The FDA recently approved two new combination regimens for hepatitis C, raising the question of whether further drug development is warranted in this area.
Gilead’s Vosevi (sofosbuvir/velpatasvir/voxilaprevir) and AbbVie’s Mavyret (glecaprevir/pibrentasvir) work against all hepatitis C virus (HCV) genotypes, with cure rates exceeding 95%. And Mavyret, which many patients will be able to take for just 8 weeks, brings a lower cost option to the market.
“One could imagine something like a single injection or pill that would cure HCV, and of course that would be an advance in terms of convenience,” Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston, told MedPage Today. “But is it worth the time and resources to get that through preclinical safety studies, clinical trials, and FDA approval?”
Experts agree, however, that more remains to be done in terms of implementation: getting everyone at risk screened for HCV infection, and getting those who test positive on effective treatment. If these goals are achieved, hepatitis C could potentially be eliminated as a public health threat.
“The largest unmet need remains identification of cases and linkage to care of those yet to be diagnosed. For those diagnosed but not yet treated, providing access to curative therapy remains an unmet need, as many in this group still face insurance restrictions,” Raymond Chung, MD, chief of Hepatology at Massachusetts General Hospital in Boston, told MedPage Today.
The development of direct-acting antiviral agents (DAAs) for HCV that can be used in interferon-free regimens is regarded as one of the major recent advances in medical science.
Today’s recommended regimens are taken for 3 or 4 months, are well tolerated, and lead to sustained virological response (SVR) in more than 95% of treated patients. This represents a big improvement over the old interferon-based therapy, which lasted 6 to 12 months, caused difficult side effects, and cured only about half of treated patients.
The approval of Vosevi and Mavyret help fill the few remaining gaps related to the effectiveness of hepatitis C treatment.
Vosevi, approved on July 18, is a single-tablet regimen containing the HCV NS5B polymerase-inhibitor sofosbuvir (marketed separately as Sovaldi), the NS5A-inhibitor velpatasvir (currently combined with sofosbuvir in the Epclusa coformulation), and the NS3/4A protease-inhibitor voxilaprevir (approved for the first time). All of these drugs are pangenotypic, or active against all six major HCV genotypes.
Vosevi was approved for retreatment of people with all HCV genotypes, with or without liver cirrhosis, who were not previously cured with prior DAA therapy including an NS5A inhibitor, and for those with genotypes 1a or 3 who were previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor. Retreatment of these patients can be challenging because HCV can develop resistance to one medication that reduces the effectiveness of other drugs in the same class.
In the POLARIS 1 and 4 trials, Vosevi taken for 12 weeks cured 97% of study participants with all HCV genotypes who were previously treated with DAAs, performing better than the two-drug Epclusa pill.
For people starting treatment for the first time in the POLARIS 2 study, Vosevi taken for 8 weeks did not quite measure up to Epclusa taken for 12 weeks, with SVR rates of 95% versus 98%, respectively. The FDA therefore did not approve the shorter 8-week regimen for first-line therapy. However, Vosevi taken for either 8 or 12 weeks cured 96% of patients with HCV genotype 3 and liver cirrhosis, considered one of the most difficult groups to treat.
Mavyret, approved on August 3, is a coformulation containing the NS3/4A protease-inhibitor glecaprevir and the NS5A-inhibitor pibrentasvir, both of which were approved for the first time.
Mavyret was approved for previously untreated patients with HCV genotypes 1 through 6, using a treatment duration of 8 weeks for those without cirrhosis and 12 weeks for those with cirrhosis. The FDA also approved a 12- or 16-week course of Mavyret for genotype 1 patients who were previously treated with an HCV protease inhibitor or NS5A inhibitor, but not both, and for genotype 3 patients who previously used interferon-based therapy or sofosbuvir.
In the phase III ENDURANCE AND EXPEDITION trials, Mavyret taken for 8 or 12 weeks cured 98% to 100% of patients with HCV genotypes 1, 2, 4, 5, and 6 with or without cirrhosis, and 95% of those with genotype 3 and cirrhosis. In addition, this combination taken for 12 weeks cured 98% of patients with chronic kidney disease, including those on dialysis.
With the latest approvals, DAA development appears to be nearing its end.
Merck, which currently markets the two-drug Zepatier (grazoprevir/elbasvir) coformulation for HCV genotypes 1 and 4, has a pangenotypic three-drug regimen containing grazoprevir, the NS5A-inhibitor ruzasvir, and the polymerase-inhibitor uprifosbuvir in late-stage development.
Janssen recently announced that it would end its hepatitis C drug development program, after completing ongoing Phase II studies of its investigational three-drug regimen containing simeprevir (marketed alone as Olysio), odalasvir, and AL-335.
“This decision was made in light of the increasing availability of a number of highly effective therapies addressing the medical need in hepatitis C,” the company said in a press release.
Sax recently conducted a reader poll for the New England Journal of Medicine asking about remaining unmet needs in the hepatitis C field. Of the more than 600 respondents, 47% mentioned a vaccine to prevent HCV infection and 46% cited improved implementation to bring existing treatment to the people who need it. Fewer than 5% mentioned better options for patients with prior treatment failure, shortening the duration of therapy even further, or other improvements.
HCV guidelines developed by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend that all patients with chronic HCV infection should receive treatment, except those with short life expectancies due to other causes.
But to date, many people living with hepatitis C have been unable to access therapy because of barriers including the high cost of the drugs, refusal of coverage by private insurers or public payers, restrictions related to liver disease severity, and requirements for abstinence from drug and alcohol use. Some payers have also required that treatment be managed by liver disease specialists, even though studies have shown that primary care providers can treat hepatitis C patients with a similar rate of success.
“Since we’re already at 98% cured with the treatments we have, and we already have salvage therapies available, I’m dubious that much more is going to be done in terms of improving DAA treatment,” Sax said. “Let’s get the people tested who are unaware of their infection so that they can get treated, and improve access once they are diagnosed. And let’s do whatever we can to stop new infections, which are occurring at a high rate among people with opiate addiction and in certain men who have sex with men.”
The end of hepatitis C drug development does not, however, suggest that liver disease is not still an active field. Researchers continue to search for therapies to cure hepatitis B and treat fatty liver disease, which is responsible for a growing proportion of cases of hepatocellular carcinoma and liver transplantation.