Two HCV Meds are Better than One for Pharmasset
Oct05

Two HCV Meds are Better than One for Pharmasset

An announcement hinting at the possibility of an all-oral hepatitis C treatment had researchers abuzz last week. Pharmasset, a Princeton, NJ company specializing in antiviral discovery, alluded to upcoming conference data that suggested a combination of ribavirin (a generic antiviral) and Pharmasset’s experimental pill PSI-7977 lowered viral counts to near-undetectable levels in a ten-patient trial (kudos to Adam Feuerstein of The Street for initial reports. . . here at The Haystack, editor Lisa Jarvis has also tracked HCV drug development for some time now). Hepatitis C virus (HCV) is a chronic liver virus with an estimated 180 million infected worldwide. Two relatively new extermination options are available: Merck’s Victrelis (boceprevir) and Vertex’s Incivek (telaprevir), approved by the FDA ten days apart last year. Unfortunately, though both drugs are administered orally, each requires co-administration of injected interferon, which can cause severe fatigue and flu-like symptoms. Both oral drugs inhibit the same enzyme: the NS3 protease, which drags down a patient’s immunity and helps the virus to produce new copies of its proteins. In contrast, the ribavirin and PSI-7977 combination involves no injections, making it easier for patients to follow the appropriate medication schedule, and lessening side effects. The PSI compound also clips a different target: NS5B polymerase, an RNA enzyme that helps viral genetic replication. In addition, the PSI-7977 is “pan-genotypic,” meaning it inhibits several genetically different strains of HCV.  A 2010 article (J. Med. Chem. 2010, 53, 7202) details the full story of PSI-7977’s synthesis. Notice anything interesting? It’s really a nucleotide strapped on to a P-chiral prodrug, a “protected” substance the body later converts to the active drug species. This P-chiral motif is seen more often in asymmetric phosphine ligands (compounds that stick to metal catalysts during reactions to modify catalyst activity) than in drug development – often chemists install drug chirality at carbon or sulfur instead. The initial drug lead was actually a mixture of both phosphorus enantiomers (“Sp” and “Rp”), until process chemists realized they could selectively crystallize out the more potent “Sp” product. In the meantime, Pharmasset scientists haven’t stopped pushing their HCV portfolio forward: a recent paper (J. Org. Chem., 2011, 76, 3782) details a new lead: PSI-352938, a cyclic phosphate prodrug attached to a purine-fluororibose nucleotide warhead. The team credits this new prodrug design with a 10-100-fold increase in potency over the “naked” adenine drug for NS5B RNA polymerase inhibition. PSI-352938 recently completed a multiple ascending dose Phase I trial, in which a daily 200 mg dose brought HCV titres down below the detection limit in 5 of 8 patients.     ...

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Merck Seals Hepatitis C Pact with Roche

Merck is going bare knuckles in the marketing battle for Hepatitis C patients. Just days after receiving FDA approval to market its protease inhibitor boceprevir, now known as Victrelis, it revealed Roche has signed on to co-promote the drug alongside its pegylated interferon drug Pegasys, a cornerstone of HCV treatment. Competition in the HCV arena is expected to be fierce, as Vertex Pharmaceuticals is expected to get the FDA nod to market its own protease inhibitor for HCV telaprevir, to be marketed as Incivek, no later than Monday. Both the Merck and Vertex drugs will need to be taken in combination with the current standard of care, pegylated interferon and ribavirin. Although the two drugs have never gone head to head in the clinic, telaprevir is widely considered to have a better dosing regimen and a slight safety and efficacy edge over Victrelis. As such, analysts have believed that Merck’s main advantage in the HCV market would be its ability to promote Victrelis alongside its own pegylated interferon PegIntron. Now, it will also have Roche’s sales force out there hawking Victrelis with Pegasys, as well. No financials for the deal were announced, so its hard to say at this point how much Merck is giving up in its quest for a bigger piece of the HCV market. It’s also important to note that this is a non-exclusive pact, so time will tell whether Roche and Vertex establish a similar alliance. The deal also allows Merck and Roche to “explore new combinations of investigational and marketed medicines.” As readers will recall, the ultimate goal is to eliminate the need for interferon and ribavirin, which have harsh side effects, and treat HCV using only a cocktail of pills. Roche and Merck each have promising small molecules against HCV in their pipelines: Merck has vaniprevir, an NS3/4a protease inhibitor in Phase II trials, while Roche has the polymerase inhibitor RG7128, the protease inhibitor RG7227, and the earlier-phase polymerase inhibitor RG7432. Read here for past coverage of the race to get new HCV drugs to...

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