“…Adnectins can be altered through various efficient in vitro techniques to bind tightly to any target sequence. One adnectin in GSK3732394 binds to domains two and three of cluster of differentiation four (CD4) cell-surface receptors on human immune cells and bends CD4 toward the cell membrane such that HIV-1 can no longer bind to domain one, thus inhibiting virus binding to CD4 via steric hindrance [8]. Figure 1. (A) Structure of GSK3732394.…”
Background The GSK3732394 multivalent protein was developed as a novel, long-acting, antiretroviral biologic treatment regimen with three independent, non–cross-resistant mechanisms for inhibiting HIV-1 entry. Methods A single-centre, Phase 1, double-blind, randomized, placebo-controlled study was conducted in healthy volunteers, using a 2-part adaptive study design: in Part 1, participants were randomized to receive subcutaneous injection of GSK3732394 or placebo (3:1) as single ascending doses (10-mg starting dose); in Part 2, participants were intended to receive multiple ascending doses. Primary and secondary objectives included safety, pharmacokinetics (PK) and pharmacodynamics (PD; cluster of differentiation four receptor occupancy [CD4 RO]) of GSK3732394 in healthy adults; PK/PD results in healthy volunteers were used to project HIV-1 treatment success. Results The most frequently reported adverse event was injection site reactions (ISRs; 8/18 [44%]). Most ISRs were mild (Grade 1–2; n = 7); one participant experienced a Grade 3 ISR (erythema ≥10 cm). All ISRs were delayed in onset (after Day 10). GSK3732394 demonstrated linear PK across all cohorts. Clearance was faster than expected, and PK/PD results were lower than expected, with the maximum dose investigated (80 mg) achieving mean trough CD4 RO of ∼25% on Day 7. The study was terminated as the PK/PD model linking PK and CD4 RO indicated that the maximum planned doses would not achieve the desired therapeutic profile. Conclusions 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).
“…Adnectins can be altered through various efficient in vitro techniques to bind tightly to any target sequence. One adnectin in GSK3732394 binds to domains two and three of cluster of differentiation four (CD4) cell-surface receptors on human immune cells and bends CD4 toward the cell membrane such that HIV-1 can no longer bind to domain one, thus inhibiting virus binding to CD4 via steric hindrance [8]. Figure 1. (A) Structure of GSK3732394.…”
Background The GSK3732394 multivalent protein was developed as a novel, long-acting, antiretroviral biologic treatment regimen with three independent, non–cross-resistant mechanisms for inhibiting HIV-1 entry. Methods A single-centre, Phase 1, double-blind, randomized, placebo-controlled study was conducted in healthy volunteers, using a 2-part adaptive study design: in Part 1, participants were randomized to receive subcutaneous injection of GSK3732394 or placebo (3:1) as single ascending doses (10-mg starting dose); in Part 2, participants were intended to receive multiple ascending doses. Primary and secondary objectives included safety, pharmacokinetics (PK) and pharmacodynamics (PD; cluster of differentiation four receptor occupancy [CD4 RO]) of GSK3732394 in healthy adults; PK/PD results in healthy volunteers were used to project HIV-1 treatment success. Results The most frequently reported adverse event was injection site reactions (ISRs; 8/18 [44%]). Most ISRs were mild (Grade 1–2; n = 7); one participant experienced a Grade 3 ISR (erythema ≥10 cm). All ISRs were delayed in onset (after Day 10). GSK3732394 demonstrated linear PK across all cohorts. Clearance was faster than expected, and PK/PD results were lower than expected, with the maximum dose investigated (80 mg) achieving mean trough CD4 RO of ∼25% on Day 7. The study was terminated as the PK/PD model linking PK and CD4 RO indicated that the maximum planned doses would not achieve the desired therapeutic profile. Conclusions 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).
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