Immune-based therapy GS-9620 shows promise for hepatitis B
Gilead's GS-9620, an experimental TLR7 agonist, stimulated interferon production and activated B-cells and T-cells in laboratory and human studies, and was active against hepatitis B and a related virus in monkeys and woodchucks.
Standard therapy for hepatitis B virus (HBV) consists of either interferon, which stimulates the body's own immune responses against the virus, or direct-acting agents like tenofovir (Viread) that interfere with the viral lifecycle. With the impending introduction of direct-acting drugs such boceprevir and telaprevir, this will soon also be the case for hepatitis C.
Three posters presented at the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this month in Berlin looked at a new type of immune-modulating therapy, a toll-like receptor agonist 7 (TLR7). By triggering with interferon signaling and other immune responses, this new agent could be effective for both hepatitis B and C.
In the first study, D. Tumas and colleagues conducted a preclinical analysis of GS-9620. The drug's selectivity -- or ability to trigger only desired immune responses -- and activity were assessed in cell lines and peripheral blood mononuclear cells (PBMCs) in the laboratory. It was then tested in mice, rats, dogs and cynomolgus monkeys.
The researchers found that in the laboratory GS-9620 had nanomolar potency for inducing interferon alfa and stimulating immune-modulating cytokines and chemokines. It directly activated B-cells and indirectly activated T-cell. GS-9620 was 30 times more selective for TLR7 than for TLR8, and had no cross-reactivity with other TLRs.
In animals, GS-9620 had good pharmacokinetics -- including moderate to high clearance and high-volume distribution -- in multiple species. It showed good oral absorption in dogs and was more active with oral vs intravenous administration in monkeys.
At low oral doses it stimulated production of interferon alfa, immune-modulating cytokines, and chemokines, and triggered interferon-stimulated genes in monkeys. Repeated oral doses up to 1.5 mg/kg administered every other day for 4 weeks were well tolerated.
Antiviral Activity in Woodchucks
In the second study, S. Menne and colleagues assessed GS-9620's antiviral efficacy and induction of antibody responses against surface antigen in woodchucks infected with woodchuck hepatitis virus (WHV), used as an animal model of chronic HBV infection. The researchers first analyzed pharmacokinetics and pharmacodynamics in uninfected woodchuck, which led them to select 5 mg/kg as a starting dose for further testing. Five groups of woodchucks (7 per group) with chronic WHV infection were treated with placebo or various GS-9620 regimens. Three groups started with 5 mg/kg every other day, with the dose later reduced to 2.5 mg/kg. Two groups were treated for 4 weeks and one for 8 weeks. Another group received 5 mg/kg once weekly for 8 weeks. The final group received placebo. GS-9620 reduced WHV viral load in all treatment groups. Mean maximal viral load reductions ranged from 2.9 to 6.1 logs. All woodchucks treated every other day for 4 weeks had maximal reductions of 4.7 to 7.4 logs. GS-9620 reduced WHV surface antigen (WHsAg) levels -- to undetectable if treated every other day for 4 weeks -- and this was sustained after treatment in two-thirds. About one-third of the animals produced WHV surface antibodies. Woodchucks treated with GS-9620 every day for 4 weeks had a markedly decreased incidence of hepatocellular carcinoma 6 months after completing treatment. Single doses of GS-9620 were generally safe and well tolerated at 5 mg/kg. Some animals experienced thrombocytopenia (low platelets), white blood cell loss, and fever, leading researchers to reduce the dose to 2.5 mg/kg. Some developed anemia and liver enzyme elevation at both doses. The researchers noted that some of these symptoms may have been due to the intended effect of increased immune inflammatory activity. Based on these findings the investigators concluded that 4 weeks of oral treatment with GS-9620 in woodchucks "resulted in a sustained, marked reduction in serum levels of viral DNA and WHsAg and in the induction of an anti-WHs antibody response." "The results suggest that GS-9620 induces a protective antiviral immune response during chronic active hepadnaviral infection and this approach presents the potential of a finite treatment duration for chronic Hepatitis B therapy using GS-9620," they added. GS-9620 in Chimpanzees R. Lanford and colleagues evaluated the efficacy of GS-9620 in chimpanzees with chronic HBV infection. Three uninfected chimps were first given a single oral dose to assess pharmacokinetics and select an appropriate starting dose. Then 3 animals with chronic HBV infection (for 20-30 years) were treated with 1 mg/kg GS-9620 3 times weekly for 4 weeks, given a 1 week rest, then treated with 2 mg/kg 3 times weekly for another 4 weeks. HBV levels in the blood and liver fell during treatment, an effect that was most pronounced in chimps with high baseline viral load. The mean maximal reduction in serum viral load was 2.2 logs, with at least a 1 log reduction from 64 to >121 days. Reductions in HBV viral load correlated with decreases in serum hepatitis B surface antigen (HBsAg) in all 3 treated animals; 1 also had reduced hepatitis B "e" antigen (HBeAg). Liver enzymes increased during treatment, but returned to baseline by the end of the study. GS?9620 induced dose-dependent increases in serum interferon alfa and triggered interferon-stimulated genes in PBMCs and the liver. Activated B-cells increased by 3-5-fold, CD4 T-cells by 2-4-fold, CD8 T-cells by 2-5 fold, and natural killer (NK) cells by 2-6 fold. GS-9620 in Humans Finally, U. Lopatin and colleagues tested the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in human volunteers without viral hepatitis. This double-blind placebo-controlled study included 75 healthy volunteers. A majority were men and white, and the average age was about 30 years. Participants received single ascending doses of 0.3, 1, 2, 4, 6, 8, and 12 mg GS-9620; 7 cohorts took the drug on an empty stomach and 3 cohorts took it with food. GS-9620 was generally safe and well tolerated with single doses through 12 mg. The most common adverse events were headaches, chills, and fever. There were no serious adverse events or discontinuations due to adverse events or laboratory abnormalities. A total of 49 treatment-emergent events in 15 people were judged to be drug-related. The number of adverse events increased with higher doses, from 1 per cohort with 2, 4, or 6 mg, to 11 with 8 mg and 31 with 12 mg. Some participants experienced mild platelet decreases, but these changes were "not notable enough to be considered adverse events," according to the researchers. GS-9620 treatment led to dose-dependent increases in various cytokines, chemokines, and interferon-stimulated genes. Systemic interferon changes were only seen with the 12mg dose. Volunteers receiving the 8 mg and 12 mg doses experienced increases in percentages of activated T-cells, B-cells, and NK cells.
"GS-9620 is a potent, oral small molecule agonist of TLR7, which was safe and well tolerated in single ascending doses up to 12 mg [by mouth," the investigators concluded.
"These findings confirm the preclinical data suggesting that GS-9620 induces multiple cytokines (including Interferon) pre-systemically, with the potential for decreased adverse events compared to systemic pegylated interferon," they continued. "GS-9620 is a promising, oral immunomodulatory agent with potency in the low milligram range and a therapeutic window which supports further evaluation in the therapy of viral hepatitis B and C."
Investigator affiliations: Abstract 1007: Department of Drug Safety Evaluation, Department of Drug Metabolism, Department of Biology, and Department of Chemistry, Gilead Sciences, Inc, Foster City, CA. Abstract 992: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC; Department of Clinical Sciences, Gastrointestinal Unit, College of Veterinary Medicine, Cornell University, Ithaca, NY; Department of Drug Metabolism and Department of Drug Safety Evaluation, Gilead Sciences, Inc, Foster City, CA. Abstract 384: Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, TX; Department of Drug Metabolism and Department of Drug Safety Evaluation, Gilead Sciences, Inc, Foster City, CA. Abstract 614: Liver Disease Therapeutic Area, Gilead Sciences, Inc., Foster City, CA; Covance, Evansville, IN; Gilead Sciences Inc., Durham, NC; Pharmasset, Princeton, NJ.
By Liz Highleyman
References D Tumas, X Zheng, B Lu, et al. Preclinical characterization of GS-9620, a potent and selective oral TLR7 agonist. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 1007. S Menne, BC Tennant, KH Liu, et al. Anti-viral efficacy and induction of an antibody response against surface antigen with the TLR7 agonist GS-9620 in the woodchuck model of chronic HBV infection. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 992. RE Lanford, B Guerra, DC Chavez, et al. Therapeutic efficacy of the TLR7 agonist GS-9620 for HBV chronic infection in chimpanzees. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 384. U Lopatin, G Wolfgang, R Kimberlin, et al. A phase-I, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single escalating oral doses of GS-9620 in healthy subjects. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 614.