The first candidate in this class, labeled GS-CA1, was more potent than efavirenz (Sustiva, Stocrin), atazanavir (Reyataz) or dolutegravir (Tivicay, DTG) in cell studies involving CD4 T lymphocytes, macrophages and peripheral blood mononuclear cells (PBMCs). Compared with dolutegravir, for example, GS-CA1 had substantially greater potency indicated by lower 50% effective concentrations (EC50) in CD4 cells (60 versus 1,000 pM), macrophages (100 versus 1,900 pM) and PBMCs (140 versus 1,200 pM). Cell studies also indicated that GS-CA1 has no measurable cytotoxicity in target and nontarget primary cells.
Related: Weekly Injections of Antibody PRO 140 Keeps HIV Undetectable in 10 of 16 Patients
GS-CA1 potency averaged 140 pM in PBMCs against HIV-1 subtypes A, B, C, D, E, F, G, CRF01_AE and CRF02_AG. The capsid inhibitor class being studied retained full activity against HIV-1 resistant to licensed antiretrovirals. These capsid inhibitors bind to a highly conserved interface between two adjacent monomers within the capsid hexamer, the 6-monomer structures that make up the capsid core. GS-CA1 selects for capsid mutations L56I, M66I, Q67H, N74D or A105E. All these mutations occur at the capsid inhibitor binding site with fold changes in EC50 relative to wild-type virus ranging from 7.7-fold to more than 2,270-fold. Mutants with the greatest fold change relative to wild-type virus have reduced fitness.
Mechanistic studies determined that GS-CA1 interrupts HIV-1 replication at two discrete steps of the viral life cycle: at an EC50 of 240 pM, the compound inhibits capsid core assembly as the cell-free viral particle matures; and at an EC50 of 53 pM, it inhibits integration of viral RNA into the target cell nucleus after the capsid disassembles inside infected cells. In these analyses, combined anti-HIV activity for a full single round of replication measured 85 pM.
Pharmacokinetic analyses in rats showed that a single subcutaneous injection of GS-CA1 maintained plasma levels above the protein-adjusted EC95 for more than 10 weeks. This finding suggests that a monthly or less frequent dosing interval may be possible in humans. Pharmacokinetic profiles in multiple species indicate low systemic drug clearances (0.08 to 0.33 L/h/kg) and long half-lives (7.2 to 18.7 h).
Gilead investigators conclude that the compound selected for clinical development has high potency, low metabolic clearance and slow-release kinetics after injection that support low-dose long-acting administration.
Mark Mascolini writes about HIV infection.