Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251

Abstract

Objective We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long-acting (LA) as pre-exposure prophylaxis (PrEP) against intravenous SIV challenge in a model that mimics blood transfusions based on the per-act probability of infection. Design CAB LA is an InSTI formulated as a 200 mg/mL injectable nanoparticle suspension that is an effective pre-exposure prophylaxis (PrEP) agent against rectal and vaginal SHIV transmission in macaques. Methods Three groups of rhesus macaques (n=8/group) were injected intramuscularly with CAB LA and challenged intravenously with 17 AID50 SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB LA dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB LA for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls. Results CAB LA was highly protective with 21 of the 24 CAB LA-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB LA injection. Conclusions These results support the clinical investigation of CAB LA as PrEP in people who inject drugs.

Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles

“…An additional benefit rests in that CAB is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1, with low potential to interact with other ARVs [ 16 , 18 ]. CAB LAP has also proven to be highly protective against rectal, vaginal, and intravenous SHIV transmission in non-human primates [ 19 – 22 ], and has been advanced into clinical trials for HIV prevention (NCT02720094). Despite such promising drug profiles, dosing pattern has limitations.…”

“…However, even with the high injection volumes, the maximal dosing interval is only 8 weeks. Recently in a phase 2a study investigating safety and tolerability of CAB LAP in HIV-uninfected men (ECLAIR; NCT02076178) [ 23 ], 800 mg dose every 12 weeks was selected based on previous clinical studies [ 17 , 24 ], aiming to maintain plasma CAB concentrations above 4 times protein-binding-adjusted 90% inhibitory concentration (4 × PA-IC 90 , 660 ng/mL), a concentration demonstrated to be protective against new infections in macaques [ 19 – 22 ]. However, two-thirds of participants had faster than anticipated drug absorption from the injection site leading to plasma drug concentrations below targeted concentration of 4 × PA-IC 90 at 12 weeks.…”

In VitroAntiviral Activity of Cabotegravir against HIV-2

“…Cabotegravir (S/GSK1265744; Shionogi/GlaxoSmithKline) is an investigational INI currently in development for the prevention and treatment of HIV-1 infection (45,46). The antiviral potency and pharmacokinetic properties of cabotegravir render the drug amenable to once-daily oral dosing, and long-acting injectable formulations of the drug have been evaluated in nonhuman primate models of HIV-1 infection and in clinical trials (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58). In contrast, there are no published data regarding the activity of cabotegravir against HIV-2, although one group reported a mean EC 50 of 0.12 nM for four HIV-2 isolates at an international meeting (59).…”

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“…56,57 In nonhuman primate (NHPmodels it has been shown that CABLA can protect against rectal, parenteral and (SHIV) challenges). [58][59][60][61][62][63] High level of protection was seen against repeated exposures, when CAB concentration in the plasma were over 4 times the protein adjusted IC 90 (PA IC 90 )(0.664µg/ml)and were generally maintained at drug concentrations above the (PA IC 90 (0.166µg/ml). The safety and pharmacokinetics of CAB LA in humans were evaluated in a phase 2a trial ,the ÉCLAIR trial, which enrolled HIVuninfected low risk men in the US.…”