Metachromatic Leukodystrophy: An Approach to Treatment (P4.6-048)

Objective: Development of Enzyme Replacement Therapy (ERT) for Metachromatic Leukodystrophy (MLD) Background: MLD is a recessive inborn error of metabolism (incidence at least 1/100,000 newborns), in which deficiency of the enzyme arylsulfatase A (ASA) leads to the accumulation of sulfated glycosphingolipids which are toxic to the central and peripheral nervous systems. This produces a spectrum of disease severity ranging from gait disorder with stereotypic progression to severe motor deficiency in younger patients, with psychiatric disease progressing to dementia in adolescents and adults. Early animal work suggested that the blood-brain barrier in MLD is excessively permeable, and that intravenously administered ASA might traverse it. Design/Methods: Recombinant Human ASA (rhASA) was developed by standard biotechnology techniques, and formulated initially for intravenous (IV: Metazym), and subsequently for intrathecal (IT: Shire: SHP611) use. Each was evaluated in sequential Phase I clinical trials in patients with the late infantile form of MLD (LI-MLD). Primary endpoint in both cases was safety; exploratory endpoints were measures of motor function (GMFC-MLD, developed for evaluation of MLD; and GMFM-88). Results: There were no major adverse events. IV (Metazym) had no evidence of efficacy. Nerve conduction studies and sural nerve biopsies from the patients in the Metazym studies indicated unchanged pathophysiology of nerve fibers and a tendency towards improved myelination. IT (SHP611) has been studied separately in a Phase I clinical program and demonstrated potential benefits in a subset of patients. Conclusions: Development of IT ERT for LI-MLD appears feasible. A Phase 2b trial of the maximum feasible dose of SHP611 (150 mg q week) will shortly be enrolling patients. Assessment of response will include both peripheral and central nervous system aspects of the disease. Disclosure: Dr. Krarup has nothing to disclose. Dr. Dali has received personal compensation in an editorial capacity for Orpahzyme A/S. Dr. Kraumlgeloh-Mann has received research support from Shire Pharmaceuticals. Dr. Whiteman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Shire Pharmaceuticals Inc. Dr. Whiteman holds stock and/or stock options in Shire Pharmaceuticals Inc. Dr. Barton has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Shire Pharmaceuticals Inc. Dr. Barton holds stock and/or stock options in Shire Pharmaceuticals Inc.