Gilead immune modulator has modest effect on hepatitis B surface antigen

Selgantolimod, a toll-like receptor agonist designed to enhance immune responses to hepatitis B virus, showed only modest effects on hepatitis B surface antigen levels in a phase 2 safety and efficacy study presented to the Digital International Liver Congress last week.

Hepatitis B is a chronic viral infection that cannot be cleared by current treatments or controlled by the immune system in the absence of antiviral treatment. Hepatitis B virus causes immune dysfunction, including lack of hepatitis B-specific T-cell responses, by mechanisms that are still not fully understood.

Immune modulating treatments that can enhance immune responses against hepatitis B virus are being explored as part of efforts to develop a functional cure for hepatitis B. A functional cure would allow people to stop treatment but still control the virus, so that it does not cause further liver damage.

Toll-like receptor agonists are compounds that can trigger toll-like receptors in the liver to produce interferons and activate natural killer cells and T-cells against the hepatitis B virus.

Several pharmaceutical companies are developing TLR-7 and TLR-8 agonists for use in hepatitis B treatment, including Gilead Sciences, Johnson & Johnson and Roche.

Selgantolimod, developed by Gilead, is a TLR-8 agonist that can activate a broad range of immune cells, including dendritic cells, monocytes, macrophages and neutrophils that produce the antiviral cytokines interleukin-12 and 18, TNF-alpha and interferon gamma.

The phase 2a study recruited 48 people with chronic hepatitis B infection with suppressed hepatitis B virus on oral antiviral treatment.

The study compared two daily doses of selgantolimod (1.5mg or 3mg) to placebo. Participants were stratified into two equal cohorts of hepatitis B e-antigen positive and negative patients. Participants received the study drug for 24 weeks in addition to nucleoside or nucleotide analogue treatment and were followed for a further 24 weeks on their existing antiviral regimen.

The primary study outcomes were safety and tolerability at week 24, and the proportion of participants who experienced a >1 log₁₀ reduction in hepatitis B surface antigen at week 24.

The study population was predominantly male (67-80% per study arm), Asian (approximately 60%) and with a mean HBsAg of 2.5 log₁₀ IU/ml in the 1.5mg group, 3.0 log₁₀ IU/ml in the 3mg group and 3.3 log₁₀ IU/ml in the placebo group.

Two study participants (one in each active drug group) experienced hepatitis B surface antigen loss during the study and surface antigen loss was sustained for at least 12 months after completing study treatment. In both cases patients had low baseline surface antigen levels (>3 log₁₀ IU/ml). Three participants in the HBeAg group receiving the 3mg dose of selgantolomid experienced HBeAg loss.

Substantial variation in the extent of hepatitis B surface antigen loss was observed within dosing groups.

By week 48, only 25% of participants in the selgantolimod groups had experienced a >0.1 log10 reduction in hepatitis B surface antigen and only one participant achieved the primary outcome of a hepatitis B surface antigen reduction of greater than 1 log₁₀ IU/ml (-1.6 log₁₀ IU/ml) at week 24.

Dose-dependent increases in levels of interferon-gamma were observed within four hours of dosing.

The most common adverse event was nausea, occurring in 18 of 39 people in the active drug arms. Episodes of nausea were short and infrequent. One participant discontinued treatment due to uveitis.

Further investigation of selgantoloimod will focus on its use in combination with an anti-PD1 checkpoint inhibitor and/or a therapeutic vaccine, said Professor Gane.