GS-6207’s resistance and pharmacokinetic profile make it a suitable candidate for low-dose, long-acting administration to treat HIV-1 infections, a study finds.
GS-6207, a first-in-class HIV capsid (CA) inhibitor has picomolar potency and a distinct pharmacokinetic and resistance profile that establishes it as a suitable candidate for a low-dose, long-acting subcutaneous administration to treat HIV infection, a new study reports.
For the study, a team of investigators aimed to describe the in vitro pharmacological profile of GS-6207, which is optimized for long-acting antiretroviral treatment that is administered monthly or less frequently.
The findings of this unique study were presented in an oral abstract session at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2019) on Thursday, March 7, 2019.
“GS-6207 prevents capsid-mediated transport of HIV DNA into the nucleus, inhibits HIV particle production, and interferes with assembly of the mature viral capsid,” Stephen Yant, PhD, presenter of the data at CROI 2019 told Contagion®. “This multi-stage mechanism of action profile is distinguishable from currently approved classes of antiretrovirals.
The study team used surface plasmon resonance and X-ray crystallography to evaluate how GS-6207 binds to HIV-1 CA hexamers.
Potency and cytotoxicity of antivirals were assessed in human T-cells and primary cells, with HIV-1 and -2 laboratory strains and clinical isolates and HIV-1 recombinant mutants resistant to other antiretroviral therapy drugs were used for antiviral profiling.
The investigators used a reporter HIV-1 to determine effects of the multiplicity of infection on antiviral potency. Additionally, cytotoxicity was profiled in 4 non-target human cell lines and primary hepatocytes and GS-6207 activity was evaluated in combination with marketed classes of antiretrovirals.
The results of the study indicate that GS-6207 binds to CA hexamers (KD =0.2 nM) with “high affinity” at the interface between 2 adjacent CA monomers. And, in MT-4 cells, GS-6207 demonstrated potent and selective antiviral activity (EC50 = 0.1 nM, CC50 = 27 µM) and exhibited a mean EC50 of 0.05 nM (0.02 - 0.16 nM) in human peripheral blood mononuclear cells against 23 HIV-1 clinical isolates which spanned all major subtypes.
“The human serum proteinadjusted EC95 for GS-6207 (4 nM) is >10-fold lower than that of efavirenz (EFV), rilpivirine, dolutegravir (DTG) and atazanavir (ATV),” the investigators write, explaining further that in primary human CD4+ T-cells and macrophages, GS-6207 is >10-fold more potent and >22-fold more selective than EFV, DTG, and ATV and also suppresses HIV-2 replication.
Results also indicate that similar to other antiretroviral therapies, GS-6207’s antiviral activity decreases with increasing multiplicity of infection; however, it remains 5- to >100-fold more potent than 4 commonly used therapies.
The study also found that GS-6207 demonstrates low cytotoxicity in 4 human cell lines and primary hepatocytes (CC50 > 44 µM) and shows “synergistic” antiviral activity when combined pairwise with agents from marketed antiretroviral therapy classes.
“Finally, GS-6207 retains full potency against a broad range of HIV-1 mutants resistant to other antiretroviral therapy classes, including those with naturally occurring Gag polymorphisms conferring resistance to maturation inhibitors,” the investigators write.
In addition to its picomolar potency, GS-6207’s resistance and pharmacokinetic profile make it a suitable candidate for low-dose, long-acting administration to treat HIV-1 infections including those resistant to current antiretroviral therapies.
“A long acting ARV agent can provide new treatment options to people living with HIV beyond oral daily therapy and remove the burden and stigma associated with daily pill taking.” Dr. Yant concluded.
The safety and pharmacokinetics of GS-6207 are now being studied in healthy human subjects.
The study, “GS-6027, a Potent and Selective First-in-Class Long-acting HIV-1 Capsid Inhibitor,” was presented on March 7, 2019, at CROI 2019 in Seattle, Washington.