Early clinical and preclinical findings presented at the 35th European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global conference in Vienna, Austria, suggest that Assembly Biosciences’ ABI-5366, a novel herpes simplex virus (HSV) helicase-primase inhibitor (HPI), could redefine the treatment landscape for recurrent genital herpes (RGH) through monthly or weekly oral dosing. With promising pharmacokinetics (PK), strong tissue distribution, and nanomolar-level potency against HSV-1 and HSV-2, ABI-5366 may address the longstanding limitations of nucleoside analogues, particularly around adherence and durability of response.
Herpes is associated with symptoms such as blisters, fever, swollen lymph nodes, and body aches, and is caused by HSV, a virus of the Herpesviridae family. There are two types of HSV. HSV-1 is predominantly an orally transmitted infection that causes cold sores around the mouth. HSV-2 is a sexually transmitted infection (STI) that predominantly causes genital herpes. Co-infection of both HSV-1 and HSV-2 can also occur. Globally, the burden of herpes is extensive. GlobalData epidemiologists estimate that there were approximately 7.4 million diagnosed cases of HSV-1 infection, approximately 52 million diagnosed cases of HSV-2 infection, and approximately 13 million diagnosed cases of HSV-1 and HSV-2 co-infection across the 16 major markets (Australia, Brazil, Canada, China, France, Germany, India, Italy, Japan, Mexico, Russia, South Africa, South Korea, Spain, the UK, and the US) in 2024.
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The current standard-of-care for RGH is nucleoside analogues administered either daily or intermittently for recurrences. However, these therapeutics are associated with suboptimal efficacy, which drives both physical and psychological burden for patients. Within this context, ABI-5366 is emerging as a promising candidate in a new class of antivirals. Its extended half-life (more than 20 days in humans) and favourable safety profile in a Phase Ia study in healthy volunteers suggest that ABI-5366 has the potential to dramatically reduce dosing frequency for patients who are currently receiving daily chronic therapy. This shift would transform real-world disease management and improve patient quality of life.
HPIs target a distinct step in HSV DNA replication. In vitro results show that ABI-5366 has low nanomolar potency (EC50 4-39nM) against both HSV-1 and HSV-2 clinical isolates, with approximately 40 times more potency than the antiviral agent acyclovir against HSV-2, according to data provided in a poster presentation by Assembly Biosciences at the conference.
The compound demonstrated high metabolic stability across rat, dog, monkey, and human liver microsomes, with very low clearance (0.002l/h/kg–0.02l/h/kg) and extended systemic half-lives (20–71 hours) in preclinical species. A rat bile-duct cannulated study confirmed that ABI-5366 is largely excreted unchanged in faeces while studies in dogs using activated charcoal revealed that intestinal reabsorption is a key factor contributing to its long duration of action.
Interim results from a randomised, placebo-controlled, Phase Ia trial (NCT06385327) in 32 healthy participants (who received single doses of 10mg–350mg) found ABI-5366 to be well tolerated, with most adverse events being mild (Grade 1) and no reported serious treatment-related events. Plasma concentration-time profiles were consistent with dose-proportional exposure and intestinal recycling, with mean half-lives exceeding 20 days across dose groups.
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By GlobalDataProjected trough concentrations (Ctrough) after weekly or monthly dosing were shown to exceed the protein-adjusted EC50 for HSV replication, supporting the compound’s clinical potential for extended-interval dosing. The study also confirmed tissue distribution to ganglia, a reservoir of latent HSV, reinforcing the biological plausibility of durable viral suppression.
If long-acting oral HPIs such as ABI-5366 prove effective in suppressing clinical recurrences in Phase Ib/II trials, they could represent the first significant advancement in genital herpes treatment in more than 25 years. No new drugs have been approved for genital herpes in the US or Europe during that time, emphasising the unmet need for therapies with improved efficacy and convenience. Current standard-of-care agents such as valacyclovir require daily adherence and have variable effectiveness, particularly in reducing viral shedding and recurrence frequency.
By enabling less frequent, more convenient dosing, ABI-5366 may unlock new market opportunities among patient populations that struggle to adhere to current treatments, including those who are burdened by stigma and psychosocial impacts. Monthly dosing could also increase treatment initiation rates and reduce HSV-2 transmission at the population level.
Phase Ib data in patients with RGH will be critical for validating ABI-5366’s antiviral efficacy, tolerability with repeated dosing, and clinical relevance of its PK advantages. Interim proof-of-concept data from the ongoing Phase Ib trial is expected in H2 2025. If successful, ABI-5366 may reshape patient expectations and set a new standard in genital herpes therapeutics.
