Data For Gilead’s Rising Hep C Star Sofosbuvir Support Initial Filing

Gilead reported results from three Phase III trials in February, with data strong enough to support U.S. and European filing for sofosbuvir, the nucleoside it plans eventually to make the foundation of a fixed-dose pill available by 2015.

Gilead Sciences Inc. released positive data in February from the last three of a series of four pivotal trials designed to support claims for its nucleoside polymerase inhibitor sofosbuvir in hepatitis C, making an initial filing for the antiviral certain for mid-2013 and bringing into sight the goal of a once-daily sofosbuvir-based pill to fight the infection.

Data from the FISSION and NEUTRINO studies announced Feb. 4 demonstrate that a sofosbuvir-based regimen can shorten the duration of hepatitis therapy to 12 weeks for treatment-naïve patients across several genotypes, Norbert Bischofberger, the Foster City, Calif. firm’s chief scientific officer, said in a statement. But those indications are only the initial steps in Gilead’s filing plans for sofosbuvir (GS-7977), the lead asset it acquired in its 2011 take-out of Pharmasset Inc. (Also see "Record-Setting Deal For Pharmasset Expected To Boost Value Of Other HCV Biotechs" - Pink Sheet, 28 Nov, 2011.).

Gilead’s FISSION, NEUTRINO, FUSION and POSITRON trials will combine to support a broad filing, expected in the second quarter, that will include treatment-naïve, treatment-experienced and interferon-intolerant HCV patients.

Gilead’s FUSION trial then showed “significant efficacy among difficult-to-treat hepatitis C patients who could not be cured by prior regimens containing pegylated interferon and now have limited treatment options,” Bischofberger said in a Feb. 19 statement announcing top-line results of the trial.

FUSION is the last to report of the four Phase III trials that will support the NDA filing. Top-line data from the POSITRON trial was released in November. Gilead said full data from the series would be presented at a coming medical conference (Also see "Gilead Steals The Show At Liver Meeting" - Pink Sheet, 14 Nov, 2012.). The initial regulatory filing, expected in the second quarter, will seek approval of sofosbuvir as part of all-oral therapy with ribavirin for genotype 2 and 3 treatment-naïve, treatment-experienced and interferon-intolerant HCV patients as well as sofosbuvir in combination with ribavirin and pegylated interferon in treatment-naïve patients with genotypes 1, 4, 5 and 6, Gilead said.

Bischofberger highlighted the company’s plans for much tougher-to-treat patient populations at the J.P. Morgan Healthcare Conference in January, indicating enrollment had begun earlier than planned to test sofosbuvir with Gilead’s own non-structural protein 5A (NS5A) inhibitor, GS-5885, in treatment-experienced populations, with a 2014 filing goal (Also see "Gilead Phase III Program For Two-Drug HCV Combo On Faster Pace Than Expected" - Pink Sheet, 7 Jan, 2013.).

The Data At Hand

The Phase III FISSION and NEUTRINO trials both met a non-inferiority endpoint. In FISSION, treatment-naïve patients with hepatitis C genotypes 2 and 3 were given either 12 weeks of sofosbuvir plus ribavirin or 24 weeks of traditional ribavirin and pegylated interferon; 67% of patients in both groups achieved sustained virologic response, considered a cure, with the sofosbuvir arm besting the non-inferiority margin.

In NEUTRINO, treatment-naïve patients with genotypes 1, 4, 5 and 6 were treated with 12 weeks of sofosbuvir added to a peg-interferon/ribavirin backbone; results were compared to a predefined historic control SVR rate of 60%. Those patients had a 90% (295/327) SVR rate after completing 12 weeks of therapy.

Among patients with genotype-1 virus, the genotype most common in the U.S., sofosbuvir performed particularly well in a short course on top of the peg-interferon/ribavirin backbone. Of the total NEUTRINO participants, 89% (291) were genotype 1, and 89% percent of those (258) achieved SVR at 12 weeks. Of the 35 patients with genotypes 4, 5 or 6, 97% made the goal.

Eighty percent of the around 55 patients on the trial with compensated cirrhosis at baseline achieved SVR at the 12-week mark, a finding that is important not for the size of the market but because these people are dangerously ill and may not be able to wait for the next breakthrough.

Sofosbuvir’s overall 90% SVR rate “represents the best-ever Phase III SVR ever seen by far” in genotype-1 patients, Matthew Roden, UBS Investment Research analyst, said in a Feb. 4 note to investors. Further, the 80% rate in cirrhotic patients “suggests potential for strong uptake in the need-to-treat patients in 2014,” Roden said.

Results for the trials across the other hepatitis C genotypes were “solid” and “we are confident that these data will support GS-7977 approval across all genotypes,” Roden said.

Sharpening The Genotype Focus

But while the combined genotype data may support approval, Gilead will need to sharpen its approach to the genotype-3 population, who are infected with an especially difficult variation of the virus. While the FISSION data should not surprise observers in the space, they do present a challenge.

In FISSION, the SVR for genotype-3 patients in the sofosbuvir plus ribavirin arm was 56%, compared to 97% for genotype-2 patients. Among patients on the peg-interferon/ribavirin arm, 63% of genotype-3 and 78% of genotype-2 patients achieved SVR.

While encouraging overall, the data for the two genotypes were mixed, demonstrating improvement for genotype 2 but not for genotype 3, J.P. Morgan analyst Geoff Meacham wrote in a Feb. 4 alert to subscribers. Acknowledging the difficulty of the genotype 3 population, Meacham also pointed out that from a commercial perspective it is smaller, at 5% to 10% of the U.S. and European population, than genotype 2, which is about 15% to 20% of patients.

Those genotype-3 FISSION data “should be in-line with expectations,” given the trial had many more patients with that genotype enrolled than most other trials, ISI analyst Mark Schoenebaum said in comments on Gilead’s report. Indeed, said Deutsche Bank analyst Robyn Karnauskas, FISSION was designed by Pharmasset to have more genotype-3 than genotype-2 patients, and Street expectations were around 67% to 73% based on historical type 3 cure rates.

In any case, Gilead “has the luxury of time to optimize the G3 regimen – there is no real competition here at the moment,” Schoenebaum said.

The FUSION trial adds more data on genotype 3 patients. In FUSION, which enrolled patients who had failed prior interferon-based therapy, 63% of subjects were infected with genotype 3 HCV; the remainder were genotype 2. The trial randomized subjects equally to a 12-week or a 16-week regimen of sofosbuvir and ribavirin. The primary endpoint was superiority compared to an historic control (sustained virologic response rate of 25%) for all patients; the topline results were a statistically significant 50% of patients in the 12-week arm and 73% of 16-week patients achieving SVR12. In the shorter arm, SVR12 rates were 86% among genotype 2 and 30% among genotype 3 patients. In patients receiving the16-week regimen, SVR12 rates were 94% among genotype 2 and 62% among genotype 3 patients.

Still An Advantage

Enthusiasm is waning for the new direct-acting antivirals that burst on the hepatitis C scene in 2011. Vertex Pharmaceuticals Inc.’s Incivek (telaprevir) and Merck & Co. Inc.’s Victrelis (boceprevir) represented a great leap forward in treatment of the disease, but their range is limited and they come with the off-putting peg-interferon/ribavirin backbone.

In addition, the regimens were not tested extensively in real-world patient populations, such as patients with cirrhotic livers, and the realities of the regimens that were so inviting short months ago have led physicians to advise patients who are healthy enough to wait for new antivirals, such as sofosbuvir (Also see "Interferon-Free Hepatitis C Regimens Within Reach" - Pink Sheet, 19 Nov, 2012.).

The “shorter duration and fewer side effects from removing the weekly interferon needle will drive initial uptake,” Deutsche Bank’s Karnauskas said, adding her belief that sofosbuvir “with standard of care [peg-interferon/ribavirin] for 12 weeks is more competitive than current protease inhibitor regimens with standard of care on the market.”