Phase III Randomized Open‑Label Non‑Inferiority Trial of NXT007 Prophylaxis versus Emicizumab in People with Hemophilia A

The primary objective is to evaluate the efficacy of NXT007 prophylaxis versus emicizumab prophylaxis in individuals with Hemophilia A by assessing the non-inferiority of treated bleeding episodes.

Secondary objectives include:

• Assessment of the superiority of NXT007 over emicizumab in reducing treated bleeds.
• Evaluation of efficacy based on combined non‑inferiority and superiority analyses of secondary efficacy endpoints.
• Comparison of health-related quality of life outcomes using a validated questionnaire.
• Examination of additional efficacy endpoints not captured by the primary or secondary bleed assessments.
• Safety evaluation of NXT007 relative to emicizumab, encompassing adverse event monitoring.
• Characterization of the pharmacokinetic profile of NXT007.
• Assessment of immunogenicity associated with NXT007 administration.
• Measurement of participant satisfaction with treatment administration.

The trial enrolled 236 individuals diagnosed with severe (factor VIII activity < 1 IU/dL) or moderate (factor VIII activity 1–5 IU/dL) congenital Hemophilia A, with or without inhibitors, encompassing both male and female participants classified as vulnerable, primarily children and adolescents aged approximately 2 to 17 years. Eligible subjects had documented FVIII inhibitor assay results within the preceding 12 months and a recorded history of prophylactic or episodic FVIII treatment, bypassing agent use, emicizumab prophylaxis, and bleeding episode details for at least six months prior to screening. Participants previously receiving on‑demand therapy were required to transition to a prophylactic regimen with either emicizumab or the investigational agent according to randomization, and all were required to comply with contraception requirements. The selection process was based on these diagnostic and historical treatment criteria, without additional lifestyle restrictions reported.

The study is a Phase III, multicenter, randomized, open‑label trial comparing subcutaneous prophylaxis with NXT007 to emicizumab in participants with Hemophilia A. Eligible individuals are screened for severe or moderate congenital disease, documented FVIII inhibitor status, and recent treatment history before random assignment to one of the two prophylactic regimens. After a screening visit, participants attend a baseline visit, followed by a Month 2 visit that marks the start of the primary efficacy assessment period, and a Month 8 visit for quality‑of‑life evaluation; additional scheduled visits continue at regular intervals until the end‑of‑study visit, which occurs after the final clinical cutoff date. The primary efficacy measure is the annualized number of treated bleeds (ABR) calculated from the Month 2 visit through the study’s clinical cutoff. Secondary assessments include bleed counts by type, injection frequency, pharmacokinetic and immunogenicity parameters, and safety outcomes such as adverse events, thrombotic complications, and injection‑site reactions. Participant involvement spans from screening through the end‑of‑study visit, encompassing an overall trial duration from the projected recruitment start on 30 June 2026 to the estimated completion on 29 January 2032. Early termination may occur if a participant experiences a serious adverse event, severe hypersensitivity reaction, thrombotic event, or other condition deemed by the investigator to preclude continued treatment, or if protocol non‑compliance is identified.

The investigational product, NXT007, is a humanised IgG4 monoclonal antibody directed against activated coagulation factors FIXa and FX. It is supplied as a sterile solution for injection and is administered by subcutaneous injection. The dosage form is defined as a “DF dosage form” with the specific dose and administration frequency determined by the study protocol and adjusted according to individual pharmacokinetic and pharmacodynamic responses.

The comparator product is Hemlibra 150 mg/mL solution for injection, containing the active substance emicizumab. It is also provided as a sterile solution for injection and delivered subcutaneously. The dosing regimen follows the approved prophylactic schedule for hemophilia A, with dose amounts and intervals specified in the protocol.

All study medications are administered according to a predefined dosing schedule that includes regular subcutaneous injections at intervals stipulated by the protocol. Participants receive training on self‑administration techniques, and injection sites are rotated to minimise local reactions. Compliance is monitored through patient diaries, electronic injection logs, and periodic review of returned medication containers. Pharmacokinetic and pharmacodynamic sampling is performed at scheduled visits to assess drug exposure and activity.

Efficacy will be assessed primarily by the Annualized number of treated bleeds (ABR) calculated from the Month 2 visit through the clinical cutoff date. Participants will record each bleed event prospectively, and investigators will classify bleeds as treated, untreated, spontaneous, joint, or target joint for analysis.

Secondary efficacy parameters include ABR for all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds; the proportion of participants with zero treated bleeds; the number of injections and dose per bleed; and the annualized factor VIII/BPA injection rate and consumption (excluding peri‑procedural use). These metrics will be derived from the continuous bleed log and treatment administration records.

Patient‑reported outcomes will be measured using a validated instrument to obtain Quality of Life domain scores. Adult (and adolescent) version scores will be collected at baseline and at the Month 8 visit. Changes from baseline in preoccupation, social activity impact, recreational activity impact, and physical impact domain scores will be evaluated at the predefined assessment points.

Data collection follows a prespecified schedule: bleed and treatment data are captured continuously from Month 2 onward; QoL questionnaires are administered at baseline and Month 8; and other specified timepoints are used for pharmacokinetic sampling. Efficacy analyses will employ descriptive statistics and appropriate inferential methods to test the non‑inferiority of NXT007 prophylaxis versus emicizumab prophylaxis in participants with Hemophilia A.