Background
Islatravir (ISL) is a potent nucleoside reverse transcriptase translocation inhibitor that was associated with lymphopenia in a dose-dependent manner in clinical studies. We recently showed that treatment with high ISL doses in macaques also resulted in lymphopenia. Here, we evaluated preclinically a poly (ε-caprolactone) (PCL) implant designed to release low levels of ISL that are not predicted to cause lymphopenia. We investigated the safety and PK of ISL releasing implants and efficacy of low-dose ISL in protecting macaques against rectal SHIV infection.
Methods
Biodegradable PCL implants (25mm length,300 µm wall-thickness) were loaded with approximately 42 mg of ISL and the in vitro release-rate (IVRR) was determined under sink conditions. A single ISL implant was placed in the arm of each rhesus macaque (n=6) using a trocar. ISL-TP levels in PBMCs were measured weekly by LC-MS/MS. Implant site reactions were graded using a modified Draize scale (range: 0-5). Macaques underwent a 7-week conditioning phase to achieve steady-state ISL-TP in PBMCs prior to rectal exposure to SHIV162p3 twice-weekly during weeks 7-10 (up to 8 SHIV challenges). Macaques were monitored for SHIV infection during the challenge and follow-up period by RT-PCR. Infection outcomes were compared to 7 untreated animals.
Results
The estimated IVRR of ISL was 135 µg/d. The median [range] ISL-TP levels in PBMCs during the conditioning phase was 136 fmol/106 cells [118-164]. During SHIV challenges, the ISL-TP level was 109 fmol/106 cells [76-141] or about 1 log10 lower than those seen in humans treated with 0.25 mg of once-daily oral ISL (1,140 fmol/106 cells)(Fig 1A). ISL implants remained intact during the 5-month study period with no evidence of migration or implant-site reactions. The untreated controls were infected after a median of 1 SHIV challenge [range = 1-3]. In contrast, all ISL-treated macaques remained protected following repeated rectal SHIV challenges, resulting in an estimated efficacy of 100% (Fig 1B).
Conclusions
ISL implants maintained structural integrity, provided sustained release of low-dose ISL, and showed no sign of local toxicities after 5 months. The ISL-TP levels in PBMCs remained below the clinical toxicity threshold and provided complete protection to macaques against rectal SHIV infection. Our study supports the development of a PCL implant that can deliver safe and effective ISL concentrations for ultra-long-acting HIV prevention.