Background: NXT007 is a next-generation bispecific antibody, based on emicizumab, that mimics the cofactor function of activated factor (F)VIII to restore intrinsic tenase activity in people with hemophilia A (PwHA). In comparison with emicizumab, NXT007 has demonstrated greater potency and higher maximum effect in thrombin generation (TG) analysis, and has a longer half-life. NXT007 was first investigated in PwHA in the multiple-ascending-dose (MAD) part of the Phase I/II NXTAGE study (Shima et al. OC 20. ISTH 2025); after a median of 68.4 weeks of follow-up, there were no safety concerns at any dose and the two highest dose cohorts had zero treated bleeds. Here, we report on the first three cohorts of the Phase I/II global MAD study of NXT007 in PwHA.

Methods: The global MAD study of NXT007 (NCT05987449) is an open-label, non-randomized, multicenter trial. Eligible participants (pts) are males aged 12–59 years with a diagnosis of severe (FVIII activity <1 IU/dL) or moderate (FVIII activity 1–5 IU/dL) congenital HA with/without FVIII inhibitors.

The primary treatment phase was 24 weeks. Each cohort received two loading doses of subcutaneous NXT007 at Days 1 and 15, followed by maintenance doses every 4 weeks from Day 29. The loading doses for cohorts 1, 2, and 3, were 0.42mg/kg, 1.05mg/kg, and 1.62mg/kg, respectively. Maintenance doses were 0.28mg/kg, 0.70mg/kg, and 1.08mg/kg, respectively; these were the same doses given to NXTAGE cohorts B2–B4, to be comparable at steady state. Pts may continue their NXT007 maintenance dose for up to 7 years in the extension phase.

The primary objective is to investigate the safety of NXT007, including incidence of adverse events (AEs) and serious AEs (SAEs). Secondary and exploratory objectives include efficacy (annualized bleeding rate [ABR] using the ISTH-SSC 72-hour rule and a negative binomial regression model), pharmacokinetics (PK), pharmacodynamics (including TG), D-dimer measurement, and immunogenicity (incidence of anti-drug antibodies [ADA]).

Results: At data cut-off (April 21, 2025), 22 pts had been treated with NXT007: seven in cohort 1, nine in cohort 2, and six in cohort 3. One pt left the study prior to any NXT007 administration due to meeting an exclusion criterion. No pt discontinued NXT007 treatment.

At enrollment, the median (range) age of pts was 36 (15–49) years. Twenty (90.9%) pts had severe HA and 2 (9.1%) had moderate HA. Nineteen (86.4%) pts had no history of FVIII inhibitors, 2 (9.1%) had previous and 1 (4.5%) had current FVIII inhibitors. Median (range) observation period in cohorts 1, 2, and 3 was 68.9 (61.1–80.0), 44.1 (42.1–46.1), and 21.6 (20.1–24.1) weeks, respectively.

At data cut-off, 6/7 (85.7%) pts in cohort 1 had experienced a total of 47 AEs; 8/9 (88.9%) pts in cohort 2 had 26 AEs; and 5/6 (83.3%) pts in cohort 3 had 23 AEs. Of 285 NXT007 administrations, 29 (10.2%) in five pts were associated with an injection-site reaction, all of which were Grade 1 and resolved by data cut-off. One other pt, in cohort 2, experienced AEs considered to be related to NXT007: transient Grade 2 aspartate aminotransferase increase and Grade 1 alanine aminotransferase increase. Two pts experienced SAEs, both of which resolved and were considered unrelated to NXT007: a pt in cohort 2 had Grade 3 adjustment disorder and a pt in cohort 3 had a Grade 3 fall. There were no thrombotic events or thrombotic microangiopathies.

ABRs (95% confidence intervals) for treated bleeds in the maintenance period were 0.11 (0.02–0.81) for cohort 1, 0.15 (0.02–1.04) for cohort 2, and 1.94 (0.73–5.16) for cohort 3. During the maintenance period, 6/7 (85.7%) pts in cohort 1, 8/9 (88.9%) in cohort 2, and 5/6 (83.3%) in cohort 3 had zero treated bleeds.

NXT007 plasma concentrations increased dose dependently and in line with population PK simulations. Activated FXI-triggered TG peak height increased from baseline and with increasing NXT007 plasma concentrations, into the non-hemophilic range. D-dimer levels were unaffected by NXT007. ADA were detected in most pts, but had no impact on PK, safety, or efficacy, and no cross-reactivity with emicizumab.

Conclusions: NXT007 was well tolerated, with a tolerable safety profile in all dose cohorts. Treated bleed ABRs were low; one pt per cohort experienced a treated bleed in the maintenance period, except for one notable outlier in cohort 3 with multiple bleeds. Presence of ADA had no impact on PK. These data support progression to Phase III trials.

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2025
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