In situ forming implants (ISFIs) may provide desirable properties for an ultra-long-acting cabotegravir (CAB) formulation including long dosing intervals, small injection volumes, and retrievability.
Herein, we developed and characterized a CAB ISFI formulation with high drug loading and that is amenable for subcutaneous administration in small volumes. We defined stability, microstructure, injectability, and release kinetics in vitro and in vivo. We show that this formulation is safe in mice and non-human primates and can release CAB for 6-11 months at levels that are above established benchmarks for PrEP protection in macaques and humans (664 ng/mL or 4x PA-IC90). We associate the extended release of CAB from the ISFI with long-lasting protection against SHIV infection in a macaque model of PrEP that predicted clinical efficacy of CAB LA and other approved oral PrEP regimens. Our study identifies a promising platform for the extended release of CAB at levels that are known to be associated with PrEP protection in humans.
To investigate if CAB delivered from ISFIs could confer rectal protection, we performed a series of SHIV challenge experiments at different times after implantation. We first evaluated short-term protection in two macaques (RH-1093 and RH-1097) challenged twice-weekly between weeks 4 and 8 (total of 8 challenges per animal) (Fig. 5a). Both animals were protected against SHIV infection as opposed to an untreated real time control (RH-1092) that was infected after a single SHIV exposure. Long-term protection was evaluated in two additional macaques (RH-1048 and RH-1080) that were exposed twice per week to SHIV between weeks 14 and 18 (8 challenges per animal) (Fig 5b). One animal (RH-1048) that maintained plasma CAB levels above 4x PA-IC90 received an additional 6 SHIV challenges between weeks 25 and 28. The two CAB treated animals were protected from infection while an untreated real time control (RH-1084) was infected after a single SHIV exposure (Fig 5b). Overall, a single ISFI treatment completely protected 4 macaques during a cumulative of 38 rectal SHIV exposures that spanned a period of 27 weeks.
Our results showing 100% protection in macaques over several months also represent to our knowledge the longest documented PrEP activity seen with a single CAB administration.