Gilead Sciences has announced findings from a pre-clinical study evaluating HIV capsid inhibitors (CAIs) for potential use as a long-acting antiretroviral (ARV) treatment. The study identified novel HIV-1 capsid inhibitors with highly potent antiviral activity and a favourable resistance profile to existing ARVs in vitro. The data are being presented in an oral session (Session O-4) at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.
“Capsid inhibition is a previously unexplored target for antiviral therapy and we are pleased to share these preclinical results showing the potential role of this class of therapy as a novel, long-acting injectable for HIV treatment and prevention in the future,” said Dr Norbert Bischofberger, executive vice president, research and development and chief scientific officer, Gilead Sciences. “This research represents Gilead’s ongoing commitment to innovation in the field of HIV and our work to advance treatments for people living with the disease.”
The pre-clinical study found that GS-CA1, an exemplified member of a novel class of CAIs, is a highly potent inhibitor of HIV-1 replication in human peripheral blood mononuclear cells (PBMCs) (EC50 = 140 pM) and displays similar potency against multiple HIV-1 clinical isolates from all major clades. The study also found that the identified CAIs bind to a broadly conserved site at the interface of two adjacent monomers within a capsid hexamer and accelerate capsid assembly in vitro.
The identified CAIs maintained full activity in vitro against HIV-1 mutants resistant to licensed antiretrovirals (ARVs) and selected for HIV capsid variants L56I, M66I, Q67H or N74D with an attenuated in vitro replication phenotype. Pre-clinical mechanistic studies revealed a dual mode of action targeting both the late-stage virion maturation and post-entry capsid functions. GS-CA1 showed high in vitro metabolic stability and displayed an extended-release pre-clinical pharmacokinetic profile following a single subcutaneous administration that maintained target plasma concentrations for over 10 weeks.
Gilead plans to evaluate a selected development candidate in Investigational New Drug (IND)-enabling toxicology studies and begin Phase 1 clinical trials in 2018.
GS-CA1 is an investigational therapy and has not been determined to be safe or efficacious.
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