Enzyme replacement therapy (ENB-0040) in hypophosphatasia improves functional outcome and decreases TNSALP substrates in adolescents and adults

Abstract

Hypophosphatasia (HPP), a heritable metabolic bone disease, results from inactivating mutation(s) in the gene for the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). The natural substrates that accumulate in HPP include inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5′ phosphate (PLP), the principal circulating form of vitamin B6. PPi excess blocks hydroxyapatite crystal formation causing rickets in growing children and osteomalacia in adults. There is no approved therapy. ENB-0040, a bone-targeted, recombinant, human TNSALP given subcutaneously has improved severely affected infants and children with HPP. Objective: Evaluate TNSALP substrate levels following 24 weeks of ENB-0040 treatment (Rx) and six-minute walk test (6MWT) function in adolescents and adults with HPP. The 6MWT is a performance-based measure of functional exercise capacity. Methods: 6 adolescents and 13 adults with HPP (mean age 42 yrs [14–68]) were randomized in an open-label, multicenter, multinational, dose-ranging, concurrent control study of the safety, efficacy, and pharmacokinetics of ENB-0040. Patients received 0, 2.1, or 3.5 mg/kg/wk of ENB-0040. Results: At baseline (BL), patients averaged 349 m during the 6MWT (6–620 m), but 10 required assistive devices. The differences walked for the Rx vs no Rx groups were +26 vs −14 m at week 24. Among those with functional impairment (n=12) whose BL 6MWT was 25%N75% of normal, 9 improved (8/9 Rx, and 1/3 no Rx). The mean improvements for the 2.1 and 3.5 mg/kg/wk groups were +35.4 m (n=5) and +43.5 m (n=4), respectively. Injection site reactions occurred in 7 patients, but did not cause discontinuation of treatment. Six serious adverse events (SAEs) were reported among 3 patients, two observation patients had 4 of the SAEs. No SAEs were from ENB-0040. Serum PLP levels decreased in both groups, from 324 and 602 ng/mL at BL to 69 ng/mL and 38 ng/L at week 24, respectively (p=0.009). Conclusion: ENB-0040 significantly decreases TNSALP substrates and improves the 6MWT in adolescents and adults with HPP. This article is part of a Special Issue entitled ECTS 2012. Disclosure of interest: M. Whyte grant/research support from Enobia, consulting fees from Enobia, C. Greenberg grant/research support from Enobia, Advisory Board Membership of Enobia, consulting fees from Enobia, P. Kishnani grant/research support from Enobia, Advisory Board Membership of Enobia, consulting fees from Enobia, K. Madson grant/research support from Enobia, A. Mhanni grant/research support from Enobia, T. Weber: none declared, K. Mack grant/research support from Enobia, A. Reeves grant/research support from Enobia, H. Plotkin employee of Enobia, N. Kreher employee of Enobia, H. Landy employee of Enobia. doi:10.1016/j.bone.2012.02.101 OC31 (recipient of a 2012 ECTS Travel Award) Detection of autoantibodies to osteoprotegerin in patients with severe idiopathic osteoporosis P. Riches⁎, T. Gilchrist, W.D. Fraser, S.H. Ralston Rheumatology Department, Institute of Genetics and Molecular Medicine, Edinburgh, UK Faculty of Medicine and Health Sciences, University of East Anglia,