Interferon-Free Hepatitis C Regimens Within Reach

Much of the hep C wish list was on display at the American Association for the Study of Liver Disease meeting in Boston Nov. 10-13 – all-oral interferon-free drug combinations for hepatitis C, regimens that don’t require ribavirin, and the possibility of a one-pill, once-a-day cure – demonstrating the Gold Rush mentality in the hep C space as drug makers race to put the pieces together and grab a share of a burgeoning market.

The quest for the optimal therapeutic regimen to cure hepatitis C boils down to safety, simplicity and efficacy in hard-to-treat populations, and researchers presenting data on behalf of pharmas in the thick of the race lined up to report their findings at the American Association for the Study of Liver Disease meeting in Boston Nov. 10-13.

The goal is to safely eliminate interferon from standard of care while cutting down the pill count and eradicating the virus in the shortest treatment time possible, and evidence of progress on all those fronts was presented. In fact, expectations are high that the first interferon-free, all-oral combinations will enter the market before 2016.

Gilead has set a high bar with the possibility of a one-pill, once-daily direct-acting antiviral regimen.

The current leaders in the effort, Abbott Laboratories Inc. and Gilead Sciences Inc., both released key Phase II proof of concept data on their all-oral regimens and both recently have launched Phase III programs that should answer questions about their efficacy in real-world populations that include difficult viral genotypes and patients with cirrhotic livers.

Gilead May Be First With A One-Pill Combo

For Gilead, the going may be less certain because the company isn’t carrying into Phase III the same nucleoside/NS5A combination that wowed the community in Phase II, though it has produced data to support the efficacy of the NS5A inhibitor it is using (Also see "Gilead Steals The Show At Liver Meeting" - Pink Sheet, 14 Nov, 2012.).

It was Gilead’s polymerase inhibitor sofosbuvir (GS-7977) and Bristol-Myer’s Squibb Co.’s NS5A inhibitor daclatasvir that turned in near-100% cure rates in a 12-week treatment regimen that includes neither interferon nor ribavirin, but Gilead is moving on with a combination that now matches sofosbuvir with its own NS5A, GS-5885. Data from a separate Phase II trial called ELECTRON, testing GS-5885, sofosbuvir and ribavirin in a 12-week regimen with 25 treatment-naïve genotype 1 patients, showed a 100% cure rate, but after only four weeks of follow-up. As those data mature, the cure rate must hold up.

Still, “it appears a potent nuc [nucleoside polymerase inhibitor] and a strong NS5A obviate the need of ribavirin,” Barclays analysts said in a Nov. 12 update. Gilead is testing a fixed-dose combination of the two direct-acting antivirals in its Phase III ION-I trial, which if successful will result in a one-pill, once-a-day regimen that lasts only 12 weeks, compared to the current 24 or even 48.

In addition, Gilead will have the flexibility to potentially add a third direct-acting antiviral in difficult to treat populations, Deutsche Bank analyst Robyn Karnauskas said in a Nov. 13 report.

Four-armed ION-I is evaluating the fixed-dose combination with and without ribavirin in a total of 800 genotype 1 patients, 20% of them with cirrhosis, for 12 weeks or 24 weeks of treatment. Results for the first 50 patients in each arm will be available to the company for interim analysis in early 2013, but Gilead has made no promises it will make those data public. If the trials are successful, the pill could reach market in 2015.

Abbott Has Robust Data But More Pills

Abbott Laboratories Inc. presented data from its Phase II Aviator program in genotype 1 treatment-naïve patients and, importantly, a group of null responders – patients for whom current treatment options did not work. Gilead’s ELECTRON included null responders, but results were available for only three patients, though they all recorded a cure at four weeks post-treatment.

The standard Abbott cocktail contains ABT-450r, a protease inhibitor co-formulated with low-dose ritonavir, which increases ‘450’s bioavailability but does not directly affect the hepatitis virus; ABT-333, a non-nucleoside polymerase inhibitor; and NS5A inhibitor ABT-267. It also has an option for ribavirin dosed by weight. But it does not include interferon.

In Aviator, 97.5% of treatment-naïve (77/79) and 93.3% of null responders (42/45) dosed for 12 weeks with Abbott’s non-nuc cocktail of three direct-acting antivirals and ribavirin achieved a sustained virologic response (considered a cure) after 12 weeks of follow-up. Among the arms without ribavirin, 87.3% of treatment-naïve patients achieved SVR. Null responders all took ribavirin (Also see "Abbott’s Interferon-free Hep C Combo With Ribavirin Has High Cure Rates" - Pink Sheet, 11 Nov, 2012.).

Of note, three null responders and one treatment-naïve patient in the ribavirin arms experienced breakthrough (a rebound of viral RNA in the blood during treatment) and one treatment-naïve patient relapsed, while in the ribavirin-free arms one patient experienced breakthrough and five relapsed, a possible indication the regimen will continue to require ribavirin.

For the recently launched Phase III SAPHIRE program, ABT-450/r will be co formulated with ABT 267 to be taken twice in the morning, and ABT 333 will be taken as one pill in the morning and one pill in the afternoon; dosing will be weight dependent in arms with ribavirin, meaning a total of six pills for those arms.

A separate Phase III trial, dubbed TURQUOISE, will study the triple direct-acting antiviral combination with ribavirin in patients with cirrhosis. Together, Abbott anticipates enrolling more than 2,000 genotype 1 patients, with 12 weeks of treatment in non-cirrhotic patients and 12 or 24 weeks in cirrhotic patients.

Abbott anticipates Phase III data in 2013, with filings in 2014 and approval in 2015.

The challenge for Abbott, of course, is the high bar Gilead has set with the one-pill regimen, “which may post similar efficacy with fewer drugs and one pill required,” J.P. Morgan analysts said in a Nov. 13 report.

As far as ribavirin goes, the side-effect burden is much less than with interferon and quite manageable, physicians at the meeting said, adding that the real push to eliminate it from standard of care is to lower the pill burden for patients.

“It’s really the interferon that carries the bulk of the side effects, so we’re finding that [regimens] without interferon in the mix are quite well tolerated,” Fred Poordad, chief medical officer at the Texas Liver Institute, said during a presentation sponsored by Achillion Pharmaceuticals Inc.“However, if we can get rid of ribavirin, the goal would be the fewer drugs we need the better.”

Achillion plans to take a combination of its NS5A inhibitor ACH-3102 and sovaprevir, a protease inhibitor, into Phase II trials plus or minus ribavirin in 2013, with an ultimate goal of getting to market in 2016 (Also see "Still In The Race: Achillion Says Its HCV Candidates Are “Best-In-Class”" - Pink Sheet, 28 Sep, 2012.)

Bristol Still In The Hunt

Bristol-Myers Squibb Co. also presented data for its interferon, ribavirin and ritonavir-free regimen at the meeting and said it anticipates launching Phase III trials in 2014.

Bristol tested its combination of daclatasvir, the NS5A inhibitor side-stepped by Gilead, asunaprevir, a protease inhibitor, and BMS-791325, a non-nucleoside polymerase inhibitor, in treatment-naïve genotype 1 patients. Interim data from the first part of the open-label trial, which randomized 32 patients to 12 or 24 weeks of treatment, showed 94% (15/16) of patients dosed for 12 weeks achieved SVR 12 weeks after completing treatment. The remaining patient was lost to follow-up until about 24 weeks post-treatment but achieved SVR.

“Of the three [direct-acting antiviral] combinations in development, we favor [Bristol’s] over that of [Abbott], despite [Bristol’s] earlier development stage,” the Barclays analysts said. Abbott’s combination appears somewhat dependent on ribavirin (97.5% SVR with ribavirin and 87.3% SVR 12 without) and there were cases of both breakthroughs and relapses from the Aviator study.

Enthusiasm For Victrelis And Incivek Has Waned

While the advent of protease inhibitors Vertex Pharmaceuticals Inc.’s Incivek (telaprevir) and Merck & Co. Inc.’s Victrelis (boceprevir) represents a big leap in hepatitis C therapy, their range is limited and they come with an interferon/ribavirin backbone that has uncomfortable and off-putting side effects. Both drugs were approved in 2011 (Also see "FDA Must Decide How To Handle Subgroups In Labeling For Boceprevir, Telaprevir" - Pink Sheet, 9 May, 2011.).

In addition, the regimens were not tested in real-world patient populations, and the adverse event rate of around 12% shown in the clinical programs increased significantly to 40% to 50% in post-approval practice, Poordad said. “This has really been eye-opening because the patients, particularly those with advanced liver disease, tend not to tolerate these regimens very well.”

Indeed, “in the first generation of protease inhibitors that came out, the studies didn’t include that many patients with cirrhosis, even in Phase III,” added Andrew Muir, who heads up the gastroenterology and hepatology research group at the Duke Clinical Research Institute.

In the last 12 months or so, there has been a significant drop in use of those therapies, not because the patient pool was exhausted but because the therapies were tried and found to be not well-tolerated, said Poordad. “When clinicians got that experience they quickly lost some of their enthusiasm.”

For those reasons, both Poordad and Muir said they are advising patients who are in the early stages of hepatitis C or who are not good candidates for interferon to wait for the new interferon-free regimens. In an interview on the sidelines of the meeting, Muir described the therapies being tested in clinical studies at Duke as “wonderful,” adding that it is heartening to see patients being cured without having to endure the side effects associated with interferon.

The physicians also pointed to the recent estimate from the Centers For Disease Control and Prevention that as many as 75% of Baby Boomers in the U.S. alone unknowingly may be infected with the virus, noting that the new regimens were going to have plenty of market to share.