Back HCV Treatment Sofosbuvir/Ledipasvir Coformulation Shows Good Early Response With or Without Ribavirin

Sofosbuvir/Ledipasvir Coformulation Shows Good Early Response With or Without Ribavirin

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A dual regimen of sofosbuvir (formerly GS-7977) plus ledipasvir (formerly GS-5885) for 8 or 12 weeks produced 4-week post-treatment sustained virological response (SVR4) rates of 95% to 100% for both treatment-naive and previously treated hepatitis C patients in a small Phase 2 study, according to a recent announcement from Gilead Sciences, developer of both drugs.

The nucleotide polymerase inhibitor sofosbuvir (then known as PSI-7977) demonstrated excellent results in combination with ribavirin alone in early arms of the Phase 2 ELECTRON trial, yielding an SVR24 rate of 100% for previously untreated people with HCV genotypes 2 or 3.

Results were less impressive for harder-to-treat patients, including prior null responders and people with HCV genotype 1. Although end-of-treatment response was promising, most participants relapsed after stopping therapy. Data presented at the EASL International Liver Congress (EASL 2013) last month indicated that this dual regimen works better against genotype 2 than genotype 3.

The early ELECTRON results, along with findings showing that 12 weeks of sofosbuvir plus Bristol-Myers Squibb's NS5A inhibitor daclatasvir cured 100% of treatment-naive genotype 1 patients (a combination Gilead declined to pursue), prompted Gilead to test sofosbuvir with a variety of its own investigational DAAs.

As Edward Gane reported at the recent EASL meeting and the AASLD Liver Meeting last November, further ELECTRON data showed that adding Gilead's NS5A inhibitor ledipasvir to sofosbuvir and ribavirin for 12 weeks cured 100% of both genotype 1 treatment-naive patients and null responders.

Adding GS-9669, a non-nucleoside polymerase inhibitor, also produced triple therapy sustained response rates in the 90% to 100% range. Gane did not describe future development plans for GS-9669, but the compound is still included in the pipeline list on Gilead's web site.

Jay Lalezari and colleagues presented a poster at EASL reporting findings from the Phase 2b QUANTUM study, which evaluated various combinations of the guanidine nucleotide analog GS-0938, sofosbuvir (a uridine nucleotide), and ribavirin. Again, the dual sofosbuvir/ribavirin regimen for 12 or 24 weeks cured only about half of treatment-naive patients with mostly genotype 1a. GS-0938 was halted at treatment week 9 after some participants experienced ALT/AST liver enzyme elevations.

Last week Gilead issued a press release describing more favorable interim early response data from the Phase 2 LONESTAR trial using a once-daily fixed-dose coformulation of sofosbuvir/ledipasvir, with or without ribavirin, for 8 or 12 weeks.

Looking at 60 treatment-naive genotype 1 patients, 100% of those treated with sofosbuvir/ledipasvir for 12 weeks had sustained undetectable HCV RNA at 4 weeks post-treatment. Further, 95% treated with sofosbuvir/ledipasvir and 100% treated with sofosbuvir/ledipasvir/ribavirin for 8 weeks still had suppressed virus at 8 weeks post-treatment.

In addition, 95% of 40 harder-to-treat patients previously treated with an HCV protease inhibitor, half of whom had cirrhosis, achieved SVR4 with either the dual or triple regimen for 12 weeks. Both sofosbuvir/ledipasvir and sofosbuvir/ledipasvir/ribavirin were generally safe and well-tolerated.

SVR4 is too soon to say patients are cured -- and some previous sofosbuvir studies have seen high relapse rates -- but U.S. and European regulatory authorities now recognize SVR12 as a cure, since few relapses happen after this point.

"The LONESTAR results suggest that once-daily all-oral therapy with the nucleotide NS5B inhibitor sofosbuvir and the NS5A inhibitor ledipasvir may have the potential to cure most genotype 1 HCV infected patients with a remarkably short treatment duration," principle investigator Eric Lawitz stated in the press release.

Based on these findings, Gilead said it will soon start a Phase 3 study dubbed ION-3 to evaluate the coformulation for 8 weeks with or without ribavirin, and for 12 weeks without ribavirin, in 600 treatment-naive, non-cirrhotic genotype 1 patients.

The company noted that 2 other Phase 3 studies are already underway, looking at the sofosbuvir/ledipasvir coformulation with and without ribavirin for 12 or 24 weeks in treatment-naive and treatment-experienced genotype 1 patients, including some with cirrhosis.

5/10/13

References

E Gane, CA Stedman, RH Hyland, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 14.

JP Lalezari, DR Nelson, RH Hyland, et al. Once daily sofosbuvir plus ribavirin for 12 and 24 weeks in treatment-naive patients with HCV infection: the QUANTUM study. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 845.

Other Source

Gilead Sciences. Gilead Reports Interim Data From Phase 2 LONESTAR Study. Press release. May 2, 2013.