One of the biggest obstacles to treatment for people with hepatitis C is that the drugs that we have now – pegylated interferon and ribavirin – just aren’t that good. They have a range of potentially severe and even life-threatening side effects that deter a lot of people from seeking treatment, especially people with a history of depression, which can be brought on or worsened by interferon. And they don’t work for everybody: treatment only results in long-term clearance of the virus (a sustained virologic response, where hepatitis C is undetectable six months after ending treatment) about half the time. Chances of success are lower for many groups, including African-Americans, people co-infected with HIV, and those with genotype 1 – the most common strain of hepatitis C in the U.S. (for two good fact sheets explaining hepatitis C genotype see Genotype from the Easy C Facts Series by the Hepatitis C Support Project/HCV Advocate and also HCV genotypes from the Hepatitis C Council of New South Wales in Australia -- both fact sheets are PDF files). Furthermore interferon needs to be injected – a big disincentive for a lot of people, particularly former drug injectors wary of relapse. All of which adds up to a compelling need for new drugs.
That’s why research presented a year and a half ago at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) sent ripples of excitement and hope throughout the hepatitis C community. Researchers from Boehringer Ingelheim (BI) presented dramatic data on a brand new drug, BILN 2061. BILN 2061 is the first drug successfully tested in humans that specifically targets the hepatitis C protease (technically, the NS3 serine protease), an enzyme essential for making new copies of the virus. BILN 2061 is a protease inhibitor: it binds to the active site of the NS3 serine protease, blocking its action and shutting down viral replication.
People in the studies took BILN 2061 for two days and saw their hepatitis C viral load drop by over 100-fold (for instance, from 2 million copies to less than 20,000 copies) before returning to original levels within a week. A couple people saw their hepatitis C viral load fall by 1,000 fold (e.g., from 2 million down to 2,000). These initial results were astonishing; in the words of Dr. Charles Rice, a prominent researcher who directs the Center for the Study of Hepatitis C in New York, “sort of a hush fell over the audience” (quoted in “H.I.V. Lessons Used in Hepatitis C Treatment” by Andrew Pollack, New York Times, 3/11/03, section F, page 6).
These drops in viral load compare favorably to, or even exceed, those seen after 48 hours of standard treatment with pegylated interferon and ribavirin. Notably, all study participants were infected with hepatitis C genotype 1, considered hardest to treat. The results presented at the 2002 AASLD meeting were subsequently published one year later in a letter to the prestigious journal Nature from BI’s Daniel Lamarre and colleagues. In an accompanying commentary, Charles Rice expressed cautious “hope that this news marks the beginning of a stampede of new compounds into clinical trials, and the dawn of new treatment options for hepatitis C.” (The letter and comment appear in the November 13 2003 issue of Nature; email me if you want the PDF files).
But this hope was tempered by an October 28, 2003 press release from BI regarding the online publication of the Nature letter: “Routine chronic safety testing of high, supra-therapeutic doses in animals did, however, show relevant side effects which need further analysis. Boehringer Ingelheim is currently studying the available pre-clinical data in order to decide on their impact on the clinical development of this substance. There are currently no trials ongoing with BILN 2061 and decisions about future trials will be made after thorough evaluation of toxicity findings in animal studies.”
This announcement followed months of rumors that cardiac (heart) toxicity had been seen in two monkeys given high doses of BILN 2061 – doses higher than humans would use (the studies desribed above used 200 mg twice a day). Larger human studies of BILN 2061 that had been planned for 2003 never materialized. Since the press release, BI has made no further public statements on the development status of BILN 2061 or their evaluation of animal toxicity data, though development of the compound is believed to be on indefinite hold while BI pursues one or more other candidate protease inhibitors.
So don't hold your breath waiting for BILN 2061 to hit the market. But the story's not over for hepatitis C protease inhibitors -- other drugs are in development, and some have been moving into preliminary human studies.
In part 2: Beyond BILN 2061 – What we’ve learned and what lies ahead