The efficacy of daily oral pre-exposure prophylaxis (PrEP) to prevent HIV-1 infection is highly dependent on adherence. Lenacapavir (LEN) is a potent first-in-class HIV capsid (CA) inhibitor with long-acting pharmacokinetics (PK), making it attractive for PrEP. We previously derived a simian-tropic HIV-1 infectious molecular clone (stHIV-A19) that encodes HIV-1 CA and replicates to high titers in pigtail macaques (PTMs). Here we evaluate LEN in vitro potency against stHIV, and the PK and efficacy of subcutaneous (SC) LEN PrEP in PTMs against a high-dose intravenous (IV) stHIV challenge.
LEN in vitro potency against stHIV was evaluated in PTM PBMCs and adjusted for PTM plasma protein binding by competitive equilibrium dialysis. To assess LEN PK, naïve PTMs (n=6) each received two SC doses of LEN 6 weeks apart (15 mg/kg x 2, n=3; 50 mg/kg x 2, n=3). LEN plasma levels were measured by LC-MS. To evaluate LEN PrEP efficacy, naïve PTMs (n=10) each received a single IV challenge with stHIV (105 infectious units). The animals received a single SC injection of LEN (25 mg/kg, n=3) or vehicle (n=4) 30 days prior to challenge, or 7 daily SC injections of a 3-drug control regimen (tenofovir disoproxil fumarate/emtricitabine/dolutegravir) starting 3 days prior to challenge (n=3). Plasma stHIV RNA (vRNA) and stHIV DNA (vDNA) in PBMC were monitored longitudinally using sensitive qRT-PCR and qPCR assays, respectively.
LEN showed potent anti-stHIV activity in PTM PBMCs, with a mean plasma protein-adjusted (pa)EC95 of 1.46 nM. In the PK study, plasma LEN concentrations peaked 3-4 weeks after the second LEN dose and declined slowly thereafter, with mean plasma LEN concentrations maintained above its paEC95 for >145 and >200 days after the second 15 mg/kg and 50 mg/kg dose, respectively. In the challenge study, mean plasma LEN concentrations exceeded target protective levels (4x paEC95) by day 1 post dose and at the time of challenge. There was no evidence of infection in any LEN or 3-drug group animals post IV challenge, with no detected plasma vRNA or PBMC vDNA through >8 months of follow-up. By contrast, all 4 placebo animals became infected, with increasing plasma vRNA and PBMC vDNA first detected 4 days post IV challenge.
A single SC LEN injection effectively prevented stHIV infection in a stringent, high dose IV challenge model. These findings highlight the utility of the stHIV/PTM model and support the clinical development of long-acting LEN for PrEP.