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Gilead Sciences’ (NASDAQ:GILD) sofosbuvir has passed all its preliminary examinations, and now is looking like a good bet for regulatory submissions in the coming months. The last of four phase III trials in combination with one or both of the mainstays of current hepatitis C treatment has met its primary endpoint, likely providing sufficient data to support approval in combination therapy in the six major genotypes of the virus.

The pivotal data leave the California company tantalisingly close to reaching the holy grail of hep C treatment: an all-oral treatment that removes interferon and ribavirin – and their associated side effects – from the treatment regimen. With filing of the fixed-dose combination with GS-5885 not expected until next year, a limited approval of sofosbuvir should help Gilead begin to earn back the $11bn it spent to acquire the candidate.

Cold Fusion

The company reported data from the Fusion trial of an all-oral combination of sofosbuvir, formerly known as GS-7977, with ribavirin in second-line genotype 2 and 3 patients. Both 12-week and 16-week treatment regimens showed superiority to a historical control of the pegylated interferon alfa and ribavirin.

The historical control achieved a virological response 12 weeks after the end of treatment in 25% of patients; the 12-week course of the Gilead combination achieved the same response in 50% of patients in the 12-week treatment arm and 73% in the 16-week arm – a statistically significant difference.

Response rates were better in genotype 2 patients, 86% for 12 weeks and 94% for 16, than in the genotype 3 patients, 30% and 62%, pointing to potentially different regimens for the two different populations.

Removing interferon, an injectable drug that has flu-like side effects, would be a step forward for patients, as it has been a barrier to compliance or even initiation of treatment (EASL – Gilead-BMS score all-oral hep C win but will pairing last?, April 19, 2012).

However, using ribavirin does not completely eliminate the problem of side effects, as its label has a black box warning of birth defects when used by pregnant women and haemolytic anaemia that can lead to worsening cardiac disease and myocardial infarction.

Data from Fusion join those from Positron, with ribavirin in genotype 2 and 3 patients intolerant of, or ineligible or unwilling to take interferon; Neutrino, with interferon and ribavirin in first-line patients with genotype 1, 4, 5 and 6 patients; and Fission, with ribavirin, in first-line treatment of genotype 2 and 3 patients (Gilead’s sofo shines in hep C while Idenix’s nucs bomb, February 5, 2013).

On The Sofo

Even in these combinations, sofosbuvir should compare well against the newer agents, the protease inhibitors Incivek and Victrelis, and its pan-genotypic efficacy and shorter treatment duration could also allow Gilead to charge a premium to the protease inhibitors’ already eye-watering prices. The Vertex Pharmaceuticals (NASDAQ:VRTX) and Merck & Co. (NYSE:MRK) products have only been indicated with interferon and ribavirin for genotype 1 patients.

In genotype 1, sofosbuvir stacks up pretty well. In the Neutrino trial, the treatment regimen was 12 weeks; Incivek and Victrelis are both used for 12 weeks, but patients continue on the peg-riba combination for at least another 12 weeks, so specialists and patients would likely see the advantages of an interferon-sparing drug. Of the patients infected with genotype 1, 89% achieved a viral response, compared with 75% for Incivek in its much larger pivotal trial in genotype 1 alone.

The quick progress of sofosbuvir has gone a long way towards explaining the plummeting forecasts for the protease inhibitors, Incivek in particular. Together with Johnson & Johnson (NYSE:JNJ) and Mitsubishi Tanabe Pharma’s ex-U.S. rights for the compound, known generically as telaprevir, Incivek achieved blockbuster sales in 2011 and 2012, its first two years on the market. However, the 2016 consensus forecast has been trimmed by $2bn in the past 12 months, EvaluatePharma data reveal.

The seemingly unstoppable progress of the compound known flippantly as “perfectivir” has been responsible for much of Gilead’s valuation rise since the California group acquired it with the buyout of Pharmasset. So far, it has lived up to expectations, but there is still plenty for sofosbuvir to play for.

Trial name Trial ID
Fusion NCT01604850
Source: Regulators Await Gilead's Hep C Candidate