Pharmacokinetics/pharmacodynamics and exposure-response modelling of VH3810109 (N6LS) in antiretroviral therapy-naïve adults with HIV-1 from the Phase IIa BANNER Study
A. Yin Edwards (1*), Waqar Ashraf (1*), Thijs Zweers (1), Kathryn Brown (1), Jan Losos (2), Peter Leone (2), Margaret Gartland (2), Paul Wannamaker (2), Yash Gandhi (3)
(1) Certara, Integrated Drug Development, Princeton, NJ, USA, (2) ViiV Healthcare, Durham, NC, USA; 3GSK, Collegeville, PA, USA, (3) GSK, Collegeville, PA, USA
Objectives: Broadly neutralizing antibodies (bnAbs) are under development for both the treatment and prevention of HIV-1. VH3810109 (N6LS) is a novel bnAb targeting the CD4-binding site of the HIV-1 envelope, which shows broad and potent neutralization activity in vitro, and has demonstrated robust antiviral effect in adults living with HIV-1 [1-3]. N6LS pharmacokinetics (PK) has been evaluated in 2 healthy participant studies (VRC 609 and 217901 [SPAN]) and in a Phase 2a study (BANNER, NCT04871113) in antiretroviral therapy naïve adults living with HIV. Here we developed a population PK (popPK) model to describe the PK of N6LS in both healthy and viremic adults following single and multiple doses. We further evaluated the relationship between N6LS PK and exposure on antiviral effect in viremic adults and assessed covariate factors, including in vitro phenotypic sensitivity, influencing the amount of N6LS required to achieve reduction in viral load.
Methods: A population PK model was developed using data from adults living with HIV in the Phase IIa BANNER study and 2 Phase I healthy adult studies. N6LS was administered as a single or multiple dose, either intravenously (IV) or subcutaneously (SC) with or without rHuPH20, at doses of 5-60 mg/kg or 70-700 mg. Viral load data from BANNER were included in the PK/ pharmacodynamic (PD) modeling and exposure-response (ER) assessment. ER modeling was performed based on the observed trends between maximum decline in plasma HIV-1 RNA during monotherapy and various exposure metrics, including N6LS concentration at the time of the maximum decline in plasma HIV-1 RNA, maximum N6LS concentration, and average N6LS concentration (Cavg) based on AUC0-14. In vitro sensitivity to N6LS (PhenoSense® mAb RNA assay) was assessed as a potential covariate for antiviral effect and various inhibitory concentrations (IC50, IC80, IC90, IC95) were compared for their impact on the ER models.
Results: N6LS PK was well described by a 2-compartment model with linear elimination and first-order SC absorption. ART-naïve participants showed 30% faster clearance than healthy participants. Co-administration of rHuPH20 provided a 57% increase in SC relative bioavailability. Allometric scaling based on body weight was included in the popPK model on clearance and volume parameters. Minimal impact of body weight on N6LS exposure was observed based on simulations. Viral dynamic changes were adequately described by an indirect response PK/PD model with an inhibitory Emax drug effect function. A feedback compartment was included to mimic the rebound of viral load observed following single dosing. A tolerance compartment was included to account for tolerance modulated by N6LS concentrations. Decrease in viral load was demonstrated at all doses, with a clear relationship between N6LS concentrations and change in viral load that was consistent between IV and SC administration. Baseline viral phenotypic sensitivity was predictive of N6LS concentrations required to achieve half maximal effect (EC50), whereas baseline viral load and baseline CD4+ count were not significant covariates. Inhibitory Emax models adequately described the relationship between the maximum decline in viral load and various exposure metrics. In all tested ER models, in vitro phenotypic IC90 value was consistently the most strongly correlated to EC50, compared to IC50, IC80 or IC95 values. Therefore, supporting the rationale of using IC90 as a potential screening tool for phenotypic sensitivity.
Conclusions: Robust antiviral activity was observed following IV and SC administration of N6LS and response was correlated with N6LS exposure. Baseline viral sensitivity to N6LS was an important predictor of drug exposure required to achieve antiviral effect. Specifically, IC90 was the most predictive covariate of the ER relationship amongst susceptibility values. This modeling demonstrates N6LS has a favorable PK/PD profile whether administered IV or SC and has been successfully applied to support dose selection for the ongoing Phase 2b study (EMBRACE, NCT05996471).
*Joint first authors
References:
[1] Leone P, Ferro A, Rolle C-P, et al. VH3810109 (N6LS) reduces viremia across a range of doses in ART-naive adults living with HIV: proof of concept achieved in the phase IIa BANNER (207959, NCT04871113) study. HIV Drug Therapy Glasgow; October 23-26, 2022; Glasgow, Scotland. Oral Presentation O34.
[2] Leone P, Cahn P, Rolle C-P, et al. Safety and tolerability of VH3810109 (N6LS) among antiretroviral therapy–naive adults living with HIV-1: results from the monotherapy phase of the phase 2a BANNER study. 19th European AIDS Conference; October 18-21, 2023; Warsaw, Poland. Oral Presentation PS8.O5.
[3] Leone P, Ferro A, Lupo S, et al. VH3810109 (N6LS) in antiretroviral therapy–naive adults with HIV-1: phase 2a BANNER efficacy data. Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO. Oral Presentation 117.
