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

• Published in: Clinical drug investigation
• Main Authors: Gerometta, Michael, Henderson, Robert D, Friend, Richard, Cooper, Leanne T, Zhao, Jing, Boyd, Andrew W, Bartlett, Perry F
• Format: Journal Article
• Language: English
• Published: New Zealand 02.12.2024
• ISSN: 1179-1918; 1179-1918
• DOI: 10.1007/s40261-024-01410-x

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. 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. 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. 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. 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. Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).