Last week, Inhibitex (NASDAQ: INHX) updated guidance on its program in HCV with positive top-line data from the first cohort of a trial of INX-189 in treatment-naïve patients infected with genotype 1 HCV. Patients in this arm received 200 mg of Inhibitex’s nucleotide polymerase inhibitor INX-189 once daily and saw a median reduction in viral load of 4.25log in only 7 days of treatment. Other arms in the trial include 100 mg as monotherapy twice daily, 100 mg with food, and 100 mg with ribavirin. It is possible that a fifth arm will be added at a higher dose in the coming months. Further along in development than its genotype 1 program, Inhibitex’s program of INX-189 in genotype 2/3 treatment-naïve patients is in Phase 2 study in combination with ribavirin and pegylated interferon, the current standard of care. The primary endpoint of this study is rapid virologic response, defined as HCV below the limit of detection within 28 days of dosing. Secondary endpoints include SVR12 and SVR24; SVR24 has typically been the FDA’s standard for an HCV cure. As with other companies in the HCV space, Inhibitex’s goal is to eventually develop an interferon-free regimen, and management provided guidance projecting INX-189 to be on the market in an all-oral treatment regimen around 2016.
To continue development of INX-189, Inhibitex is evaluating INX-189 in combination with other directly acting antivirals (DAAs). Although management would not disclose which DAA is being tested, a Phase 1 drug-drug interaction study has begun in healthy volunteers with INX-189 and another DAA. Results from this trial, which should be available in 1Q2012, will inform the design of trials in 2012 in genotypes 1-3 of an all-oral regimen. Management noted that other DAAs will most likely be tested, and many different combinations are being considered to inform design of an eventual Phase 3 program.
One class of DAA being considered for combination therapy is the HCV protease inhibitors (PIs); Merck’s boceprevir and Vertex’s telaprevir are the two commercially available drugs in this class approved earlier this year. Management disclosed that in cell-based assays, boceprevir has an additive effect with INX-189 while telaprevir has a detrimental effect. Pharmasset has reported similar results in their own studies, noting that telaprevir’s off-target inhibition of an esterase required to cleave the nucleotide DAAs to their active form decreases the activity of these prodrugs in combination with Vertex’s PI. This is obviously bad news for Vertex. While telaprevir outperformed boceprevir in combination with interferon and ribavirin, a shift in HCV treatment away from interferon and towards an all-oral regimen may negate all of Vertex’s advantage. If telaprevir does prove to be detrimental for nucleotide DAAs in humans and boceprevir ends up as the PI of choice for an HCV cocktail, Vertex’s flagship program could be dead in the water. It is too early to tell, however, as results from cell-based assays and results in people can differ dramatically.
The HCV space continues to evolve as the polymerase inhibitors take center stage. Management projects the interferon free era of HCV treatment to begin in 2015 and expects to be competitive in this arena. Roche’s recent acquisition of Anadys and Pharmasset’s continued attention for its robust clinical program in HCV polymerase inhibitors across many genotypes of the virus both highlight how important this therapeutic area has become. Inhibitex jumped more than 100% when its data was announced, and the Phase 2 program is still early in development. Many variables still need to be ironed out, such as what the proper dose should be and what DAA(s) are best for combination therapy. HCV affects 4 million in the US alone and 170 million worldwide. With a patient population that large, any company that can develop a cure stands to reap the rewards, and Inhibitex is one of many well on the way to this goal.
Disclosure: No position in any stocks mentioned.
