HIV PrEP Dose Rationale for Cabotegravir (GSK1265744) Long-acting Injectable Nanosuspension

OA03.02 LB

Background: Long acting (LA) drugs such as the integrase inhibitor cabotegravir (CAB, GSK1265744) may bolster PrEP adherence and efficacy. PrEP dose selection is challenging given lack of validated surrogate markers and low rates of HIV seroconversion.

Methods: CAB PrEP dose selection was based on in vitro virology, human antiviral activity, healthy volunteer (HV) single and repeat dose safety and PK studies and non-human primate (NHP) PK and SHIV rectal/vaginal challenge studies. Data were integrated in population-based PK (PPK) analyses/dose simulations to identify a dose predicted to be efficacious and clinically practical.

Results: In a 10-day monotherapy study in ART-naïve patients CAB 5 mg/day p.o. (n = 7) yielded geomean blood plasma (BP) C_tau of 0.57 ug/mL, >3-fold above protein-adjusted (PA)-IC₉₀ of 0.166 ug/mL, and produced a 2.14 log median decrease in HIV RNA, providing a PK/PD correlate. Single injection CAB LA (SC or IM) in 58 HV evaluated ascending doses for safety and PK. CAB LA 800 mg IM BP levels exceeded C_tau of oral 5 mg/day for 16 weeks. A repeat dose HV (n = 40) study confirmed safety and PK of 800 mg IM dose; geomean C_tau (week 12) was 1.11 ug/mL or 7x PA-IC₉₀. NHP PK studies targeting CAB concentration-time profiles in BP approximating human values were followed by SHIV162p3 rectal challenges (50xTCID₅₀) to establish POC and evaluate threshold of protection. CAB BP ≥1xPAIC₉₀ correlated with ≥97% protection. SHIV vaginal challenge showed protection in 6/8 rhesus macaques (300xTCID₅₀) and 8/8 pigtail macaques (50xTCID₅₀). PPK based simulation of dosing regimens achieving target BP levels with quarterly injections enabled selection of 800 mg IM q12week dose.

Conclusions: CAB LA PrEP dose selection was guided by human safety, PK and antiviral activity studies and NHP challenge studies. CAB LA 800 mg IM q12weeks is predicted to yield drug levels correlated with robust anti-HIV activity and protection against SHIV rectal and vaginal challenge. This dose is under study in phase 2 safety and PK trials.