Intravenously Administered Iduronate-2-Sulfatase Fused with Anti-Human Transferrin Receptor Antibody (Jr-141) Crosses the Blood-Brain Barrier to Address Central Nervous System Disorders in Hunter Syndrome: A Randomised, Open-Label, Phase 1/2 Trial

Background: Hunter syndrome (mucopolysaccharidosis II, MPS II) is an X-linked recessive lysosomal storage disease in which a deficiency of iduronate-2-sulfatase causes an accumulation of glycosaminoglycans, giving rise to multiple systemic as well as central nervous system (CNS) symptoms. The currently available enzyme replacement therapy with idursulfase is ineffective against the associated CNS symptoms, because the blood-brain barrier (BBB) prevents the enzyme from reaching the brain. A novel iduronate-2-sulfatase fused with anti-human transferrin receptor antibody (JR-141) has been shown to penetrate the BBB and ameliorate learning deficits in model mice. This first-in-human translational study evaluated the pharmacokinetics, safety and efficacy of JR-141 in patients with MPS II. Methods: In this phase 1/2 multicentre, open-label, randomised clinical trial, 15 patients with MPS II who were being treated with intravenous idursulfase were recruited in Japan, and treatment was switched to intravenous administration of JR-141. In Part 1 of the study, which was designed to evaluate the safety of JR-141, the dosage was escalated over a period of 4 weeks (from 0.01 to 2.0 mg/kg/week); in Part 2, a 4-week randomised evaluation of the pharmacokinetics, safety and exploratory efficacy of JR-141 (at 1.0 or 2.0 mg/kg/week) was made. Cerebrospinal fluid (CSF) concentrations of heparan sulfate (HS) and dermatan sulfate (DS) were compared at the start of JR-141 administration and after 3 weeks, and plasma and urine concentrations of HS and DS were compared at the start and after 4 weeks. Findings: Between 10th May, 2017 and 25th October, 2017, we recruited a total of 15 male patients from 9 investigational sites in Japan. Of these, 14 were enrolled after 1 was excluded as unsuitable. Two patients without intellectual disabilities were selected for the dose escalation study (Part 1) and were given 0*01, 0*1, 1.0, and 2*0 mg/kg/week of JR-141 intravenously; plasma concentrations of JR-141 were dose-dependent and peaked at 3 h after initiation of each infusion. One patient developed erythema and pyrexia, which abated quickly, and the other exhibited no adverse reactions. In Part 2, the remaining 12 patients were randomly allocated to JR-141 dosing groups of 1*0 or 2*0 mg/kg/week. The plasma concentration profiles of JR-141 did not differ between the first and final administration, indicating no drug accumulation. Plasma and urinary levels of HS and DS were both suppressed by JR-141, and HS concentrations in the CSF had significantly decreased after the last administration (by an average of 25*1% in patients taking 1*0 mg/kg/week, and 31*5% in those taking 2*0 mg/kg/week). Two patients showed some amelioration of neurocognitive and motor symptoms following the 4-week treatment. No drug-related serious adverse events were observed during the study period. Interpretation: Patients with Hunter syndrome who were treated with JR-141 showed significant reductions in neurotoxin levels in the CSF, suggesting the drug successfully penetrated the BBB. Furthermore, JR-141 was no less effective in treating systemic symptoms than conventional enzyme replacement therapy with idursulfase. If JR-141 reduces glycosaminoglycan accumulation in the CSF, it should also be effective in treating CNS symptoms. This will be investigated in future clinical trials. Clinical Trial Number: NCT03128593 Funding Statement: The trial was funded by JCR Pharmaceuticals. Declaration of Interests: Torayuki Okuyama reports research grants from Sanofi, JCR Pharmaceuticals, GC Pharma, Dainippon Sumitomo Pharma, Actelion, Alexion and Anges, along with honoraria from Sanofi, Dainippon Sumitomo Pharma, Actelion and Anges. Yoshikatsu Eto has conducted consultancy for JCR Pharmaceuticals, and he has been awarded grants and research support from Actelion, BioMarin Pharmaceutical Inc. and Sanofi; he has also received honoraria from Actelion, BioMarin Pharmaceutical Inc., Sanofi, Shire and Dainippon Sumitomo Pharma. Norio Sakai has conducted consultancy for JCR Pharmaceuticals, and he has been awarded grant/research support from Sanofi and Dainippon Sumitomo Pharma, and honoraria from Actelion, BioMarin Pharmaceutical Inc., Sanofi, Shire and Dainippon Sumitomo Pharma. Ethics Approval Statement: The study was conducted in 8 hospitals and specialised MPS centres in Japan, and was in compliance with the Declaration of Helsinki. The protocol and patient informed consent were reviewed and approved by the Institutional Review Board at each participating institution.