Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.

Background: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.
Objective: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.
Methods: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.
Results: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (± 22.8) h in healthy volunteers (n = 20) and 74.4 (± 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (± 26.6) to 101.1 (± 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.
Conclusions: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.
Clinical Trial Registration: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).
Competing Interests: Declarations. Funding: This study was funded by NuNerve Pty Ltd, the manufacturer of NUN-004. NuNerve Pty Ltd was involved in the study design, data collection, data analysis and preparation of the manuscript. Conflict of Interest: Perry F. Bartlett, Andrew W. Boyd, Michael Gerometta and Leanne T. Cooper are inventors of NUN-004 and are thus listed inventors on granted patents. As such, they have a direct interest in the current clinical trial and a potential pecuniary interest if this drug is commercialised. Robert D. Henderson, Richard Friend and Jing Zhao have no relevant financial or non-financial interests that are directly relevant to the content of this article. Ethics Approval: The study was carried out in compliance with the clinical protocol and approved by an independent ethics committee (The Alfred Human Research Ethics Committee, project 743/20 [HREC/71737/Alfred-2020], approved on 18 December, 2020). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to Participate: Each participant signed and dated an informed consent form according to the local regulatory and legal requirements and Good Clinical Practices. Consent for Publication: Not applicable. Availability of Data and Material: The data that support the findings of this study are not openly available because of reasons of commercial sensitivity but may be available from the corresponding author upon reasonable request under an appropriate agreement. Code Availability: Not applicable. Authors’ Contributions: PFB, AWB, MG and JZ contributed to the study concept and design and provided ongoing advice to the clinical trial team when requested. RF and RH were involved in the acquisition of study data. LTC contributed to the custom assay design and development. All authors contributed towards the preparation of the manuscript, and read and approved the final submitted version.
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