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Sofosbuvir/Ledipasvir Cures More than 90% of Genotype 1 Hepatitis C

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Gilead Sciences this week announced sustained virological response rates from the Phase 3 ION trials testing a combination pill containing its newly approved HCV polymerase inhibitor sofosbuvir (Sovaldi) plus the NS5A inhibitor ledipasvir. Across the 3 studies, sofosbuvir/ledipasvir taken for 8 or 12 weeks cured more than 90% of treatment-naive and treatment-experienced genotype 1 patients.

The U.S. Food and Drug Administration this month approved sofosbuvir for use with ribavirin alone for people with HCV genotype 2 or 3, or as an add-on to pegylated interferon/ribavirin for those with genotype 1. While the agency said a longer course of sofosbuvir/ribavirin could be used for genotype 1 patients who cannot tolerate interferon, many still await more effective and shorter duration interferon-free regimens.

Gilead said it expects to request approval of the sofosbuvir/ledipasvir coformulation in early 2014, putting it on track for approval by the end of next year.

Below is an edited excerpt from a Gilead press release describing the study findings.

Gilead Announces SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients

  • High Cure Rates Observed with Single Tablet Regimen May Eliminate Interferon and Ribavirin from HCV Therapy for Genotype 1 Patients
  • U.S. NDA Submission Planned for Q1 2014

Foster City, Calif. -- December 18, 2013 -- Gilead Sciences, Inc. (Nasdaq: GILD) today announced topline results from three Phase 3 clinical trials (ION-1, ION-2 and ION-3) evaluating the investigational once-daily fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg and the NS5A inhibitor ledipasvir (LDV) 90 mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection.

Across the three studies, 1,952 patients with genotype 1 HCV infection were randomized to receive SOF/LDV with or without RBV for eight, 12 or 24 weeks of therapy. Of these, 1,512 patients were treatment-naive, 440 were treatment experienced and 224 had compensated cirrhosis.

The intent-to-treat SVR12 rates observed to date in the ION studies are summarized in the table below. Results of the 24-week arms from ION-1 will be available in the first quarter of 2014 and will be presented at a future scientific meeting.

Study

 

Population

 

Treatment

 

Duration

 

SVR12 Rates

ION-1

 

GT 1 treatment-naive

(including 15.7%
(136/865) with cirrhosis)

 

SOF/LDV

 

12 weeks

 

97.7% (209/214)

   

SOF/LDV + RBV

 

12 weeks

 

97.2% (211/217)

   

SOF/LDV

 

24 weeks

 

NA (n=217)

 

 

SOF/LDV + RBV

 

24 weeks

 

NA (n=217)

ION-2

 

GT 1 treatment-experienced

(including 20.0%
(88/440) with cirrhosis)

 

SOF/LDV

 

12 weeks

 

93.6% (102/109)

   

SOF/LDV+RBV

 

12 weeks

 

96.4% (107/111)

   

SOF/LDV

 

24 weeks

 

99.1% (108/109)

 

 

SOF/LDV+RBV

 

24 weeks

 

99.1% (110/111)

ION-3

 

GT 1 treatment-naive

 

SOF/LDV

 

8 weeks

 

94.0% (202/215)

   

SOF/LDV + RBV

 

8 weeks

 

93.1% (201/216)

 

 

SOF/LDV

 

12 weeks

 

95.4% (206/216)

               

 

Of the 1,518 patients randomized to the 12-week arms of ION-1 and to all arms of ION-2 and ION-3, 1,456 patients (95.9 percent) achieved the primary efficacy endpoint of SVR12. Of the 62 patients (4.1 percent) who failed to achieve SVR12, 36 patients (2.4 percent) experienced virologic failure: 35 due to relapse and only one patient due to on-treatment breakthrough (with documented non-compliance). Twenty-six patients (1.7 percent) were lost to follow-up or withdrew consent.

Fewer adverse events were observed in the RBV-free, fixed-dose combination arms compared to the RBV-containing arms in all ION studies. Adverse events observed in those taking the SOF/LDV tablet were generally mild and included fatigue and headache. In the RBV-containing arms of the ION studies, the most common adverse events were fatigue, headache, nausea and insomnia. Anemia, which is a common side effect associated with RBV, was reported in 0.5 percent of patients in the SOF/LDV arms versus 9.2 percent of patients in the RBV-containing arms. Less than 1 percent of patients in the studies discontinued treatment due to treatment-emergent adverse events.

"The results of the ION studies demonstrate that a simple, safe and short course of therapy with a single tablet regimen of sofosbuvir/ledipasvir can provide high cure rates among patients with genotype 1 HCV infection, while eliminating the need for both interferon and ribavirin," said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer. "With the availability of these results, Gilead is finalizing its regulatory filing for sofosbuvir/ledipasvir, with the goal of submitting a New Drug Application in the first quarter of 2014."

The FDA has assigned the SOF/LDV fixed-dose combination a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. Sofosbuvir was approved as Sovaldi in the United States on December 6 and in Canada on December 13. Applications are pending in the European Union, Australia and New Zealand, Switzerland and Turkey.

About the ION Studies

The Phase 3 ION studies are randomized, open-label Phase 3 clinical trials evaluating the efficacy and safety of a once-daily fixed-dose combination of SOF/LDV for 8, 12 or 24 weeks, with and without RBV, among 1,952 genotype 1 HCV patients. The studies included patients who were treatment-naive or who had failed previous treatment, including protease inhibitor-based regimens. The primary endpoint for each study was SVR12. Complete results from all three studies will be presented at a future scientific conference.

In ION-1, 865 treatment-naive genotype 1 HCV patients, including those with cirrhosis, received SOF/LDV with or without RBV for 12 or 24 weeks. In March 2013, a planned review by the study’s Data and Safety Monitoring Board (DSMB) of interim safety and efficacy data from an initial enrollment of patients concluded that the trial should continue without modification. Enrollment of the remaining patients was completed in May 2013. Prior to the DSMB meeting, the statistical analysis plan was amended to allow for the analysis of the primary efficacy endpoint for the two 12-week arms, independent of the 24-week arms. Per the amendment, if SVR12 rates in the 12-week arms were >90 percent (including among those with cirrhosis), early regulatory filings could be pursued, given that longer treatment durations would not be able to show statistically significantly higher SVR12 rates.

The ION-2 study evaluated 440 treatment-experienced genotype 1 HCV patients who had failed past therapy with regimens containing Peg-IFN (including Peg-IFN plus a protease inhibitor). Patients received SOF/LDV with or without RBV for 12 or 24 weeks.

In ION-3, 647 non-cirrhotic treatment-naïve genotype 1 HCV patients received SOF/LDV with or without RBV for 8 weeks or without RBV for 12 weeks.

The SOF/LDV fixed-dose combination is an investigational product and its safety and efficacy has not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

U.S. full prescribing information for Sovaldi is available at www.Sovaldi.com.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

12/18/13

Source

Gilead Sciences. Gilead Announces SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients. Press release. December 18, 2013.