ESPE Abstracts

Introduction: Generation of neutralizing antibodies (Nab) is a complication in enzyme replacement therapies and can lead to loss of treatment efficacy. Asfotase alfa (AA) was recently approved as the first replacement therapy in severe hypophosphatasia (congenital deficiency of alkaline phosphatase [TNSALP]). We report a case of neutralizing antibody mediated loss of efficacy of AA treatment in hypophosphatasia and the successful result of immune tolerance induction (ITI) therapy.

Clinical case: A boy affected with severe (craniosynostosis, rib cage deformity, intense metaphyseal impairment), early onset (below 6 months) hypophosphatasia due to compound heterozygosity in ALPL (c.542C>T/c.644T>C) started enzyme replacement therapy with AA (6 mg/kg jper week in 3 doses) at age 4.42 years, showing complete biochemical (pyridoxal-5-phosphate [PLP] and inorganic pysophosphate [PPi] serum levels) and radiological (metaphyseal impairment) normalization and evident clinical improvement (bone pain resolution, achieved autonomous locomotion, improved muscle strength and endurance with no need of ambulatory-assisting devices). After 2.5 years on therapy, clinical symptoms and radiological signs reappeared and serum TNSALP substrate PLP levels increased (343 μg/l [N.V. 6.7–18.5]), up to a maximum of 999 μg/l despite increasing treatment to 3-fold standard dose (18 mg/kg per week). Antidrug (ADA) and Nab titers were low (1:2), but serum neutralizing activity was 40.4% (normal <4.478%). A Nab mediated loss of treatment efficacy was diagnosed and ITI therapy was scheduled (immunoadsorption [Therasorb^®]+ rituximab [375 mg/m2] weekly x 4 weeks, with concomitant immunoglobulin infusion [500 mg/Kg]) in addition to stopping AA treatment for one month. During this time, the patient needed a wheelchair even for in-home movement, suffered from continuous skeletal pain, had undetectable ALP serum levels and extremely high plasma PLP (997 mcg/l), but lymphocyte B depletion was complete and the patient’s serum neutralizing activity dropped to 4.75%. AA treatment was restarted at 6 mg/kg/week and was well tolerated, with no adverse effects. The patient showed substantial improvement in pain and physical performance (no need of ambulatory-assisting devices after 1 month, restarting school attendance, autonomous walking and physical games with classmates) and full Nab abrogation, normal PLP levels and substantial radiological healing were achieved 6 months after the ITI.

Conclusions: i) Nab generation can engender loss of efficacy of AA treatment in hypophosphatasia.

ii) The proposed ITI (weekly immunoadsorption plus rituximab for 4 weeks) can achieve Nab abrogation and restore treatment efficacy after 6 months of follow-up.