* Pharmasset (VRUS), acquired for nearly $11 billion this week, will provide Gilead (GILD) with two developmental hepatitis C virus (HCV) polymerase inhibitors, complementing Gilead’s NS5A inhibitor and protease inhibitor candidates.
* Still, Pharmasset is a high risk acquisition given the recent competition among HCV drug developers, especially in light of the fact that Gilead could likely have acquired Vertex (VRTX) with its blockbuster HCV drug Incivek for the same price as it paid for Pharmasset.
* With the acquisition, Gilead moves to the forefront of the race to develop an all-oral HCV regimen, joining Abbott (ABT), Boehringer Ingelheim, Bristol-Myers Squibb (BMY), Vertex (VRTX) and Roche (RHHBY).
* Gilead is hoping to repeat its success in the HIV market, perhaps finding synergy between its HIV and HCV drug development strategies and possibly focusing on HIV/HCV co-infected patients.
Pharmasset
Pharmasset’s pipeline contains three hepatitis C (HCV) drugs and one HIV compound. In HCV, mericitabine (RG 7128) is in phase II, PSI-7977 is in phase II with phase III planned, and PSI-938 is in phase I. Racivir is an oral, once-daily nucleoside analog for HIV that has completed a phase II study. The company focus, at least recently, has been HCV.
Pharmasset has licensed mericitabine, a nucleoside polymerase inhibitor, to Roche. Roche also entered into an agreement with Merck in May 2011 where both companies will collaborate to investigate other novel HCV combinations.
PSI-7977 is a nucleoside polymerase inhibitor, for which Pharmasset owns all the rights. The potency of PSI-7977 in early HCV trials has been impressive. In the PROTON trial, 100% of genotype 2 and 3 patients receiving the drug achieved sustained viral response (SVR), maintaining HCV RNA below detectable levels 24 weeks post treatment. In a phase IIa study on treatment naïve, genotype 1 patients, 94% and 93% of patients achieved HCV RNA below detectable levels after 28 days of treatment.
PSI-938 is a nucleotide polymerase inhibitor that has demonstrated potency against the S282T mutant HCV, which has reduced sensitivity to several other nucleoside analogs including RG7128, PSI-7977, NM283, and IDX184. PSI-938 is metabolized through a different pathway than RG 7128 or PSI-7977. In the NUCLEAR study, PSI-938 is studied as a monotherapy and in combination with PSI-7977. As a monotherapy, PSI-938 demonstrated an impressive >5 log decline in HCV RNA at day 14. The decline in HCV RNA was similar for monotherapy and combination therapy.
Gilead
Gilead is studying seven compounds for HCV. Two could be an especially good match for PSI-7977. GS-9451 and GS-9256 are both NS3 protease inhibitors that could be combined with a potent nucleoside polymerase inhibitor like PSI-7977. However, if PSI-7977 isn’t the right combination, Gilead has its own nucleotide and non-nucleoside polymerase inhibitors. Gilead’s rationale for the Pharmasset acquisition is clouded by these similar compounds. In any case, it will take near five years to successfully develop any of these HCV drugs and begin to recoup the $10 billion+ price tag. Gilead is betting on a winning all-oral HCV combination. In this regard, PSI-938, which has shown strong monotherapy results and may help prevent resistance, is an interesting fit. Another potential direction for Gilead is to develop its HCV drugs specifically for HIV / HCV co-infected individuals, and approach that plays to its strengths in the HIV market and an approach not yet a focus of other HCV programs.
Competition
In any scenario, Gilead now moves to the forefront of a furious race to develop the first all-oral HCV therapy, avoiding poorly tolerated interferons with long treatment durations. A flurry of new results and planned trials were announced at the American Association for the Study of Liver Disease (AASLD) annual meeting in San Francisco Nov 4-8. The latest results suggest that a protease inhibitor, a polymerase inhibitor, and ribavirin may be a winning combination. Table 1 summarizes current approaches.
At AASLD, Boehringer Inge heim released data from its SOUND clinical trials that evaluate the combination of BI 201335, a protease inhibitor, and BI 207127, a non-nucleoside polymerase inhibitor. Results showed 100% rapid viral response (RVR) at 4 weeks in genotype 1 treatment naïve patients taking the highest dose of BI 207127 (600mg). In another study of that all-oral combination, SVR at 12-weeks was 70%, which is the SVR rate that Incevik provides with pegylated interferons and ribavirin.
Bristol-Myers Squibb also demonstrated impressive results in study with its BMS-60052, an inhibitor of the NS3 protease, and BMS-790052, an NS5A inhibitor. In Japanese null responders with genotype 1a and 1b HCV infections, 90% achieved SVR at 12-weeks. Vertex, the current market leader, announced that it will initiate an all-oral trial with Incevik, a protease inhibitor, and it’s VX-222 non-nucleoside polymerase inhibitor plus ribavirin. With Roche also in the mix for an all-oral therapy and Johnson & Johnson likely the next tomarket with its impressively potent TMC-435 protease inhibitor, the HCV market has steep competition. Although Johnson & Johnson does not yet have a polymerase inhibitor or all-oralcombination, acquiring Inhibitex or a similarcompany would improve its competitive position.
