A study evaluating the safety, tolerability, and pharmacokinetics of a high-concentration (CAB 400mg/ml) cabotegravir long-acting injectable formulation following subcutaneous and intramuscular administration in healthy adult participants

BACKGROUND: Long-acting (LA) injectable cabotegravir (CAB200mg/mL) administered intramuscularly is approved for HIV-1 prevention (every-2-months), and treatment (suppressed switch) with rilpivirine (monthly or every-2-months). A high-concentration (CAB400mg/mL) formulation was developed to support less frequent dosing and/or potential self-administration via subcutaneous or thigh injections.
METHODS: The safety and pharmacokinetics of single/repeat administration of CAB400mg/mL 200'800mg (Cohorts 1'4, 4b, 4h, 5) intramuscularly (gluteus medius, vastus lateralis) or subcutaneously (abdominal) in healthy adults was evaluated in this ongoing Phase I study (NCT04484337). CAB200mg/mL active controls (n=1'2 per cohort) were matched by dose or volume. In Cohort 4h, recombinant human hyaluronidase rHuPH20 will be co-administered subcutaneously. Pharmacokinetic parameters were estimated via noncompartmental analysis and population pharmacokinetic (PPK) modelling. Simulations were performed using PPK model to assess various CAB400mg/mL regimens. Participant-reported outcome measures (PROMs) were also assessed.
RESULTS: Seventy participants received CAB (oral and/or injection) across Cohorts 1'4; 40% were female (sex), 40% were non-White. Median age, weight, and BMI were 34y, 76.9kg, and 26.1kg/m², respectively. Overall, safety profiles, including injection site reaction (ISR) frequency, were similar between formulations. CAB400mg/mL ISRs occurred in 92'100% of injections; most were Grade 1'2 (88'94%, maximum grade) (Table 1). Erythema and induration/swelling occurred more commonly after subcutaneous versus intramuscular injections. CAB400mg/mL pharmacokinetics were similar across administration routes (Table 2). CAB400mg/mL C_max was higher and half-life was 62% shorter than CAB200mg/mL after adjusting for demographics. CAB400mg/mL administered monthly, regardless of route, was predicted to exceed the plasma concentrations of approved CAB200mg/mL regimens. The conference presentation will include Cohort 4b, 4h, and 5 and PROM results.

Table 1. Safety Summaryof CAB400mg/mL in Healthy Adult Participants (Cohorts 1'4)
	IM gluteal		IM thigh		SC abdominal
	600mg [1.5mL] (n=18)	400mg [1mL] (n=34)	600mg [1.5mL] (n=11)	400mg [1mL] (n=12)*	600mg [1.5mL] (n=9)	200mg [0.5mL] (n=24)
Any AE, n (%) Drug-related AEs, n (%) Drug-related serious AEs, n (%) Drug-related AEs leading to withdrawal, n (%)	17 (94) 17 (94) 0 2 (11)	33 (97) 33 (97) 0 1 (3)	11 (100) 11 (100) 0 1 (9)	12 (100) 12 (100) 0 0	9 (100) 9 (100) 0 0	24 (100) 24 (100) 0 0
Any ISR AE, n (% of injections) Grade 1 events, n (% of ISRs)'  Grade 2 events, n (% of ISRs)'  Grade 3 events, n (% of ISRs)'	17 (94) 8 (47) 8 (47) 1 (6)	33 (97) 19 (58) 10 (30) 4 (12)	11 (100) 4 (36) 6 (55) 1 (9)	11 (92) 4 (36) 6 (55) 1 (9)	9 (100) 2 (22) 6 (67) 1 (11)	24 (100) 6 (25) 16 (67) 2 (8)
Note. Participants receiving CAB400mg/mL across Cohorts 1'4 were pooled by administration route and dose. All participants were scheduled to receive two injections. Each participant received a single injection at one dose/administration route (except the one detailed below), with the other injection being at a different dose/administration route (as seen in Table 2). Therefore, the n numbers are event level and represent the number of participants receiving an injection at each dose/administration route. *One participant received two injections at the indicated dose/volume for injection 1 and 2 and is therefore counted twice. ' Maximum grade reported following each injection. The denominator is the total number of injections leading to '¥1 ISR. There were no Grade 4 or 5 ISRs. AE, adverse event; CAB, cabotegravir; gluteal,gluteus medius;IM, intramuscular; ISR, injection site reaction; SC, subcutaneous.

Table 2. Plasma Pharmacokinetic Parameters of CAB400mg/mL in Healthy Adult Participants (Cohorts 1'4)
Cohort route	Cohort 1 IM gluteal		Cohort 2 SC abdominal		Cohort 3 IM thigh		Cohort 4 IM gluteal	Cohort 4 SC abdominal
Injection dose	Injection 1 600mg (n=18)	Injection 2 400mg (n=16)	Injection 1 600mg (n=9)	Injection 2 200mg (n=8)	Injection 1 600mg* (n=13)	Injection 2 400mg (n=10)	Injection 1 400mg (n=18)	Injection 2 200mg (n=16)
Cmax (µg/mL)	6.51 (28.6%)	7.10 (25.8%)	6.76 (37.7%)	4.32 (33.5%)	7.14 (69.4%)	5.87 (75.3%)	3.98 (61.6%)	3.03 (21.1%)
Concentration at: Week 4 (µg/mL) Week 8 (µg/mL)	2.78 (45.2%) NA	2.90 (37%) 0.745 (131.5%)	1.31 (82.4%) NA	1.29 (65.3%) 0.308 (95.8%)	0.784 (198.6%) NA	1.59 (57.2%) 0.24 (215.6%)	1.22 (31.7%) NA	1.26 (38.6%) 0.328 (13.8%)
LA absorption rate constant (h'1)	NA	0.00155 (56.2%)	NA	0.00203 (62.8%)	NA	0.00191 (112.3%)	NA	0.00186 (40.8%)
Terminal half-life (weeks)	NA	2.67 (56.2%)	NA	2.03 (62.8%)	NA	2.16 (112.3%)	NA	2.22 (40.8%)
PK parameters were estimated using noncompartmental analysis. Values displayed are geometric mean (CV%). *Two participants in Cohort 3 received 400mg instead of 600mg for injection 1, and their plasma concentrations were increased by 50% (dose normalized to 600mg) for estimating PK parameters. CAB, cabotegravir; Cmax, maximum plasma concentration post IM injection; gluteal,gluteus medius; IM, intramuscular; LA, long-acting; NA, not applicable; PK, pharmacokinetic; SC, subcutaneous (abdominal); thigh, vastus lateralis.

CONCLUSIONS: CAB400mg/mL could potentially expand options for LA injectable ART, and these interim safety and pharmacokinetic data support further clinical evaluation.

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