Hypophosphatasia: enzyme replacement therapy (ENB-0040) decreases TNSALP substrate accumulation and improves functional outcome in affected adolescents and adults
P. Kishnani1, C. Rockman-Greenberg2, M. Whyte3, T. Weber1, A. Mhanni2, K. Madson3, A. Reeves3, K. Mack3, H. Plotkin4, N. Kreher4 & H. Landy4
Author affiliations
1Duke University, Durham, North Carolina, USA; 2University of Manitoba, Winnipeg, Manitoba, Canada; 3Shriners Hospital for Children, St. Louis, Missouri, USA; 4Enobia Pharma, Cambridge, Massachusetts, USA.
Hypophosphatasia (HPP), a heritable metabolic bone disease, results from low alkaline phosphatase (TNSALP) activity. Inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5′-phosphate (PLP), are substrates that accumulate in HPP. There is no approved therapy. ENB-0040, a bone-targeted, recombinant, human TNSALP improves skeletal mineralization in affected infants and children with HPP.
Objective: Evaluate substrate levels and six-minute walk test (6MWT) following 24 weeks of treatment.
Methods: Six adolescents and 13 adults with HPP (mean age 42 years (14–68)) were randomized in an open-label, multicenter, concurrent control study of the safety and efficacy of ENB-0040. Patients received no treatment, 2.1 or 3.5 mg/kg per week via daily SUBCUTANEOUS injections of ENB-0040.
Results: Statistically significant decreases in PPi and PLP (P=0.002 and P=0.009, respectively) occurred in the treated groups (2.1 and 3.5 mg/kg per week) vs non-treated group. Serum PPi levels decreased from baseline levels of 5.5 to 3.5 μM at week 24 (2.1 mg/kg per week) and from 5 μM at baseline to 2.8 μM at week 24 (3.5 mg/kg per week). Serum PLP levels decreased from 324 ng/ml at baseline to 69 ng/ml at week 24 (2.1 mg/kg per week) and from 603 to 38 ng/ml at week 24 (3.5 mg/kg per week).
At baseline, patients averaged 349 m (6 – 620 m) during the 6MWT, with 10/19 requiring assistive devices during testing. At week 24, treated patients improved +26 m vs no improvement (−14 m change) for controls. Of 12 patients with functional impairment (BL 6MWT was 25%–75% of normal), nine improved (8/9 treated, 1/3 no treatment). The mean improvements for the 2.1 and 3.5 mg/kg per week groups were +35.4 m (n=5) and +43.5 m (n=4) respectively.
Injection site reactions occurred in seven patients, but did not cause discontinuation of treatment. Six serious adverse events (SAEs) were reported among 3 patients, two control (no treatment) patients had four of the SAEs. No SAEs were associated with ENB-0040.
Conclusion: ENB-0040 significantly decreases TNSALP substrates and improves function in adolescents and adults with HPP.
Declaration of interest: The authors declare that there is a conflict of interest.
Funding: This work was supported, however funding details are unavailable.