Alena Yin Edwards 1, Thijs Jan Zweers 1, Kathryn Brown 1, Jan Losos 2, Peter Leone 2, Paul Wannamaker 2, Margaret Gartland 2, Rulan Griesel 3, Yash Gandhi 4
1 Certara (Radnor, United States), 2 ViiV Healthcare (Durham, USA), 3 ViiV Healthcare (London, UK), 4 GSK (Collegeville, USA)
Introduction: Lotivibart (LVB, VH3810109, N6LS) is a broadly neutralizing antibody targeting the CD4-binding site of the HIV-1 envelope, currently being investigated as an ultra-long-acting (ULA; ≥ 4-month [Q4M] dosing interval) antiretroviral option [1-5]. In the phase 2b EMBRACE study, LVB was administered 60 mg/kg intravenously (IV) or 3000 mg subcutaneously (SC) co-administered with recombinant human hyaluronidase PH20 (rHuPH20) Q4M, together with approved monthly (Q1M) cabotegravir as a 2-drug combination in virologically suppressed adults.
Objectives: The objectives of this analysis were to characterize the population pharmacokinetics (PK) of LVB and to evaluate relationships between LVB exposure and efficacy and safety endpoints through exposure–response (ER) analyses, including assessment of the impact of antidrug antibodies (ADAs).
Methods: A previously reported LVB population PK model, developed using data from 2 phase 1 studies in adult participants without HIV and a phase 2a study in antiretroviral therapy naïve adults living with HIV, was updated with EMBRACE data and used to generate individual exposure metrics. Model refinement included reassessment of covariate effects, including body weight. Logistic regression–based ER analyses were performed to assess the relationship between LVB exposure and the incidence of infusion site reactions (ISRs) and proportion of participants with plasma HIV-1 RNA ≥50 c/mL at the Month 6 primary endpoint. ER analyses for safety were conducted separately by route of administration. Baseline characteristics, including baseline viral load, phenotypic sensitivity to LVB and CD4+ cell count, and occurrence of ADAs were assessed to understand if there was any influence of these factors on ER.
Results: LVB PK in EMBRACE was consistent with PK observed in previous clinical studies. PK was well described by a 2-compartment model with linear elimination and first-order SC absorption. Allometric scaling based on body weight was included in the population PK model on clearance and volume parameters. Simulations indicated minimal impact of body weight on exposure. Participants who had HIV-1 RNA ≥ 50 c/mL at Month 6 tended to have lower LVB exposure, with a trend for higher probability of HIV-1 RNA ≥ 50 c/mL in participants with detectable baseline viral load (>20 c/mL) or lower baseline CD4+ count. There was no relationship between occurrence of ISRs and LVB exposure following either IV or SC administration. The incidence of ADAs was low, with no impact of ADAs on LVB PK, efficacy or safety.
Conclusions: A low occurrence of plasma HIV-1 RNA ≥50 c/mL at Month 6 was observed in the LVB phase 2b study EMBRACE. This population PK and ER modeling i) indicates multiple factors contribute to the observations of plasma HIV-1 RNA ≥50 c/mL at Month 6; ii) supports moving from mg/kg to flat IV dosing; and iii) demonstrates ADAs had no impact following Q4M dosing in virally suppressed participants.
Encore disclosure: This work was previously presented as a poster at the European AIDS Conference (EACS) 2025.
References:
[1] Leone et al. HIV Drug Therapy Glasgow 2022; Oral presentation O34.
[2] Leone et al. EACS 2023; Oral presentation PS8.O5.
[3] Locke et al. Drug Delivery. 2019;26:98–106.
[4] Morcos et al. Int J Clin Pharmacol Ther. 2013;51:537–548.
[5] Edwards et al. EACS 2023; Poster eP.A.099.
Reference: PAGE 34 (2026) Abstr 11893 [www.page-meeting.org/?abstract=11893]
Poster: Drug/Disease Modelling - Infection