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
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
Chemical "messengers" exchanged between immune cells that affect the function of
the immune system. Interleukins such as IL-2 are a particular type of
- immune modulator
substance that changes an aspect of the way the immune system is working.
cells in the blood which can attack bacteria and fungal infections.
of the middle layer of the eye.
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
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.