Clinical Trials

Date: 2016-10-20

Type of information: Results

phase: 3

Announcement: results

Company: Gilead Sciences (USA - CA)

Product: sofosbuvir, velpatasvir (GS-5816) and voxilaprevir (GS-9857)

Action mechanism:

• direct-acting antiviral agent/RNA polymerase (NS5B) inhibitor/ nonstructural protein 5A (NS5A) inhibitor/ NS3/4A protease inhibitor. 
• Sofosbuvir is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. This direct-acting agent interferes directly with the HCV life cycle by suppressing viral replication.
• Velpatasvir (GS-5816) is a second-generation investigational NS5A inhibitor.
• Voxilaprevir (GS-9857) is an investigational NS3/4A protease inhibitor.

Disease: genotype 1-6 chronic hepatitis C virus (HCV) infection

Therapeutic area: Infectious diseases

Country: Australia, Canada, France, Germany, New Zealand, Puerto Rico, UK, USA

Trial details: The POLARIS-1 study was a double-blind, placebo-controlled study in 415 genotype 1-6 NS5A inhibitor-experienced patients. The most common prior NS5A inhibitors were ledipasvir (55 percent) and daclatasvir (23 percent). (NCT02607735) The open-label POLARIS-4 study evaluated the use of SOF/VEL/VOX or SOF/VEL for 12 weeks in 333 genotype 1-4 HCV-infected patients with prior DAA experience that did not include an NS5A inhibitor. Most patients (85 percent) had prior DAA experience with sofosbuvir. The open-label POLARIS-2 study evaluated the use of SOF/VEL/VOX for eight weeks or SOF/VEL for 12 weeks in 941 genotype 1-6 DAA-naïve HCV-infected patients, including 18 percent with cirrhosis and 23 percent who had previously failed treatment with an interferon-based regimen. (NCT02607800) The open-label POLARIS-3 study randomized patients with genotype 3 HCV infection and cirrhosis to receive SOF/VEL/VOX daily for eight weeks or SOF/VEL for 12 weeks. Of the 219 patients treated, 31 percent had previously failed treatment with an interferon-based regimen. In the POLARIS-1 and POLARIS-4 studies, 445 patients with genotype 1-6 HCV infection who were previously treated with direct-acting antiviral agents (DAAs) received 12 weeks of SOF/VEL/VOX. The POLARIS-1 study enrolled patients who failed prior treatment with an NS5A inhibitor. The POLARIS-4 study enrolled patients who failed prior treatment with a DAA that was not an NS5A inhibitor, most with either an NS5B inhibitor alone (73 percent) or an NS5B inhibitor and an NS3/4A protease inhibitor (25 percent). In the POLARIS-2 and POLARIS-3 studies, 611 patients who were not previously treated with a DAA received 8 weeks of SOF/VEL/VOX. The POLARIS-2 study enrolled patients with genotype 1-6 HCV infection with or without compensated cirrhosis. The POLARIS-3 study enrolled patients with genotype 3 HCV infection, all of whom had compensated cirrhosis. The primary endpoint for all studies was SVR12.

Latest news:

• • On October 20, 2016, Gilead Sciences announced results from four international Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluating a once-daily, fixed-dose combination of sofosbuvir (SOF), velpatasvir (VEL) and voxilaprevir (VOX; GS-9857) for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection.  The POLARIS-1, POLARIS-3 and POLARIS-4 studies met their respective pre-specified primary endpoints for the patients receiving SOF/VEL/VOX. The POLARIS-2 study did not meet its primary endpoint; with a pre-specified 5 percent margin, the SVR12 rate for patients receiving treatment with SOF/VEL/VOX for eight weeks was not statistically non-inferior to the SVR12 rate for patients receiving SOF/VEL for 12 weeks. The intent-to-treat SVR12 rates observed in the POLARIS studies are summarized in the following table.

Study	Population	Genotype	Treatment	Duration	SVR12 Rates
POLARIS-1	NS5A inhibitor-experienced 41 percent (172/415) had cirrhosis	1, 2, 3, 4, 5, 6	SOF/VEL/VOX	12 Weeks	96% (253/263)
			Placebo	12 Weeks	0% (0/152)
POLARIS-4	DAA-experienced (No NS5A inhibitor) 46 percent (153/333) had cirrhosis	1,2,3,4	SOF/VEL/VOX	12 Weeks	97% (177/182)
			SOF/VEL	12 Weeks	90% (136/151)
POLARIS-2	DAA-naïve 18 percent (174/941) had cirrhosis	1, 2, 3, 4, 5, 6	SOF/VEL/VOX	8 Weeks	95% (476/501)
			SOF/VEL	12 Weeks	98% (432/440)
POLARIS-3	DAA-naïve All had cirrhosis	3	SOF/VEL/VOX	8 Weeks	96% (106/110)
			SOF/VEL	12 Weeks	96% (105/109)

• Patients treated with SOF/VEL/VOX for 12 or eight weeks had similar overall incidence of adverse events compared to placebo-treated or SOF/VEL-treated patients. The most common adverse events among patients who received SOF/VEL/VOX were headache, fatigue, diarrhea and nausea. Among the 1,056 patients who received SOF/VEL/VOX in the four studies, one patient (less than one percent) receiving SOF/VEL/VOX for 12 weeks discontinued due to an adverse event.
• Based on these Phase 3 results, Gilead plan to submit regulatory applications for SOF/VEL/VOX for the treatment of chronic HCV in the United States in the fourth quarter of 2016 and shortly thereafter in Europe.

Is general: Yes