P205: Efficacy and safety of asfotase alfa in adults with hypophosphatasia: A systematic review of randomized and non-randomized studies

Introduction: Hypophosphatasia (HPP) is a rare, inherited metabolic bone disorder caused by pathogenic variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity and resulting in impaired mineralization, musculoskeletal pain, reduced mobility, and increased morbidity in adults.Asfotase alfa, a recombinant human TNSALP, is approved for pediatric-onset HPP; however, evidence supporting its efficacy and safety in adults remains limited and derived from heterogeneous clinical studies.A comprehensive synthesis of available data is needed to clarify treatment benefits in this population.Methods: This systematic review followed PRISMA guidelines and was prospectively registered in PROSPERO (CRD420251182140).A comprehensive search of PubMed, Embase, and the Cochrane Library was performed from inception to the most recent search date using the terms (adult) AND (hypophosphatasia OR HPP) AND ("asfotase alfa" OR Strensiq OR "enzyme replacement therapy" OR TNSALP).Eligible studies included randomized controlled trials and non-randomized observational studies evaluating asfotase alfa in adults with confirmed HPP.Two reviewers independently screened all records, extracted data, and assessed risk of bias according to Cochrane methodological guidance.Outcomes of interest included six-minute walk test (6MWT), pain scores, health-related quality of life, biochemical markers, radiologic findings, and adverse events.Results: A total of 730 records were identified, of which 43 underwent full-text review and 5 met all inclusion criteria.Across studies, asfotase alfa consistently improved functional capacity, with increases in 6MWT distance from baseline, and reduced musculoskeletal pain.Improvements in patientreported quality of life and stabilization or enhancement of skeletal imaging findings were also noted.Biochemical analyses showed increased alkaline phosphatase activity and reductions in disease-associated substrates, reflecting pharmacodynamic response.Adverse events were predominantly mild to moderate, most commonly injection-site reactions, with few treatment discontinuations reported.Conclusion: Current evidence suggests that asfotase alfa provides meaningful clinical benefits to adults with hypophosphatasia, including improved mobility, reduced pain, better quality of life, and favorable biochemical responses, with an acceptable safety profile.However, existing studies are limited by small sample sizes and predominantly non-randomized designs.Larger, well-controlled trials focused specifically on adult populations are required to confirm longterm efficacy and safety.