EASL 2013: NS5A Inhibitor GS-5816 Looks Good in Phase 1 Study, Now In Phase 2

The next-generation HCV NS5A inhibitor GS-5816 demonstrated potent antiviral activity against a range of viral genotypes in a preclinical study presented at the recent EASL International Liver Congress in Amsterdam (EASL 2013), paving the way for a Phase 2 trial of GS-5816 plus sofosbuvir in an interferon-free dual regimen.

The advent of direct-acting antiviral agents (DAAs) has ushered a new treatment paradigm for chronic hepatitis C, but many patients and providers are awaiting all-oral regimens that dispense with interferon and its difficult side effects.

Though its function is not fully understood, drugs that interfere with the HCV NS5A replication complex -- including Gilead Sciences' ledipasvir (formerly GS-5885) and Bristol-Myers Squibb's daclatasvir -- have shown potent antiviral activity when combined with HCV polymerase and protease inhibitors.  

In a poster presented at EASL, Guofeng Cheng and colleagues from Gilead described the discovery of the second-generation NS5A inhibitor GS-5816, which they tested in a laboratory "replicon" model of hepatitis C.

Results

• GS-5816 was found to have "potent and consistent" antiviral activity against NS5A from HCV genotypes 1 through 6.
• The new drug showed greater potency against genotypes 2a and 2b -- recently shown to be harder to treat than genotype 3 -- compared with first generation NS5A inhibitors.
• GS-5816 retained its potency activity against common NS5A polymorphisms and resistance mutations.
• It appears to have a "significantly higher resistance barrier" than first-generation inhibitors.
• GS-5816 showed additive to moderately synergistic activist when combined with other anti-HCV drugs including sofosbuvir.
• GS-5816 had low cytotoxicity, or propensity to kill or damage cells.

"GS-5816 is a second-generation HCV NS5A inhibitor with potent antiviral activity, broad genotype coverage and broad coverage of first-generation NS5A inhibitor [resistance associated variants] and prevalent polymorphs." The researchers concluded. "The preclinical pharmacology profile of GS-5816 support its development in combination with sofosbuvir and other DAAs to treat a broad range of HCV genotypes."

In a related presentation, Polina German and colleagues, also from Gilead, reported findings from a Phase 1, first-in-humans study to evaluate the pharmacokinetics, safety, and tolerability of single and multiple doses of GS-5816 at 5, 50, 150, or 450 mg, with or without food, in healthy HCV negative volunteers.

GS-5816 appeared safe and well-tolerated at all doses studied. All participants (12 taking GS-5816 and 3 taking placebo in each dose cohort) completed the study and none discontinued early. No clinically significant laboratory or electrocardiogram (ECG) abnormalities were observed. GS-5816 was absorbed quickly following single and multiple oral doses, with maximum plasma concentrations reached after about 2 to 3 hours. The median drug half-life in the body was about 15 hours, supporting once-daily dosing.

Phase 2 Trial Underway

Based on these findings, Gilead has started a Phase 2 study to evaluate 25 or 100 mg GS-5816 plus 400 mg sofosbuvir in a 12-week all-oral dual regimen without pegylated interferon or ribavirin.

The open-label trial is now recruiting 140 previously untreated chronic hepatitis C patients without cirrhosis at more than 50 sites in the U.S. For more details see http://clinicaltrials.gov/ct2/show/NCT01858766 or contact Juan Betular at JLIB_HTML_CLOAKING .

6/19/13

References

G Cheng, Y Tian, M Yu, et al. GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1191.

P German, P Pang, C Yang, et al. Healthy Volunteer First-in-Human Evaluation of GS-5816, a Novel Second Generation Broad-Genotypic NS5A Inhibitor with Potential for Once-Daily Dosing. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1195.

Other Source

ClinicalTrials.gov. Phase 2 Study of SOF+GS-5816 in Treatment Naive Subjects with Chronic HCV. http://clinicaltrials.gov/ct2/show/NCT01858766. Updated June 3, 2013.