Background:
Long-acting cabotegravir (CAB) administered intramuscularly (IM) every 2 months (Q2M) is approved for HIV-1 prevention; CAB and rilpivirine administered IM monthly or Q2M is approved for HIV-1 treatment. To support less frequent dosing, we evaluated safety and pharmacokinetics (PK) of the approved CAB 200 mg/mL (CAB200) formulation administered subcutaneously (SC) with recombinant human hyaluronidase PH20 (rHuPH20) and a new CAB 400 mg/mL (CAB400) formulation administered SC or IM without rHuPH20.
Methods:
This is an ongoing, open-label, single-dose, dose-escalation, phase I study (NCT05418868) in healthy adults with 2 sentinel participants (pts) per cohort. In part A, rHuPH20 (10,000 IU) and CAB200 (A1, 800 mg; A2, 1600 mg; A3, 3200 mg; 4 to 16 mL) were sequentially co-administered SC (abdominal). In part C, CAB400 (800 mg, 2 mL) was administered SC (abdominal; C1) or IM (gluteus medius; C2). To evaluate potential CAB400 dosing regimens, CAB PK profiles were simulated using an established CAB200 IM population PK model modified based on observed PK data in part C.
Results:
To date, 38 pts total received CAB (Table); 61% were male sex at birth, and 61% were non-White. Median age, weight, and BMI were 37.5 years, 74.7 kg, and 26.7 kg/m…2, respectively. In part A, maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve from 0 to infinity (AUC0-∞) increased with dose proportionally and were higher than CAB200 IM, indicating potentially increased bioavailability, while t1…/2 was similar to CAB200 IM. Cmax in C1 was lower than in C2; both were lower than CAB200 IM. CAB t…1/2 in C1 was longer than in C2; both were longer than CAB200 IM, even though some pts have not reached terminal phase due to long t…1/2. PK simulations predict a CAB400 SC/IM dose interval of ≥4 months achieves similar exposure to the approved CAB200 IM. Injection site reactions (ISRs) occurred in all pts dosed SC in part A (22/22) with a dose-related trend for increased ISR grades. A sentinel pt in cohort A3 experienced a drug-related serious adverse event of injection site erythema with necrosis. ISRs in C1 (8/8 pts) and C2 (3/8 pts) were grade 1 or 2.
Conclusions:
Safety and PK results from part A indicate low potential to achieve less frequent dosing with CAB200 and rHuPH20. The new CAB400 formulation (SC and IM) exhibits favorable safety and PK commensurate with dose intervals of ≥4 months and is in ongoing clinical development.
