combinectin (GSK3732394) / ViiV Healthcare, GSK - LARVOL DELTA

A Phase 1 randomized study of GSK3732394, an investigational long-acting biologic treatment regimen for HIV-1 infection. (PubMed, Antivir Ther) - P1 | "This study demonstrated successful deployment of PK/PD dose relationships in the design and conduct of clinical trials by leveraging the findings toward predicting probability of success, resulting in appropriate early termination (ClinicalTrials.gov, NCT03984812)."

Journal • P1 data • Dermatology • Human Immunodeficiency Virus • Infectious Disease • CD4

Novel Bent Conformation of CD4 Induced by HIV-1 Inhibitor Indirectly Prevents Productive Viral Attachment. (PubMed, J Mol Biol) - "GSK3732394 is a multi-specific biologic inhibitor of HIV entry currently under clinical evaluation...In addition, an X-ray crystal structure of the ibalizumab Fab/CD4(D1-D4)/adnectin complex revealed an extensive interface between the adnectin and residues on CD4 domains D2-D4 that stabilize a novel T-shaped CD4 conformation...In addition, amino acid L151 was shown to be a critical indirect determinant of the specificity for binding to the human CD4 protein over related primate CD4 molecules, as it appears to modulate CD4's flexibility to adopt the adnectin-bound conformation. The significant conformational change of CD4 upon adnectin binding brings the D1 domain of CD4 in proximity to the host cell membrane surface, thereby re-orienting the gp120 binding site in a direction that is inaccessible to incoming virus due to a steric clash between gp160 trimers on the virus surface and the target cell membrane."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Evaluation of the Safety, Tolerability and Pharmacokinetics (PK) of GSK3732394 First-Time-in-Human (FTIH) Study (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: ViiV Healthcare; Terminated ➔ Completed

Clinical • Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

Evaluation of the Safety, Tolerability and Pharmacokinetics (PK) of GSK3732394 First-Time-in-Human (FTIH) Study (clinicaltrials.gov) - P1; N=24; Terminated; Sponsor: ViiV Healthcare; Completed ➔ Terminated; The study was terminated early (following completion of SAD Cohort 3; 80 mg) based on PK/PD modelling which demonstrated the medicine's intended target profile was not achievable.

Clinical • Trial termination • Human Immunodeficiency Virus • Infectious Disease • CD4

Evaluation of the Safety, Tolerability and Pharmacokinetics (PK) of GSK3732394 First-Time-in-Human (FTIH) Study (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: ViiV Healthcare; Recruiting ➔ Completed; N=80 ➔ 24

Clinical • Enrollment change • Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4

GSK3732394: A multi-specific inhibitor of HIV entry. (PubMed, J Virol) - "The addition of human serum albumin to the tri-specific inhibitor could allow it to function as a long acting self-administered treatment for patients with HIV infection. This molecule is currently in early clinical trials."

Journal • Gene Therapies • Infectious Disease

[VIRTUAL] STRUCTURAL ANALYSES OF A BOUND ANTI-CD4 ADNECTIN INHIBITOR OF HIV-1 (CROI 2020) - "GSK3732394 is a multi-specific biologic inhibitor of HIV entry currently under clinical evaluation...In addition, crystal structures of CD4 bound to both the Adnectin and a Fab subunit of ibalizumab were solved at a 3.7Å resolution...The significant conformational change of CD4 upon Adnectin binding brings the D1 domain of CD4 in proximity to the host cell membrane surface and provides a potential explanation for the ability of the CD4-bound Adnectin to inhibit HIV-1 infection. In addition, mutations of D2-D3-interface residues, specifically F202 and L151, dramatically impacted Adnectin binding to human and primate CD4, providing a rationale for the observed species specificity of the Adnectin."

A Novel gp41-Binding Adnectin with Potent Anti-HIV Activity Is Highly Synergistic when Linked to a CD4-Binding Adnectin. (PubMed, J Virol) - "Moreover, when fused to a similar Adnectin targeted to the human CD4 protein, the receptor for HIV-1, significant synergies in potency and efficacy are observed. These inhibitors are part of an effort to develop a larger biologic molecule that function as a long acting self-administered regimen for patients with HIV-1 infection."

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