Asfotase alfa 18mg/0.45ml solution for injection vials

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.

Abstract licence: CC BY-NC

Hypophosphatasia (HPP) is a rare, dento-osseous disorder caused by impaired activity of tissue non-specific alkaline phosphatase (TNSALP), a key enzyme in tissue mineralization. This review provides a clinical perspective on the current medical treatment of both children and adults with HPP. Dental problems, rickets in children, and osteomalacia in adults are common in HPP. However, disease manifestations in individual patients are exceptionally variable. Recent studies broadened our understanding of HPP symptoms. For example, data showed behavioral health challenges in HPP children, and a large, real-world data set from the Global HPP Registry demonstrated that HPP adults regardless of the time of disease onset exhibit significant disease burden and are broadly affected by non-skeletal impairments, such as pain and chronic fatigue. Treatment for HPP relies on the enzyme replacement asfotase alfa. Small, mostly pediatric trials initially established dosing, safety and efficacy of asfotase alfa, and latest data corroborated the long-term safety and efficacy in both children and pediatric-onset adults. Data from several recent observational studies, including the Global HPP Registry, underscored that asfotase alfa improves physical functions, non-skeletal symptoms such as pain, and quality-of-life (QoL) in adults irrespective of age-of-onset. Clinical use of asfotase alfa is based on prescribing information and evidence-based consensus guidelines. However, recommendations for initiation of therapy are just emerging. Alternatives to asfotase alfa remain limited, but a derivative, efzimfotase alfa, currently undergoes clinical testing. Studies in larger HPP patient populations suggest efficacy of enzyme replacement therapy independent of patient age and time of disease onset.

Abstract licence: CC BY 4.0