NXTAGE: a phase 1/2 study of NXT007 to assess safety, pharmacokinetics, and efficacy in hemophilia A without inhibitors.

abstractNXT007 is a next-generation, activated factor VIII (FVIIIa)-mimetic bispecific antibody under investigation in the phase 1/2 NXTAGE trial. Here, we report the primary analysis of the multiple-ascending-dose Part B study in people with hemophilia A (PwHA). Eligible participants were men with severe HA without FVIII inhibitors. Four dose cohorts (B1-B4) were planned, with NXT007 administered subcutaneously at maintenance doses of 0.072 mg/kg, 0.28 mg/kg, 0.70 mg/kg, and 1.08 mg/kg, respectively, every 4 weeks. Primary end points were safety (adverse events [AEs] and serious AEs [SAEs]), tolerability, pharmacokinetics, pharmacodynamics, and efficacy; secondary end points included incidence of anti-drug antibodies (ADAs). Participants in cohorts B1 (n = 10), B2 (n = 6), B3 (n = 6), and B4 (n = 8) had received NXT007 for a median (minimum to maximum) of 114.1 (29-140), 96.4 (88-112), 58.1 (52-72), and 22.2 (4-28) weeks, respectively. Two participants discontinued treatment: NXT007-unrelated AE (n = 1) and complete loss of NXT007 exposure due to ADAs (n = 1). Participants' plasma NXT007 concentration showed a dose-dependent increase, and predicted FVIII-equivalent activity reached a nonhemophilic level (≥40 IU/dL) in B2 onward. NXT007 had a favorable safety profile at all doses. Most AEs were mild/moderate and all 3 SAEs were considered unrelated to NXT007. Mean annualized treated bleed rates were 1.48 (B1), 0.28 (B2), 0.00 (B3), and 0.00 (B4). Two participants had pharmacokinetics-affecting NXT007 ADAs, including the B1 participant who discontinued treatment. NXTAGE Part B demonstrates that NXT007 could provide nonhemophilic coagulation activity in PwHA, with a less burdensome dose regimen than currently available therapies. This trial was registered at Japan Registry of Clinical Trials as jRCT2080224835.