The analyst community might have already written the epitaph for Vertex Pharmaceuticals’ (NASDAQ:VRTX) Incivek and Merck & Co’s (NYSE:MRK) Victrelis, but the search for growth for the two hepatitis C treatments continues apace. The AASLD Liver Meeting became an opportunity for the two companies to showcase potential new uses in hard-to-treat populations.
They were joined by a host of competitors with new agents looking to highlight efficacy in patients such as those who have progressed to fibrosis, cirrhosis or liver transplants. In so doing, developers appear to be acknowledging that Gilead Sciences (NASDAQ:GILD), Bristol-Myers Squibb (NYSE:BMY) or Abbott Laboratories (NYSE:ABT) are likely to be first to market with the first broadly used all-oral hep C antiviral combination.
The billion-dollar drop
Forecasts for Incivek and Victrelis, the first hep C protease inhibitors that have been able to shorten the standard treatment with interferon and ribavirin, have plunged in the past 12 months on continued clinical success from Gilead’s GS-7977 (Vertex’s hep C plans play second fiddle to cystic fibrosis, September 26, 2012).
The belief is that GS-7977, the nucleoside NS5B polymerase inhibitor known generically as sofosbuvir, can eliminate interferon and side effects that include psychiatric and flu-like symptoms, which discourage many patients from seeking treatments.
Likewise, many of the compounds trailing sofosbuvir, Bristol-Myers’ daclatasvir and Abbott’s ABT-450 have not been given much attention, the belief being that one or more of these will break through and become the blockbuster that gobbles up the market. EvaluatePharma’s consensus forecast for sofosbuvir stands at $5.78bn for 2018, for example.
However, with multiple genotypes, difficult outcomes of untreated disease and growth in emerging markets, there is still much to play for in the space. Thus attention is now turning to patients resistant to treatment in the past or those for whom current therapies are unproven.
With the disease progressing from infection to liver dysfunction, fibrosis, cirrhosis, cancer and transplant – not to mention frequent co-infection with HIV – compounds that can prove to repel the virus during the various stages of the disease will be welcomed by patients and physicians.
The established players
The biggest news came from Vertex and its ex-North America partner Johnson & Johnson, which announced new data on the use of Incivek in HIV co-infected patients, with a backbone of pegylated interferon and ribavirin and HIV anti-retroviral treatments Sustiva or Reyataz. Of patients treated with Incivek, 74% had achieved undetectable hep C viral loads 24 weeks following the end of treatments, compared with 45% of those taking a placebo plus interferon and ribavirin.
Given that 25% of HIV patients in the U.S. are estimated to have a hep C co-infection – common among intravenous drug users with HIV – and the population at greater risk of liver-related disease, failure and death, this could be an important new use for Incivek and help the partners extend its lifecycle.
Data on Victrelis and Incivek in cirrhosis patients were mixed, with an analysis of cirrhotic patients who had never received hep C treatment before, demonstrating that they can successfully complete protease inhibitor therapy if ribavirin doses are reduced or erythropoietin-stimulating agents are used in the event of anaemia. However, a French compassionate-use trial in cirrhotic patients who have failed to respond to treatment suggested that severe adverse events were common in that population when treated with protease inhibitors.
Both Vertex and Merck announced phase I data for follow-on hep C drugs – Vertex’s ALS-2200 is a nucleoside NS5b inhibitor, and Merck has a protease inhibitor in MK-5172 along with the early-stage NS5a inhibitor MK-8742, which could make for a useful combination treatment. But as they are well behind the likes of Gilead, Bristol-Myers and Abbott, stretching out sales for the marketed protease inhibitors would allow both companies to maintain a presence in the space.
The newer agents
Poor treatment responders and those with advanced disease have also been a focus of newer agents, with data on Medivir and J&J’s simeprevir, Roche’s danoprevir, Boehringer Ingelheim’s combination of BI 201335 and BI 207127 along with daclatasvir getting their moments at AASLD.
Ambitiously, Medivir and J&J are pursuing treatment in post-transplant with hepatitis C – data showed that simeprevir had no clinically relevant impact on the blood levels of the immunosuppressives tacrolimus or cyclosporine in healthy participaints.
Danoprevir plus mericitabine, one of the quieter developing combinations in the field, showed that it has potential in patients who have failed or partially responded to earlier treatment: in the Matterhorn study it suppressed the virus 12 weeks after the end of treatment in up to 100% of patients, depending on genotype and previous response, when used in combination with ritonavir, ribavirin and interferon. Lower response rates were reported with an interferon-free regimen.
Like Roche, Boehringer’s combination has also been quietly developing: the private German company detailed an analysis of cirrhotic patients included in its phase II trial of the two drugs with ribavirin – a trial that significantly did not include interferon. Viral suppression was achieved in up to 50% of patients with genotype 1a and 86% of those with genotype 1b.
For now sofosbuvir is at the cutting edge, and while the continued positive news from the Gilead drug has let some of the air out of the hep C bubble, competitors have not given up (Signs are growing that the hep C ship is sailing, August 1, 2012). Success in niche populations could yet be a winning strategy.