VH3810109 / GSK, ViiV Healthcare, National Institute of Allergy and Infectious Diseases - LARVOL DELTA

Safety and pharmacokinetics of N6LS, a broadly neutralising monoclonal antibody for HIV: a phase 1, open-label, dose-escalation study in healthy adults. (PubMed, Lancet HIV) - P1 | "N6LS showed a promising safety and pharmacokinetics profile while retaining its potent neutralisation characteristics in serum, making it a promising candidate for inclusion in HIV-1 prevention and therapeutic combination strategies. The addition of EDP can enable safe subcutaneous administration of higher doses and larger volumes of N6LS, supporting additional methods for prophylactic and therapeutic bNAb administration."

Journal • P1 data • PK/PD data • Allergy • Dermatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Pain

Preclinical Evaluation of Effector Function-Enhanced Variants of N6 bNAb (CROI 2025) - P2 | "The contribution of native effector functions to the antiviral activity of N6LS has previously been explored (Wang, et al...Conclusions Multiple variants of the N6 bnAb displayed suitable developability properties and varying degrees of effector function enhancement in vitro. Four variants were identified for continued in vitro and in vivo assessment, including initiation of stable cell lines for potential manufacture."

Preclinical • Human Immunodeficiency Virus • Infectious Disease • FCGR2A • FCGR3A

VH3810109 (N6LS) Efficacy and Safety in Adults Who Are Virologically Suppressed: The EMBRACE Study (CROI 2025) - "Grade ≥3 N6LS-related infusion site reactions (ISRs) were reported in 0/50 (0%) participants receiving N6LS 60 mg/kg IV and 7/49 (14%) receiving N6LS 3000 mg SC + rHuPH20; mean (SD) duration of all ISRs was 2.0 (0.8) and 6.4 (5.2) days with N6LS dosed IV or SC + rHuPH20, respectively. Conclusions N6LS administered IV or SC + rHuPH20 every 4 months in combination with monthly CAB LA maintained viral suppression in most adults who were sensitive to N6LS at baseline, with tolerability favoring IV N6LS."

Clinical • Late-breaking abstract • Human Immunodeficiency Virus • Infectious Disease • CD4

EMBRACE: A Study to Investigate the Virologic Efficacy and Safety of VH3810109 + Cabotegravir Compared to Standard of Care (SOC) in Male and Female Adults Living With Human Immunodeficiency Virus (HIV) (clinicaltrials.gov) - P2 | N=135 | Active, not recruiting | Sponsor: ViiV Healthcare | Trial completion date: Jun 2026 ➔ Jan 2029

Trial completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

VH3810109 (N6LS) administration dose‐responsively enhances anti‐HIV antibody‐dependent cellular cytotoxicity (ADCC) and antibody‐dependent cellular phagocytosis (ADCP) activity in ex vivo models (HIV-Glasgow 2024) - "We demonstrate that VH3810109 has immunological activities ex vivo that correlate with clinically relevant virological outcomes. These data underscore the importance of the immunological activities of bNAbs and support continued development of these agents as direct-acting antiviral agents as well as components of remission/cure regimens."

Preclinical • Human Immunodeficiency Virus • Infectious Disease • GLI2

Correlation of baseline phenotypic sensitivity with virological response to VH3810109 (N6LS) in BANNER (HIV-Glasgow 2024) - "Baseline N6LS viral sensitivity correlated with magnitude and duration of antiviral response, which were linked to dose and resulting N6LS serum concentration. Other factors (baseline VL, baseline CD4+ T-cell count, inherent control by the individual) may impact response to N6LS. Overall, 81% of participants with successful phenotypic testing met protocol-defined N6LS sensitivity criteria for enrolment in the ongoing phase IIb study."

Human Immunodeficiency Virus • Infectious Disease • CD4

Potent and broadly neutralizing HIV-1 antibodies with improved pharmacokinetics achieved by negative supercharging (AIDS 2024) - "While confirmation is needed regarding whether the enhanced potency observed in in vitro pseudovirus assays translates to improved protection in non-human primates, the conservation of the CH1 and CL domains in IgG1 suggests that these substitutions in the CH1 and CL, along with the addition of acidic tails, have the potential to enhance the PK and potency of various therapeutic antibodies."

Late-breaking abstract • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

EMBRACE: A Study to Investigate the Virologic Efficacy and Safety of VH3810109 + Cabotegravir Compared to Standard of Care (SOC) in Male and Female Adults Living With Human Immunodeficiency Virus (HIV) (clinicaltrials.gov) - P2 | N=99 | Active, not recruiting | Sponsor: ViiV Healthcare | N=45 ➔ 99

Combination therapy • Enrollment change • Human Immunodeficiency Virus • Infectious Disease • CD4

EMBRACE: A Study to Investigate the Virologic Efficacy and Safety of VH3810109 + Cabotegravir Compared to Standard of Care (SOC) in Male and Female Adults Living With Human Immunodeficiency Virus (HIV) (clinicaltrials.gov) - P2 | N=45 | Active, not recruiting | Sponsor: ViiV Healthcare | Recruiting ➔ Active, not recruiting | N=150 ➔ 45

Combination therapy • Enrollment change • Enrollment closed • Human Immunodeficiency Virus • Infectious Disease • CD4

High-Dose VH3810109 (N6LS) ± Recombinant Human Hyaluronidase PH20: Phase I SPAN Study Safety Results (CROI 2024) - P1 | "High-dose N6LS, when given IV or SC + rHuPH20, was generally safe and well tolerated in this study. These results support the ongoing clinical development of N6LS 3000 mg SC + rHuPH20 and N6LS 60 mg/kg IV into phase IIb."

Clinical • P1 data • Dermatology • Human Immunodeficiency Virus • Infectious Disease • Pain • CD4

VH3810109 (N6LS) in Adults With HIV-1 Who Are ART-Naive-: Phase IIa BANNER Efficacy Data (CROI 2024) - "Robust antiviral activity was observed after IV and SC administration of N6LS; response was correlated with N6LS exposure. Response with SC vs IV dosing was lower and likely due to differences in BL susceptibility, serum antibody levels, and slower time to reach Cmax. Overall, N6LS led to dose-dependent declines in VL consistent with antiviral activity reported for other bNAbs."

Clinical • P2a data • Human Immunodeficiency Virus • Infectious Disease • CD4

EMBRACE: A Study to Investigate the Virologic Efficacy and Safety of VH3810109 + Cabotegravir Compared to Standard of Care (SOC) in Male and Female Adults Living With Human Immunodeficiency Virus (HIV) (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: ViiV Healthcare | Phase classification: P2b ➔ P2

Combination therapy • Phase classification • Human Immunodeficiency Virus • Infectious Disease • CD4

A Study to Evaluate the Antiviral Effect, Safety and Tolerability of GSK3810109A in Viremic Human Immunodeficiency Virus (HIV)-1 Infected Adults (clinicaltrials.gov) - P2 | N=63 | Completed | Sponsor: ViiV Healthcare | Active, not recruiting ➔ Completed | Phase classification: P2a ➔ P2

Phase classification • Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4

Pharmacokinetics/Pharmacodynamics and Virological Activity of VH3810109 (N6LS) in Antiretroviral-Naive Viremic Adults From the Phase IIa BANNER Study (EACS 2023) - "Baseline viral sensitivity to N6LS was an important predictor of drug exposure required to achieve response. This modeling demonstrates N6LS has a viable PK/PD profile whether administered IV or SC and has been successfully applied to support dose selection for the planned Phase IIb study."

Clinical • P2a data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • CD4

Pharmacokinetics/Pharmacodynamics and Virological Activity of VH3810109 (N6LS) in Antiretroviral-Naive Viremic Adults From the Phase IIa BANNER Study (EACS 2023) - "Baseline viral sensitivity to N6LS was an important predictor of drug exposure required to achieve response. This modeling demonstrates N6LS has a viable PK/PD profile whether administered IV or SC and has been successfully applied to support dose selection for the planned Phase IIb study."

Clinical • P2a data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • CD4

Safety and Tolerability of VH3810109 (N6LS) Among Antiretroviral Therapy–Naive Adults Living With HIV-1: Results From the Monotherapy Phase of the Phase IIa BANNER Study (EACS 2023) - "No clinically significant safety trends in vital signs, electrocardiograms, or laboratory tests were observed across dose groups. Conclusions : N6LS was well tolerated when given IV or SC, with few drug-related AEs, including mild ISRs, and no serious AEs."

Clinical • Monotherapy • P2a data • Human Immunodeficiency Virus • Infectious Disease • CD4

EMBRACE: A Study to Investigate the Virologic Efficacy and Safety of VH3810109 + Cabotegravir Compared to Standard of Care (SOC) in Male and Female Adults Living With Human Immunodeficiency Virus (HIV) (clinicaltrials.gov) - P2b | N=150 | Recruiting | Sponsor: ViiV Healthcare | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

EMBRACE: A Study to Investigate the Virologic Efficacy and Safety of VH3810109 + Cabotegravir Compared to Standard of Care (SOC) in Male and Female Adults Living With Human Immunodeficiency Virus (HIV) (clinicaltrials.gov) - P2b | N=150 | Not yet recruiting | Sponsor: ViiV Healthcare

Combination therapy • New P2b trial • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain. (PubMed, MAbs) - "Here, we sought to improve the PK of the broad HIV-1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable domains. Another variant, N6LS.C49, with two charge substitutions, had an observed in vivo half-life and an estimated human half-life of 14.5 and 80 days (versus 9.0 and 44 days for N6LS) and neutralized ~80% of 208 strains at a geometric mean IC <1 µg/mL. Since Arg and Lys residues are prevalent in human antibodies, we propose substitution of select Arg or Lys with Asp, Gln, Glu, or Ser in the framework region as a general means to improve PK of therapeutic antibodies."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Phenotypic analysis of HIV-1 resistance to CD4 binding site broadly-neutralizing antibodies (P455) (IMMUNOLOGY 2023) - "The ex vivo assay used pre-infusion CD4+ T cells from participants enrolled in the VRC 607/ACTG A5378 phase I study of the CD4 binding site (CD4bs) bNAbs’ VRC01LS (n=7) or VRC07-523LS (n=9). From these assays, the escape variant signatures of outgrowth viruses that replicated in presence of CD4bs bNAbs, were identified. We found complementary escape profiles from 3 CD4bs bNAbs (1-18LS, N6LS, and VRC01v23)  with ex vivo and neutralization assays showing suppression by 1 or 2 but not all 3 bNAbs, supporting the potential for combination bNAb therapy. Our data suggest that the simultaneous use of multiple CD4 binding site bNAbs together could aid in limiting viral escape."

IO biomarker • Human Immunodeficiency Virus • Infectious Disease • CD4

SPAN: A Study to Investigate the Safety and Pharmacokinetics of a Single Dose of VH3810109 (Also Known as GSK3810109), Administered Either Subcutaneously (SC) With rHuPH20 or Intravenously (IV), in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: ViiV Healthcare | Recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease

N6LS WITH rHuPH20 ENABLES SAFE HIGH-DOSE MONOCLONAL ANTIBODY SUBCUTAENOUS DELIVERY (CROI 2023) - P1 | "In summary, N6LS was safe and well tolerated when administered with or without rHuPH20. Given its broad and potent neutralization of circulating HIV-1 clades, N6LS remains a promising candidate for HIV-1 prevention and therapy. As demonstrated in this trial, the ability to safely administer higher doses/volumes of N6LS subcutaneously opens new potential avenues for prophylactic and therapeutic self-administration of bnMAbs."

Dermatology • Human Immunodeficiency Virus • Infectious Disease • CD4

EFFICACY AND COMPLEMENTARITY OF HIV-1 SUPPRESSION BY CD4-BINDING bNAbs (CROI 2023) - "In vivo and ex vivo effect of HIV-1 bNAbs comparison suggest that the ex vivo assay shows potential to reliably predict bNAbs antiviral effect in clinical trials and contribute to analysis of resistant strains that could emerge in vivo. Our data indicate that optimal combinations of CD4bs bNAbs can be used to mitigate viral resistance to bNAb-based immunotherapies. Comparative suppression profiles of VRC01LS, VRC07-523LS, VRC01v23, N6LS and 1-18LS treated conditions in ex vivo assay"

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease • CD4

IMPACT OF BASELINE FACTORS ON VIROLOGIC RESPONSE TO bNAb VH3810109 (N6LS) IN BANNER (CROI 2023) - "In BANNER part 1, a single IV infusion of VH3810109 was well tolerated, with few drug-related AEs and robust antiviral efficacy at both doses studied. In this small study, viral sensitivity to VH3810109 and BL CD4+ cell count correlated with magnitude and duration of antiviral response. However, other factors may impact virologic outcome, including pre-treatment VL, serum antibody concentration, and an individual’s inherent control of viral replication."

Human Immunodeficiency Virus • Infectious Disease • CD4

A Study to Evaluate the Antiviral Effect, Safety and Tolerability of GSK3810109A in Viremic Human Immunodeficiency Virus (HIV)-1 Infected Adults (clinicaltrials.gov) - P2a | N=62 | Active, not recruiting | Sponsor: ViiV Healthcare | N=44 ➔ 62

Enrollment change • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4