Background
TMB-365, a second-generation post-attachment bNAb binds to the second domain of CD4 and displays improved PK, antiviral activity, and breadth of coverage when compared to ibalizumab. TMB-380 (VRC07-523LS) is a bNAb that binds to the CD4 binding site of HIV Env and has potent antiviral activity and favorable safety and PK profile. Here we present results of a 24-week phase 2 maintenance study of the combination with complementary MOA in people with suppressed HIV-1 infection (NCT05275998).
Methods
Participants suppressed (VL<50 c/mL) with continuous oral cART for at least 6 months, clinically stable, and had no history of virologic failure (VF) were enrolled (target N=20). After screening, oral cART was discontinued and 4800 mg of TMB-365 and TMB-380 were infused every 8 weeks for 3 doses (baseline, week 8, week 16). Oral cART was restarted at the week 24 visit. All infusions were performed over 60 minutes in outpatient clinics with vital sign determinations every 15 minutes during and up to 60 minutes post-infusion. VF was defined as 2 consecutive HIV-RNA values >50 c/mL at least 2 weeks apart. Efficacy was evaluated as % participants with VL<50 c/mL at week 24.
Results
21 individuals were enrolled; 1 developed a GI bleed (before dosing, unrelated) between screening and day 1 and was replaced. 18 of 20 completed the study. Age range was 24 to 67 years; 1/21 were female; 10/21 were White (non-Hispanic); and median CD4 count was 706 cells/µL. Two participants did not complete the study. One participant developed a generalized rash 32 days after the first infusion and participation was terminated. One participant developed an atypical papular eruption 7 days after infusion #1 and withdrew. No SAEs, Grade 3 or 4 adverse events or acute infusion reactions were observed. Treatment-emergent AEs (N=48) were mild to moderate. 16 were attributed to infusions with bNAbs; rash (4), fatigue (4), headache (3), flushing (2), fever (1), chills (1), aches (1). No cases of protocol-defined VF were observed. At week 24, 16/17 (94%) with plasma VL below 50 c/mL, one had VL of 59 c/mL, N=2 early D/C, N=1 no data. The preliminary mean TMB-365 and TMB-380 concentrations at week 24 are 29 and 107 μg/mL, respectively.
Conclusions
Every 8-week infusions of TMB-365 and TMB-380 with complementary MOA at 4800 mg each are safe and effective as a complete maintenance therapy in people with suppressed HIV-1 infection. No confirmed VF was observed. Results support the development of TMB-365/TMB-380 into phase 2b.