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May 3, 2010
Volume 88, Number 18

Alternative Interferons

Small molecules aren't the only new drugs in development to treat hepatitis C

Lisa M. Jarvis

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Over the past decade, the pharmaceutical pipeline has become packed with small molecules that treat the hepatitis C virus (HCV). Hopes are high that the current standard of care—a combination of PEGylated interferon and ribavirin that only works in 50% of patients—can be replaced with a more effective cocktail of orally administered antivirals.

But a handful of firms are also looking at ways to improve upon the standard of care by developing alternative interferons that quell the HCV infection in more people and create milder side effects than the currently approved versions of interferon-alfa.

Now, people with HCV are given once-weekly injections of PEGylated interferon—either Roche's Pegasys or Merck & Co.'s PegIntron—along with twice-daily ribavirin pills. It takes nearly a year to complete the course of treatment, and interferon is tough to tolerate. On top of the anemia caused by ribavirin, interferon often causes flulike symptoms. Many patients drop out of treatment because they can't handle the regimen. "This is not something you want to be on for 48 weeks," Douglas E. Williams, chief executive officer of ZymoGenetics, told investors at Canaccord Adams' Hepatitis C Conference last month.

And although many doctors hope that one day HCV can be treated completely with small molecules, studies of combinations of antivirals are still in the early stage. "A better-tolerated interferon will find a place, irrespective of the small-molecule market," Williams said.

Big pharma firms clearly see potential for an alternative interferon. In 2006, Novartis paid $45 million up front and agreed to nearly half a billion dollars in milestone payments for access to Zalbin, Human Genome Sciences' (HGS) albinterferon-alfa-2b. Last year, Bristol-Myers Squibb handed ZymoGenetics $85 million upfront plus a $20 million license fee for access to PEGylated interferon-lambda. The Seattle-based biotech firm could get milestones worth up to $430 million as the therapy winds its way to approval and another $287 million as it is tested for other diseases.

Zalbin has advanced the farthest of the alternative interferons in development. HGS announced in November 2009 that it had submitted a biologics license application to the Food & Drug Administration. A month later, it filed for approval in Europe.

Zalbin is a genetic fusion of human albumin and interferon-alfa. The idea is that by tethering the therapeutic protein to albumin, a common blood protein that stays in circulation for nearly 20 days, the interferon can stick around in the body longer to work its magic.

HGS is seeking approval to give patients Zalbin once every two weeks, and the firm is studying its efficacy when dosed every four weeks. However, last month the company withdrew its European application for approval after authorities questioned whether the therapeutic benefit of dosing only every two weeks outweighed the risks.

ZymoGenetics is developing interferon-lambda, which uses the same cell-signaling pathway as interferon-alfa to muster an antiviral attack. However, interferon-lambda has fewer functions in the body than interferon-alfa, meaning the therapy could be as effective but with fewer side effects.

In an early-phase trial in relapsed HCV patients—or as Williams put it, "people who know what it feels like to be on alfa-interferon"—the side-effect profile for interferon-lambda was mild. The drug is now in Phase II trials. As soon as the dose is defined, ZymoGenetics plans to begin exploring combinations with some of the small molecules in development.

Despite improvements to the side-effect profile, not everyone thinks the alternative interferons will have a major impact. "In terms of safety, I don't think they offer any benefits over what we currently have," says Mansi Shah, an infectious disease analyst at the health care consultancy Datamonitor. Aside from side effects, Shah points out, the major issue with Pegasys and PegIntron is their limited efficacy in patients with genotype 1, the type of HCV that is most prevalent in the U.S.

Idera Pharmaceuticals hopes to create a broader response by coaxing the body to launch its own reserves of interferon. The company's lead HCV candidate, IMO-2125, is a nucleic acid-based drug that stimulates toll-like receptor 9, part of a family of immune system receptors that coordinate an immune response.

"The body is inducing all interferons to fight against the infection in a more balanced way," explains Idera's CEO, Sudhir Agrawal.

Idera has completed a Phase I trial in which it gave IMO-2125 alone to so-called null responders—genotype 1 patients who do not respond to the standard interferon/ribavirin combination. The drug raised endogenous levels of interferon-alfa and reduced the viral load in 75% of the patients given the maximum dose.

By mid-2011, the company expects to have data from a Phase II trial in null responders who have been given both IMO-2125 and ribavirin, Agrawal notes. That time frame corresponds to the projected launches of the first new antivirals, Vertex Pharmaceuticals' telaprevir and Merck's boceprevir. As such, Idera believes it will be in a good position to begin studies combining IMO-2125 with the new HCV treatments.

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ISSN 0009-2347
Copyright © 2011 American Chemical Society
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