ESPE Yearbook of Paediatric Endocrinology

Abstract: Lancet Diabetes Endocrinol. 2019 Feb;7(2):93–105.

In brief: The study reports outcomes of a single-arm 7-year phase 2 extension trial of Asfotase alfa for infants and children with life-threatening hypophosphatasia who received a median of 6·6 years of therapy. The early improvements previously reported were sustained for up to 7 years of treatment.

Comment: Perinatal and infantile hypophosphatasia are severe, life-threatening diseases of skeletal under-mineralisation due to lack of alkaline phosphatase activity and accumulation of its substrate inorganic pyrophosphate (PPi). The development of an enzyme replacement therapy with bone-targeted alkaline phosphatase (Asfotase alfa) is one of the most shining examples of novel therapies for rare disorders with dramatic effects in short-term phase 2 trials promising to effectively convert a deadly disease to a chronic condition requiring life-long injection therapy. Concerns that treatment efficacy would decrease with time or that the patients would develop neutralizing antibodies or unacceptable side-effects have lingered.

In the preceding 6 month phase 2 study, 10/11 participants completed the trial (one withdrew due to infusion reaction) and entered this extension trial. One patient died (sepsis unrelated to treatment) leaving 9 patients to complete the study receiving asfotase alfa for at least 6 years. The study found that the skeletal healing reported in the previous short-term trial was sustained over 7 years of treatment, that no patient who completed the study required respiratory support after year 4, body weight improved to within normal range from year 3 and height improved but remained below normal. Serious adverse events related to asfotase alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness). No patient developed resistance to treatment.

This study show that the dramatic result reported from asfotase alfa treatment of children with life-threatening hypofosfatasia before 3 years of age are maintained over a long period and is followed by improved weight, motor and cognitive functions. This study provides important reassurance and reinforces previous evidence for asfotase alfa as an emerging therapy for a rare and deadly skeletal disorder.

Reference: 1. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millán JL, Skrinar AM, Crine P, Landy H. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012, PMID: 22397652.