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Pharmasset (VRUS) is a biotech company focused on the development of HCV therapeutics. It has multiple drugs in development, all based on its core strength in RNA nucleoside analog chemistry.
The current standard of care for HCV is a combination of pegylated alpha interferon (IFN-α) and ribavirin taken for up to 48 weeks depending on patient response. Unfortunately, only 55% of patients on this regimen achieve a sustained virologic response (SVR), where levels of HCV RNA remain undetectable six months after treatment has stopped.
Both Vertex (NASDAQ:VRTX) and Merck (NYSE:MRK) intend on launching new HCV treatments in 2011 based on a new class of compounds known as NS3 protease inhibitors (PI). These drugs herald a new breed of targeted medicines- sometimes called direct acting antivirals (DAA). The advantage is a significantly higher cure rate and shorter duration of treatment. However, these drugs are susceptible to viral resistance and require concurrent use with both interferon and ribavirin.
A second type of compound focuses on inhibition of the NS5B polymerase. Of these there are two classes, non-nucleoside polymerase inhibitors (non-nucs), and nucleoside polymerase inhibitors (nucs). Both have been shown to be effective in combination with interferon + ribavirin, but non-nucs, like protease inhibitors, are also prone to mutation driven resistance. On the other hand, nucleoside polymerase inhibitors have a high barrier to resistance.
In studies shown by Roche (OTCQX:RHHBY), no resistance was observed in cultures treated with R7128, its nucleoside polymerase inhibitor licensed from Pharmasset, for two weeks as monotherapy. Cultures treated with non-nucs or protease inhibitors all developed resistance. R7128 was also shown to reduce the formation of resistant colonies when added to either a non-nuc or PI. These studies show the flexibility of nucs in combination treatment.
The race is on to develop the next generation of HCV treatments even before the first generation has been approved. Side effects of interferon + ribavirin therapy include fatigue, flu-like symptoms, rash, and nausea. The goal for drug developers is a treatment that can dispense with these two drugs. Heavy viral loads and high mutation rates preclude the use of monotherapies, hence, multi-drug cocktails is the next best thing.
At least seven companies are pursuing the development of drug combos for HCV. Nearly all consist of a protease inhibitor combined with a compound of a different class. Additive or synergistic effects and non-overlapping resistance profiles drive the combo selection.
Pharmasset’s lead compound is currently in multiple Phase II trials. Results from the 12 week R7128 treatment portion of a 48 week triple combo PROPEL trial with interferon + ribavirin trial have been released showing high rapid virologic responses and a low rate of adverse events. Full SVR data will be available in 2011. A longer trial involving 24 weeks of dosing called JUMP-C is now dosing. Phase III studies are expected to begin in 2011 as well, with an NDA filing anticipated in 2013.
Roche is conducting a combination trial of R7128 with the protease inhibitor R7227 from Intermune (NASDAQ:ITMN). Results from a 14 day INFORM-1 trial showed the drugs were safe when administered together and resulted in a sustained viral load reduction. Continuing studies will add the drug Ritonavir to boost R7227 without increasing side effects.
The balance of Pharmasset’s HCV pipeline consists of PSI-7977, which is enrolling patients in Phase IIb and PSI-938, which has completed Phase 1b. The company is planning studies combining these two nucs; initial data should be available Q1 next year. Phase II combo studies are expected to begin around the second or third quarter of 2011.
Nucleoside polymerase inhibitors look to have significant potential in HCV therapy, with possible advantages over protease inhibitors and non-nucs. Pharmasset is the leader in nuc development. A bet on Pharmasset is a bet on the entire compound class.

Disclosure: Long, RHHBY.PK, VRUS, MRK
Source: Pharmasset Rides High on Compound Development for HCV Drugs