Hepatitis C Harm Reduction Project

FDA Reviews Research Issues for New Hepatitis C Drugs

The Food and Drug Administration’s Antiviral Drugs Advisory Committee met on October 19 and 20 to discuss issues regarding the development and approval of new drugs to treat hepatitis C. A number of investigational drugs – particularly hepatitis C protease and polymerase inhibitors – are far along in development, making the meeting a timely one. Questions examined by the Committee related focused on four broad areas:

1. Identification of appropriate control arms (in clinical trials, people receiving the investigational drug are compared to those in the ‘control arm’, who typically receive the standard of care – pegylated interferon and ribavirin – plus placebo)

2. Populations for study (including whether to include people with all hepatitis C genotypes, people with advanced liver disease, and people co-infected with HIV; the importance of studies in people who have never been previously treated for hepatitis C vs. in people who have prior treatment experience but did not clear the virus; racial/ethnic diversity in study participants; the need for data on new drugs in children and in liver transplant recipients)

3. Endpoints (the measurement of treatment success – for hepatitis C, typically a sustained virologic response [SVR], defined as undetectable viral load six months after the end of treatment; other possible endpoints include normalization of liver enzyme values such as ALTs, and reduction in liver inflammation as measured by biopsy)

4. Long-term follow-up (whether people with an SVR after treatment remain undetectable several years later, and whether successful treatment results in improvements in the liver and reductions in complications of liver disease [such as decompensated cirrhosis and liver cancer])

Jules Levin of NATAP presented a community perspective (online here, or here for PowerPoint file), emphasizing the importance of research new drugs in people co-infected with HIV prior to approval, and the desirability of study designs that allow participants to receive two investigational agents, due to concerns about drug resistance (resistance to new hepatitis C protease and polymerase inhibitors can emerge quickly and compromise treatment success). The Advisory Committee also included two community members and long-time advocates, Tracy Swan of Treatment Action Group and Bob Munk of AIDS InfoNet.

Documents from the meeting, including slides and transcripts, are available online here.

Highlights from the meeting, and other research issues, follow below.

Exclusion of African Americans from Schering Hepatitis C Protease Inhibitor Study

A group of community advocates have written the FDA with concerns about a study of a new hepatitis C drug that initially excluded African Americans.  The study, sponsored by Schering-Plough, investigates different doses of SCH 503034 (a new hepatitis C protease inhibitor) in combination with Peg-Intron (pegylated interferon), with or without ribavirin.  The initial study design called for the enrollment of 300 people with hepatitis C genotype 1 who did not respond to prior hepatitis C treatment.  The study was recently amended to add an additional group who would receive a higher dose of SCH 503034 (800 mg, compared to initial doses of 100, 200, or 400 mg) in combination with Peg-Intron; this higher-dose arm allows enrollment of African Americans.

There's been some debate within the community about Schering's initial exclusion of African Americans from this study, with different perspectives on the scientific justification (which hinges on the well-established fact that for unknown reasons, African Americans have lower overall response rates to interferon-based treatment for hepatitis C) and ethical issues.  For some perspectives, see the following articles and posts:

Press release (PDF) and background document (PDF) from the Hepatitis C Action and Advocacy Coalition (HAAC) and Community HIV/AIDS Mobilization Project

No Blacks Allowed? A Drug Trial Comes Under Fire - article from Poz Magazine, April 5, 2006

Advocates Slam 'Racist' Drug Trial - article from Newark Star Ledger, March 29, 2006

Blog posts from Karama C. Neal here and here

See also Test for All, Cure for All - a blog from Hepatitis C Multicultural Outreach.

Download the letter to the FDA here, or read the text by clicking on the link below.

Holly Hagan on Hep C and Drug Use

Attached are the slides from Holly Hagan's plenary talk on the epidemiology of hepatitis C and injection drug use in New York, from our recent conference.  Her presentation suggested that we're getting closer to understanding the dynamics of the hepatitis C epidemic among injection drug users (IDUs), and that while prevention will be difficult, it may not be impossible.

Here are some of her conclusions (adapted from her last slide):

HCV is easily transmitted and difficult to prevent -- we can’t apply what we know about HIV prevention to HCV and expect the same results.

However, variation in prevalence and incidence indicates that there are cases where HCV spreads more slowly:

Prevalence between 30 - 90%

Time to HCV seroconversion: 1.5 - 3.5 years from initiating drug injection

This is logical, because not all IDUs are alike and not all injection settings are alike.

We need to study this variation, to understand how we can alter behavior, beliefs and settings to reduce HCV transmission.

For more, see the full set of slides -- and check out the upcoming National Viral Hepatitis Prevention Conference in December, 2005.

Download epi_of_drug_use_and_hcv_in_nyc_hagan_2005.ppt [PowerPoint file]

More from the Liver Meeting

Some quick news and updates:

- A handful of studies explored refining the duration of hepatitis C treatment to improve response and tolerability. Specifically, researchers looked at the value of extending the duration of treatment for people with genotype 1 beyond 48 weeks, and shortening the duration of treatment for people with genotype 2 or 3 to less than 24 weeks. The latter approach seems promising, but the jury's still out on the value of extending treatment for people with genotype 1 -- it may work best for a subset of people, depending on how rapidly and how much their viral load declines during the early weeks of treatment. In general, we're seeing a trend towards individualizing the duration of treatment, but there's no clear rules or guidelines yet.

- New drugs: Idenix' NM283 was the subject of a presentation yesterday, based on results from initial phase I/II studies in people with hepatitis C. At the highest dose (800 mg, once a day), people with genotype 1 experienced on average a 1.2 log drop in HCV viral load by day 7 of NM283 monotherapy. Preliminary results from a 28-day study combining NM283 with pegylated interferon were also reported, though difficult to interpret without a control group. Perhaps the most exciting thing about this drug is how far along it is in clinical development, relative to other investigational agents. Vertex and InterMune also presented posters about their HCV protease inhibitor programs -- Vertex has completed a preliminary study in healthy (HCV-negative) volunteers, and is now moving into an initial study in people with HCV. InterMune hopes to have a compound in clinical trials later next year. Both companies are hoping their agents avoid the cardiac toxicity which led to the cancellation of Boehringer Ingelheim's BILN 2061.

That's it for now -- more thoughts, and sources for other updates, over the next few days.

Update from the Liver Meeting

I'm at the American Association for the Study of Liver Diseases' annual Liver Meeting, the major U.S. conference on hepatitis C and other liver diseases. Here's some quick notes from the research presented so far:

- Daily marijuana (cannabis) smoking appears to accelerate and worsen fibrosis progression, according to French researchers. They found that long-term daily marijuana smokers were more likely to experience rapid fibrosis progression, and more likely to have serious fibrosis, than non-smokers or occasional smokers. Other research to be presented today will suggest a biological mechanism to explain these findings. While this data should be confirmed through other studies, it suggests that people with chronic hepatitis C should avoid daily marijuana smoking.

- A growing body of data implicates insulin resistance (associated with obesity and diabetes) in poorer responses to hepatitis C treatment. Poorer response to treatment has been seen in people with greater weights and body mass indices, and insulin resistance may explain why this group is less likely to experience sustained virologic responses. In test tube studies, high insulin levels appear to mitigate the antiviral effects of interferon.

- New research suggests that in people who achieve sustained virologic responses, very low levels of hepatitis C can persist for several years, despite undetectable viral loads using conventional tests. The implications of these findings is unclear -- rates of relapse to detectable viral loads remain low in long-term follow-up studies, and growing evidence shows that people who achieve sustained virologic responses have good long-term outcomes overall, low rates of liver cancer, and improvements in fibrosis and liver inflammation. But this research suggests that it would be premature to classify a sustained virologic response as having "cured" hepatitis C infection.

- New (acute) hepatitis C infection can be successfully treated with only 3 months of pegylated interferon monotherapy (e.g., no ribavirin), according to two new studies from Europe. One of these studies, conducted in Italy, included a large proportion of acutely infected injection drug users. Sustained virologic response rates were very high (in the range of 70-90%), and tolerability and adherence were very good. These results suggest the value of very early diagnosis and treatment, particularly in groups with high rates of new infections -- injection drug users. Currently, very few hepatitis C infections are diagnosed during the acute phase.

More later -- several presentations today will provide results on clinical trials of new drugs to treat hepatitis C.

InterMune Update

Despite my earlier pessimism about InterMune's fortunes and future earlier this year, I was encouraged by their presentation to investors and financial analysts at the recent UBS Global Life Sciences Conference (audio archive here).

InterMune's gone through a change in leadership over the past year, and looks to be getting their financial house in order. More importantly, they're focusing much of their research efforts on hepatitis C.

NIH Response on Harm Reduction and Needle Exchange

Earlier this year, the Harm Reduction Coalition (HRC) sent a letter to the National Institutes of Health (NIH), following an inquiry to the NIH questioning research on harm reduction, drug users, needle exchange, and HIV from Rep. Mark Souder (see background and original letters from HRC and Rep. Souder). HRC's letter challenged Rep. Souder's characterization of harm reduction and research on drug use and HIV, and called upon the NIH to affirm the body of research demonstrating the effectiveness of needle exchange.

HRC received a response from Dr. Nora Volkow, director of the National Institute on Drug Abuse (NIDA), stating that:

"...the majority of studies have shown that NEPs/SEPs are strongly associated with reductions in the spread of HIV when used as a component of comprehensive approach to HIV prevention.... NIDA will continue to work with research communities and various stakeholders to ensure that the research findings surrounding NEPs/SEPs are presented in a manner consistent with the current state of science."

In the current political climate, ideologically-motivated attacks on science and research -- particularly around HIV prevention -- have become increasingly common. The NIH deserves credit for standing by the quality and integrity of research on needle exchange, and resisting the further politicization of science.

Full text of Dr. Volkow's response appears below.

Notes on Hepatitis C treatment and research

A few links on current and future treatment:

1. Roche has filed an application to the Food and Drugs Administration to approve Pegasys (pegylated interferon) and Copegus (ribavirin) for treatment of hepatitis C in people co-infected with HIV (see press release). This filing is based on results of the APRICOT study (discussed here and here), which found that Pegasys/Copegus was more effective in co-infected people than Pegasys alone or standard interferon/ribavirin. The FDA has granted fast-track status to the application, with a decision expected in early 2005.

The value of this application is largely symbolic -- people co-infected with HIV can already take Pegasys and Copegus for hepatitis C treatment -- but may increase awareness of treatment options and efficacy in co-infected people and their health care providers. Roche has also requested FDA approval for the use of Pegasys in hepatitis B treatment (see press release). Roche's Pegasys currently has over 57% of the U.S. market for pegylated interferon, trailed by Schering-Plough's Peg-Intron (see Reuters article).

2. Vertex Pharmaceuticals announced the successful completion of the dosing phase of the first human study of VX-950, an investigational hepatitis C protease inhibitor (see press release). VX-950 was studied at a range of single doses in 'healthy volunteers' (people not infected with hepatitis C). Based on blood levels, the company believes the drug will achieve concentrations needed to suppress hepatitis C replication, and may be suitable for twice-daily dosing. Further studies in people with hepatitis C, given for up to 14 days, are expected to begin by the end of 2004.

Vertex recently met with a few community advocates and treatment writers to discuss their development plans for VX-950 and merimepodib, another drug being investigated for hepatitis C treatment in combination with pegylated interferon and ribavirin. I'll be writing in more detail about this meeting later. For more on hepatitis C protease inhibitors, see this article; for more on merimepodib, see here under 'IMPDH inhibitors'.

3. A new review published in the Journal of Hepatology suggests that amantadine may be useful as part of triple-combination therapy (with interferon and ribavirin) for people who do not respond to standard combination therapy (abstract here). Amantadine is an antiviral drug, like ribavirin, that has been researched extensively in hepatitis C treatment, with conflicting results. The authors of the review combined data from all available trials, finding that amantadine shows a marginal benefit in non-responders, but not in people who were treatment naive, or who initially responded to therapy but subsequently relapsed without achieving a sustained virologic response.

The authors conclude that these findings should be confirmed in new trials. For more on amantadine, see here.

Chiron's Hepatitis C Patents

The Los Angeles Times reports that Chiron, the California biotech responsible for the identification of the hepatitis C virus (HCV) in the 1980s, has introduced a new policy for companies wishing to license its HCV patents. Chiron holds over 100 patents related to the HCV genome, which won't expire until 2015. Any company that develops a new drug targeting hepatitis C (such as a protease inhibitor), or a diagnostic test to detect and measure HCV (viral load; test for screening the blood supply), needs to license Chiron's patents, typically by negotiating a licensing fee and royalties on product sales. Chiron typically charges each company millions of dollars in licensing fees during research and development alone, and makes millions more each year in royalties from HCV tests.

Chiron's enforcement of its patent rights has slowed the pace of HCV drug development considerably, as other companies struggled to reach reasonable terms for licensing -- with Chiron filing several lawsuits beginning in the late 1990s that effectively halted much of the research into HCV protease inhibitors. Nobody can say how close we'd be today to having an effective HCV protease inhibitor on the market, were it not for Chiron's use (or abuse) of its patent position. But it's arguable that Chiron's actions -- or, put differently, greed -- will result in thousand of needless deaths from HCV-related liver disease over the next several years.

Hepatitis C Drug Pipeline

It seems like every week, companies are issuing press releases about their new hepatitis C drug candidates—protease inhibitors, polymerase inhibitors, immunomodulators, you name it and it seems like everyone and their cousin is cooking something up in their labs. And every few months you’ll see a batch of reports from scientific conferences touting new data—this week it’s Digestive Disease Week (DDW) in New Orleans, last month it was the 39th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin. How do you keep up, and how do you make sense of it all?

If you want to hear about all the latest drug development news and data, here are three websites (in alphabetical order) that do a good job of covering the waterfront:

HCV Advocate/Hepatitis C Support Project

HIVandHepatitis.com

National AIDS Treatment Advocacy Project (NATAP)

All three sites compile news stories and conference reports, and all three let you sign up for email updates. Each is well worth checking out.

HCV Advocate also maintains a chart [PDF version] of hepatitis C treatments in clinical development (clinical = human studies; preclinical = in vitro/test tube and animal studies), last updated in February. Another chart that includes compounds in preclinical development is available here, last updated in November.

Now, as for making sense of it all….