Abstract Body

Background:

Lenacapavir (LEN) is a first-in-class HIV-1 capsid inhibitor in development for long-acting HIV treatment and prevention. GS-5423 and GS-2872 are broadly neutralizing antibodies (bNAbs). GS-5423 is derived from 3BNC117 and targets the CD4 binding site of HIV-1 glycoprotein (gp) 120; GS-2872 is derived from 10-1074 and binds to the V3 loop of gp120. Both bNAbs were modified to extend their half-life to allow less frequent dosing. We conducted a phase 1b randomized clinical trial to evaluate the safety and efficacy of LEN + GS-5423 + GS-2872 dosed every 6 months in people with HIV.

Methods:

Participants were adults living with HIV virologically-suppressed ≥ 2 years (HIV-1 RNA < 50 copies/mL) on ART, sensitive to both bNAbs by HIV proviral DNA phenotype (PhenoSense mAb IC90 ≤2ug/mL, Monogram Biosciences), a CD4 nadir ≥350, and CD4 count ≥500 at study entry. Participants were randomized 1:1 to two active treatment groups consisting of LEN (927 mg subcutaneous after oral loading) + GS-5423 (30mg/kg IV) + GS-2872 (10 mg/kg in Group 1 and 30 mg/kg in Group 2 IV). Participants were monitored clinically with plasma HIV-1 RNA every four weeks until the primary endpoint at Week 26. The primary endpoint was safety; secondary endpoints included virologic outcomes by FDA Snapshot analysis.

Results:

Of 124 screened participants, 55 were sensitive to both bNAbs, 21 were randomized, and 20 received the complete study regimen. The median age was 44 yrs (IQR 34, 51); 14% were female; 14% Black, 14% Asian, 33% Hispanic/Latinx; median CD4 count was 909 (IQR 687, 1270). There were no serious adverse events (AEs), no grade 4 or 5 AEs, and no AEs leading to study drug discontinuation. Two participants had grade 3 AEs: one with injection site cellulitis and one with injection site erythema at the site of LEN injection. One participant in Group 1 had a confirmed HIV RNA ≥ 50 copies/mL (155 copies/mL, confirmed 524 copies/mL) at Week 16 and resuppressed with reinitiation of baseline ART; one participant in Group 2 withdrew consent at Week 12 (with HIV-1 RNA < 50 copies/mL). 18/20 (90%) participants had HIV-1 RNA < 50 copies/mL at Week 26. (Table 1).

Conclusions:

The combination of LEN + GS-5423 + GS-2872 was well-tolerated with high efficacy for 6 months in selected virologically-suppressed persons living with HIV. These results provide a proof-of-concept that this combination could provide long-acting treatment for HIV with twice-yearly dosing.

Table 1: Efficacy as determined by the US FDA-defined Snapshot Algorithm at Week 26