P-1248. Phase 2 Pharmacokinetics and Anti-Drug Antibody Results of the Investigational Twice-Yearly HIV-1 Treatment Regimen Lenacapavir, Teropavimab, and Zinlirvimab

TL;DR

This study evaluates the drug levels and immune responses to a twice-yearly HIV treatment regimen involving three investigational drugs in people with HIV.

Contribution

The study reports pharmacokinetics and anti-drug antibody data for a novel twice-yearly HIV treatment regimen.

Findings

LEN, TAB, and ZAB maintained therapeutic concentrations at Week 52 with no drug accumulation.

ADAs and NAbs against TAB and ZAB were low in titer and did not affect drug levels.

The drugs have long half-lives, supporting twice-yearly dosing in HIV patients.

Abstract

Teropavimab (TAB, GS-5423) and zinlirvimab (ZAB, GS-2872) are broadly neutralizing antibodies (bNAbs) under investigation as a twice-yearly (Q6M) combination treatment with lenacapavir (LEN) for people with HIV-1 (PWH). An ongoing Phase 2 study (NCT05729568) reported efficacy and safety of Q6M LEN, TAB, and ZAB in virologically suppressed (VS) PWH consistent with the standard of care; here, we report Week (W) 52 pharmacokinetics (PK), anti-drug antibody (ADA), and neutralizing antibody (NAb) responses.Figure 1.Distribution of Ctrough by ADA status of TAB at Day 1–Week 26 (A) and Week 26–52 (B)ADA-positive refers to any antibody that binds to the drug. NAb-positive are a subset of ADA-positive, which refers specifically to ADAs that are neutralizing. Box plots show the interquartile range; the bold central line represents the median.ADA, anti-drug antibody; Ctrough, trough concentration; NAb, neutralizing antibody; TAB, teropavimab.Figure 2.Distribution of Ctrough by ADA status of ZAB at Day 1–Week 26 (A) and Week 26–52 (B)ADA-positive refers to any antibody that binds to the drug. NAb-positive are a subset of ADA-positive, which refers specifically to ADAs that are neutralizing. Box plots show the interquartile range; the bold central line represents the median.ADA, anti-drug antibody; Ctrough, trough concentration; NAb, neutralizing antibody; ZAB, zinlirvimab.

Distribution of Ctrough by ADA status of TAB at Day 1–Week 26 (A) and Week 26–52 (B)

ADA-positive refers to any antibody that binds to the drug. NAb-positive are a subset of ADA-positive, which refers specifically to ADAs that are neutralizing. Box plots show the interquartile range; the bold central line represents the median.

ADA, anti-drug antibody; Ctrough, trough concentration; NAb, neutralizing antibody; TAB, teropavimab.

Distribution of Ctrough by ADA status of ZAB at Day 1–Week 26 (A) and Week 26–52 (B)

ADA-positive refers to any antibody that binds to the drug. NAb-positive are a subset of ADA-positive, which refers specifically to ADAs that are neutralizing. Box plots show the interquartile range; the bold central line represents the median.

ADA, anti-drug antibody; Ctrough, trough concentration; NAb, neutralizing antibody; ZAB, zinlirvimab.

PK serum samples of TAB and ZAB and plasma samples of LEN were tested with validated electrochemiluminescence (ECL) immunoassay and liquid chromatography-mass spectrometry methods, respectively. Non-compartmental analyses based on LEN, TAB, and ZAB concentration data were conducted with WinNonLin software. Samples were tested for ADAs, with NAb assessment on ADA-positive samples, using validated ECL-based assays.

Fifty-three participants received LEN, TAB, and ZAB. Half-lives of TAB and ZAB were 63.5 and 89.1 days, respectively. Limited accumulation was observed after the second dose of TAB and ZAB at W26. After the Day 1 subcutaneous (SC) LEN dose (plus oral loading on Days 1+2), mean (90% CI) trough concentration (Ctrough) was 20.2 ng/mL (17.8; 22.7) at W26 (n=52); after the second SC LEN dose at W26, mean (90% CI) Ctrough was 25.8 ng/mL (22.3; 29.3) at W52 (n=46). LEN concentrations were above the 4-fold inhibitory quotient (IQ4; 15.5 ng/mL) for wild-type HIV-1 at both timepoints. Emergent ADAs against TAB and ZAB were generally low in titer and detected in 6 (11.3%) and 9 (17.0%) participants, respectively; of these, 3 (5.7%) had emergent NAbs against TAB and ZAB, individually. All ADAs were treatment-induced; 2 (3.8%) and 6 (11.3%) participants had persistent ADAs against TAB and ZAB, respectively. There was no impact of ADAs or NAbs on the PK of TAB (Figure 1) or ZAB (Figure 2).

Mean therapeutic concentrations of LEN, TAB, and ZAB were maintained at W52, with no evidence of drug accumulation over time. There was a low incidence of ADAs/NAbs against TAB and ZAB, and titers were generally low. No association was observed between assay-positive ADAs/NAbs and PK. LEN, TAB, and ZAB had prolonged half-lives, supporting Q6M dosing in VS PWH.

Nan Zhang, PhD, Exelixis: Employee|Gilead science, inc.: Employee|Gilead science, inc.: Stocks/Bonds (Public Company) Jianmin Li, MS, Gilead Sciences, Inc.: Employee Hui Liu, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Kwad Mponponsuo, MD, MSc, Gilead Sciences, Inc.: Employee and shareholder Sean E. Collins, MD, MS, Gilead Sciences, Inc: Employee Yanan Zheng, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

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