Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study

Abstract

Objective: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA), resulting in severe motor and cognitive dysfunction. This phase 1/2 study evaluated the safety and efficacy of intravenous (IV) recombinant human ASA (rhASA; HGT-1111, previously known as Metazym) in children with MLD.

Methods: Thirteen children with MLD (symptom onset < 4 years of age) were enrolled in an open-label, nonrandomized, dose-escalation trial and received IV rhASA at 50, 100, or 200 U/kg body weight every 14 (± 4) days for 52 weeks (NCT00418561; NCT00633139). Eleven children continued to receive rhASA at 100 or 200 U/kg during a 24-month extension period (NCT00681811). Outcome measures included safety observations, changes in motor and cognitive function, and changes in nerve conduction and morphometry.

Results: There were no serious adverse events considered related to IV rhASA. Motor function and developmental testing scores declined during the study in all dose groups; no significant differences were observed between groups. Nerve conduction studies and morphometric analysis indicated that peripheral nerve pathology did not worsen during the study in any dose group.

Interpretation: IV rhASA was generally well tolerated. There was no evidence of efficacy in preventing motor and cognitive deterioration, suggesting that IV rhASA may not cross the blood-brain barrier in therapeutic quantities. The relative stability of peripheral nerve function during the study indicates that rhASA may be beneficial if delivered to the appropriate target site and supports the development of rhASA for intrathecal administration in MLD.

Conflict of interest statement

CíD reports personal fees from University Hospital Copenhagen Rigshospitalet during the conduct of the study. MM has nothing to disclose. MHF has nothing to disclose. IKM reports grants from Shire (a Takeda company) during the conduct of the study. MW reports fees for consulting services from ID Remedies LLC. In addition, Dr Wasilewski has a patent pending: Wasilewski, Margaret, Wijatyk, Anna; c/o Shire Human Genetic Therapies, Inc., 300 Shire Way, Lexington, MA 02421 (US) PCT/US20 17/0 18440, Methods and Compositions for CNS Delivery of Arylsulfatase A. 17 February 2017. She was also an employee of Shire (a Takeda company) from July 2015 to August 2018 and is a Takeda stock owner. JL is an employee of Shire (a Takeda company). NB is an employee of Shire (a Takeda company). SG reports an institutional research grant from Shire (a Takeda company) outside of the submitted work. He serves as an advisor for trials in metachromatic leukodystrophy (Shire [a Takeda company], Orchard, Bioclinica, Homology Medicine) but receives no personal payment related to this role. CK reports grants and personal fees from Shire (a Takeda company) and grants from Danish Medical Research during the conduct of the study.

© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1

Study design and patient characteristics. aMedian age at baseline (the start of Study‐048).

Figure 2

Sulfatide measurements, lysosulfatide measurements, and light microscopic measurements of the right sural nerve at baseline and the left sural nerve at 26 weeks. (A) Sulfatide concentrations in all patients with available data (n = 12 at baseline; n = 11 at 26 weeks). (B) Lysosulfatide concentrations in all patients with available data (n = 11 at baseline and 26 weeks). (C) Total number of large fibers> 7 µm in diameter (cross‐section of whole nerve) in all patients with available data (n = 12 at baseline; n = 11 at 26 weeks). (D) Total number of small fibers < 7 µm in diameter (cross‐section of whole nerve) in all patients with available data (n = 12 at baseline; n = 11 at 26 weeks). (E) Examples of transverse light microscopic sections of the sural nerves in two patients. (F) Fiber diameter distributions for sural nerves from the patients in (E). The external diameters of fibers were traced (as shown in E) and the diameter of the fiber was calculated from the area enclosed by the trace. The diameters were compared using paired nonparametric tests.

Figure 3

Sensory nerve conduction studies of the right and left sural nerves at baseline and the left sural nerve at 10 and 26 weeks. (A) SNAP amplitudes in all patients with available data (n = 12 at baseline; n = 11 at 10 weeks and 26 weeks). Values measured as zero are plotted at 0.01 to enable visualization on the logarithmic scale. (B) SNCVs in all patients with available data (n = 11 at baseline and 10 weeks; n = 10 at 26 weeks). (C) Example SNAP recordings in two patients, one with less severe disease and one with severe disease. The values above the traces refer to SNAP amplitudes (μV) and SNCVs (m/s). Comparisons of the parameters were carried out using nonparametric tests. L, left; R, right; SNAP, sensory nerve action potential; SNCV, sensory nerve conduction velocity.

Figure 4

Motor nerve conduction studies of the right median nerve at baseline and 10, 26, 52, and 78 weeks. (A) CMAP amplitudes in the APB in all patients with available data (n = 13 at baseline; n = 12 at 10 weeks and 26 weeks; n = 11 at 52 weeks; n = 9 at 78 weeks). (B) DMLs in the APB in all patients with available data (n = 13 at baseline; n = 12 at 10 weeks and 26 weeks; n = 11 at 52 weeks; n = 9 at 78 weeks). (C) MNCVs of the median nerve in all patients with available data (n = 13 at baseline; n = 12 at 10 weeks and 26 weeks; n = 11 at 52 weeks; n = 9 at 78 weeks). (D) Example recordings of median nerve action potentials in an individual patient. The values above the traces refer to CMAP amplitudes (mV), DMLs (ms), and MNCVs (m/s). Comparisons of the parameters were carried out using nonparametric tests. APB, abductor pollicis brevis; CMAP, compound muscle action potential; DML, distal motor latency; MNCV, motor nerve conduction velocity.

Figure 5

Individual MRI total scores and MRS‐derived NAA values from baseline to 52 weeks by patient age. (A) MRI total scores. (B) MRS‐derived NAA values from the occipital cortex. (C) MRS‐derived NAA values from white matter, parieto‐occipital area. (D) MRS‐derived NAA values from white matter, frontal area. IV, intravenous; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N‐acetylaspartate; rhASA, recombinant human arylsulfatase A.