, Drenth argued that the arrival of new agents that act directly against the virus is "unprecedented" and raises the hope that clinicians will be able to do away with interferon, which is regarded as hard to take and dangerous to use.
In particular, it has been just 3 years between the publication of the chemical structure of the compound and the current phase III trials.
In many ways, Drenth noted, treatment of HCV today is a matter of managing the adverse effects of the standard treatments and many researchers are eyeing the demise of interferon therapy.
But since ribavirin is still in the game – playing an important role in all four of these studies – "it may be premature to start dismantling the dedicated [treatment] centers now that interferon is in retreat," he wrote.
In one industry-sponsored phase III trial – dubbed NEUTRINO -- Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand, and colleagues investigated the effect of sofosbuvir in 327 patients mainly with HCV genotype 1, although a handful of patients had genotypes 4, 5, and 6.
They were treated with the drug, plus pegylated interferon and ribavirin, for 12 weeks in a single-arm, open-label study. For genotype 1 patients, the current standard of care is one of two approved protease inhibitors for 12 to 32 weeks combined with 24 to 48 weeks of peginterferon and ribavirin.
The primary endpoint of the study was the so-called sustained virologic response 12 weeks after the end of therapy (SVR12), where SVR was defined as a viral load too low to quantify.
Gane and colleagues noted that regulatory authorities had agreed that a comparator arm using the standard of care was not needed, owing to the "expectation of high response rates, improved safety, and shorter treatment duration."
In fact, they found that 90% of the patients reached an SVR12, compared with an adjusted historical response rate of 60%. There were no major differences in response rates by genotype -- 89% for the 291 patients with HCV genotype 1 and 96% for the 28 genotype 4 patients, while all six patients with genotype 6 and the lone genotype 5 patient reached SVR12.
In the second industry-sponsored phase III study called FISSION, Gane and colleagues studied the effect of 12 weeks of sofosbuvir and ribavirin in 499 patients with viral genotypes 2 and 3, compared with 24 weeks of pegylated interferon and ribavirin, which is the standard of care for such patients.
The study was designed to shown noninferiority of the all-oral sofosbuvir/ribavirin regimen to the standard regimen, in which interferon is given intravenously.
Gane and colleagues reported that SVR12 rates for the two regimens were identical at 67%, showing the all-oral regimen was not inferior to standard care.
In both studies, the most common adverse events were fatigue, headache, nausea, and insomnia.
Patients with HCV genotypes 2 and 3 were the target of the two other industry-sponsored phase III studies, reported by Ira Jacobson, MD, of Weill Cornell Medical College in New York City, and colleagues in NEJM.
The POSITRON trial looked at 278 patients for whom treatment with peginterferon was not an option, because of other health issues such as psychiatric or autoimmune disorders.
They were randomly assigned in roughly a 3:1 fashion to get either oral sofosbuvir and ribavirin or placebo for 12 weeks. Jacobson and colleagues reported that the SVR12 rate was 78% among those treated with sofosbuvir and ribavirin versus 0% in the placebo group (P<0.001).
The second trial by Jacobson's group studied 201 patients who had not responded to previous therapy with interferon and ribavirin and were randomly assigned to receive sofosbuvir and ribavirin for either 12 or 16 weeks.
Jacobson and colleagues found that half the patients who got the 12 weeks of therapy achieved an SVR12, compared with 73% among those treated for 16 weeks. The 23-percentage point difference was significant (P<0.001).
As in the other studies, the most common adverse events were headache, fatigue, nausea, and insomnia. Overall, only 1% to 2% rate of patients stopped using sofosbuvir.
Both studies were supported by Gilead Sciences. Gane reported financial links with Gilead, Janssen-Zilag, Novartis, AbbVie, Roche, and Vertex. Jacobson reported financial links with Abbott, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta, Gilead Sciences, GlaxoSmithKline, Idenix, Kadmon, Novartis, Presidio, Roche–Genentech, Schering-Plough (now part of Merck), Tibotec, and Vertex Pharmaceuticals.
Primary source: New England Journal of Medicine
Lawitz E, et al "Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection" N Engl J Med 2013; DOI: 10.1056/NEJMoa1214853.
Additional source: New England Journal of Medicine
Jacobson IM, et al "Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options" N Engl J Med 2013; DOI: 10.1056/NEJMoa1214854.
Additional source: New England Journal of Medicine
Drenth JP "HCV Treatment -- No More Room for Interferonologists?" N Engl J Med 2013; DOI: 10.1056/NEJMe1303818.