A randomized Phase 1b trial evaluating the pharmacodynamics of ilofotase alfa in adults with hypophosphatasia

Hypophosphatasia is a rare genetic disease caused by deficient alkaline phosphatase (AP) activity. In adults, this causes functional limitations, substantial disability with pain and reduced quality of life. This Phase 1b, single-center, open-label trial investigated ilofotase alfa, a fully human recombinant protein intended as enzyme replacement therapy, in adults with hypophosphatasia. Changes in plasma levels of AP substrates inorganic pyrophosphate and pyridoxal-5'-phosphate were evaluated. Participants were randomized 1:1 to receive at 0.8 or 3.2 mg/kg ilofotase alfa intravenously over 1 h. Twelve participants were enrolled and completed the trial. At baseline, all participants had reduced AP activity and elevated pyridoxal-5'-phosphate. The greatest reduction in inorganic pyrophosphate and pyridoxal-5'-phosphate occurred 2 h after start of dosing in both treatment groups. Across the 10-d follow-up period, inorganic pyrophosphate values returned to baseline levels more rapidly in the 0.8 mg/kg group compared with the 3.2 mg/kg group. Mean circulating AP activity peaked 24 h after dosing and subsequently declined but remained above the lower limit of normal throughout the study. A dose-proportional increase in ilofotase alfa was observed, reaching peak concentration 1-h post-infusion. Eight treatment-emergent adverse events occurred, all classified as mild. These data demonstrate that single-dose ilofotase alfa enhances AP activity and results in dose-dependent reductions in primary disease-specific biomarkers without undesired effects on mineral homeostasis. Clinical trial registration number: ClinicalTrials.gov number: NCT05890794.