Forbes.com: Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Posted 6/29/12 on Forbes.com . Commentary on the implications of BMS restricting enrollment in COMMAND-3 to subjects with genotype 1b, which makes up only 25% of the genotype 1 patients here in the US. Also see http://www.viralmatters.blogspot.com/2012/06/presidio-pharmaceuticals-completes.html on a tx-naive patient having baseline resistance to PPI-668, Presidio's NS5A inhibitor.

Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Is a promising new class of drugs for treating hepatitis C going to be limited because patients with the most common genotype of the virus are likely to develop resistance to the medications? This is the possibility raised by a Wall Street analyst after learning that Bristol-Myers Squibb has altered the protocol for a clinical trial for its daclatasvir antiviral, which is believed to be the most potent in the forthcoming NS5a class of hepatitis c treatments.

According to ClinicalTrials.gov, the drugmaker changed the protocol to its COMMAND-3 trial, which compares its drug in combination with interferon and ribavirin to Incivek, a protease inhibitor sold by Vertex Pharmaceuticals, along with interferon and ribavarin. What was the change? Bristol-Myers restricted future enrollment to patients who have only genotype 1b HCV, rather than all genotype 1 patients (see this and this).

“This effectively eliminates from the trial the most common HCV genotype in the US – 75 percent of HCV is genotype 1 in the US, 80 percent of genotype 1 is genotype 1a,” Sanford Bernstein analyst Tim Anderson wrote in a recent investor note. “This change, some three months after the study started enrollment, suggests that some form of virologic failure has emerged in the patients with these genotypes… The NS5a class, as a whole, might be limited by the propensity to rapidly develop virological resistance, and by significant differences in potency from one viral genotype to another.”

He adds that the change in the protocol has “major strategic and tactical implications” for the hot and fast-growing hepatitis C market. How so? Several drugmakers are developing NS5a treatments and the possibility that these drugs generate resistance to the virus may prompt changes in how different types of medications are combined and, consequently, alter various corporate strategies for drug development, alliances and dealmaking.

Take Gilead Sciences. The drugmaker is developing an NS5a, which has the code name of GS5885, as well as another that is a nucleotide inhibitor, or nuke, which Gilead calls GS7977 and believes could be the cornerstone of the first all-oral regimen for hepatitis C. Gilead, you may recall, acquired GS7977 last fall as part of its $11 billion acquisition of Pharmasset, a bet that has transformed the investor view of the drugmaker (back story).

Two months ago, results of a study that combined daclatasvir with GS7977 suppressed hepatitis C in most patients four weeks after completing treatment, raising hopes about the prospects for a therapy that does not involve an injectable medication. But further collaboration between the two drugmakers appeared uncertain, because Gilead indicated a preference for developing its own NS5a drug with GS7977 (look here).

However, as Anderson notes, the Gilead NS5a drug is less potent than daclatasvir, which “increases the risk for Gilead of sticking with GS5885. On the Bristol side, their ‘go-it-alone’ strategy may be developing a hole, increasing the urgency of incorporating daclatasvir into an all-oral combination with a potent resistance-fighting nuke such as GS7977. This collaboration appears to have become more important to both parties,” he writes.

Both drugmakers declined comment on this topic, although late last month, Bristol-Myers ceo Lamberto Andreotti renewed a call for Gilead to jointly develop their hepatitis C medications. And Bristol-Myers has not responded to questions about the change in the trial protocol.

Looking ahead, Anderson sees greater potential for combination therapy that relies on three drugs, instead of two, including GS7977 from Gilead, since the response to NS5a drugs suggests there can be limitations to at least one of the agents that drug developers would want to use in a one-two punch. And he believes Gilead’s prospects for creating one “super-regimen” for all subtypes with GS7977 and GS5885 alone, or even with ribavirin, have fallen.

As for other drugmakers, the questions concerning the NS5a drugs may result in slightly extended utility for Incivek as well as Victrelis, another protease inhibitor that is sold by Merck. This also suggests additional jockeying surrounding the NS5a drugs being developed by Achillion Pharmaceuticals and Idenix Pharmaceuticals, since larger drugmakers may decide to adjust their strategies and portfolios in response to the changing dynamics of this class of treatments.