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New Triple Combo Cures Most DAA-Experienced and Hard-to-Treat Hepatitis C Patients Without Ribavirin

An investigational 3-drug coformulation from Gilead Sciences produced sustained virological response (SVR) in 95% to 97% of hard-to-treat hepatitis C patients in the Phase 3 POLARIS trials, including people who were previously treated with direct-acting antivirals and those with hepatitis C virus (HCV) genotype 3 and compensated cirrhosis, according to a recent company announcement. Gilead plans to request Food and Drug Administration approval of the new combination by the end of the year.

The advent of direct-acting antiviral agents (DAAs) that can be used in interferon-free regimens has revolutionized treatment for chronic hepatitis C. While the new drugs are far more effective and better tolerated than interferon-based therapy, there is still room for better options for some difficult-to-treat individuals including those who did not respond to prior DAA therapy and may have drug-resistant virus.

Some current standard-of-care DAA regimens require a longer duration or addition of ribavirin for hard-to-treat patients, which adds to the side effects, cost, and inconvenience of treatment.

The new single-tablet regimen combines drugs from 3 different classes -- the previously approved HCV polymerase inhibitor sofosbuvir and NS5A inhibitor velpatasvir, plus the investigational protease inhibitor voxilaprevir (formerly GS-9857). All agents are pangenotypic, meaning they are active against all HCV genotypes and can potentially be used on a global basis without the need for genotypic testing.

The Phase 3 POLARIS trials tested the triple combination taken for 8 or 12 weeks without ribavirin in more than 1000 patients.

In POLARIS-1, 96% of NS5A-experienced patients with HCV genotypes 1-6 were cured with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir, compared with none of the placebo recipients. POLARIS-4 showed that the triple combination for 12 weeks worked better than a dual combination of sofosbuvir/velpatasvir for DAA-experienced patients who had not used NS5A inhibitors (SVR12 97% vs 90%).

POLARIS-3 demonstrated that 8 weeks of sofosbuvir/velpatasvir/voxilaprevir worked as well as 12 weeks of sofosbuvir/velpatasvir for patients with hard-to-treat genotype 3 and liver cirrhosis. However POLARIS-2, with a more diverse group of mostly non-cirrhotic DAA-naive patients with genotypes 1-6, did not reach the threshold for non-inferiority.

Below is an edited excerpt from a Gilead press release describing the studies and their findings in more detail.

Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velapatasvir and Voxilaprevir in Treatment-Naive and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients

- If Approved, SOF/VEL/VOX Would Be the First Once-Daily Single-Tablet Regimen Available for Salvage for Patients Who Have Failed Prior HCV Therapy with Oral Direct-Acting Antiviral Agent Regimens

- U.S. NDA Planned for Q4 2016

Foster City, Calif. -- October 20, 2016 -- Gilead Sciences, Inc.(NASDAQ: GILD) today announced topline results from four international Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4) evaluating an investigational, once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection.

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. The intent-to-treat SVR12 rates observed in the POLARIS studies are summarized in the following table. Complete results from all four studies will be presented at The Liver Meeting 2016 in Boston.

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.

"Despite recent advances that have provided high cure rates and simplified treatment for most HCV patients, those who have failed previous treatment with direct acting antivirals continue to represent an unmet medical need. The POLARIS study results demonstrate that combining three potent antivirals with different mechanisms of action and high barriers to resistance can provide high cure rates for patients who have failed other highly effective oral DAA regimens," said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. "Based on these Phase 3 results, we 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."

About the POLARIS Studies

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).

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-naive HCV-infected patients, including 18 percent with cirrhosis and 23 percent who had previously failed treatment with an interferon-based regimen.

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.

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.

About SOF/VEL/VOX

The SOF/VEL/VOX fixed-dose combination is an investigational product and its safety and efficacy have not been established. It has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration for the treatment of chronic genotype 1 HCV patients who have previously failed an NS5A inhibitor-containing regimen.

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. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

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.

10/24/16

Source

Gilead Sciences. Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velpatasvir and Voxilaprevir in Treatment-Naive and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients. Press release. October 20, 2016.