Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial

Abstract

BackgroundMucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline.ResultsDrug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1±7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion.ConclusionClinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6-phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI.Trial registrationClinical Trials.Gov, NCT03053089. Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341. Registered 6 March, 2017.

Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood–Brain Barrier Using Receptor-Mediated Transcytosis

“…125 I-bio-Aβ 1-40 /8314-SA exhibited higher uptake in the brain than 125 I-bio-Aβ in in vivo assay after intravenous injection to rhesus monkeys. 33) At present, this strategy is presumed to be simpler than using 124 I-PET.…”

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

“…Table 2 summarizes information currently available on seven clinical trials for neuropathic MPS in which various novel approaches to address CNS manifestations have been or will be evaluated. Several reports on the results of these clinical trials have been published [3,5,6,40], yet none of the compounds tested have yet been approved for general clinical use. There are several notable challenges in the development of novel ERTs for neuropathic MPS.…”

“…Efforts have been made to boost brain uptake of drugs across the BBB by targeting various receptors (e.g., insulin and transferrin) located on the vascular endothelial cells where, by way of transcytosis, modified enzymes are delivered into and exert effects on the brain. Positive results have been reported in preclinical and clinical studies on MPS-I [3] and MPS-II [4,5]. Administration routes other than intravenous injection (e.g., intrathecal [6,7] and intracerebroventricular [8] injections) have also been attempted with the aim of delivering enzymes directly into the brain, but they invariably involve significant practical difficulties for both physicians and patients.…”

How Not to Miss the Mild Forms of Mucopolysaccharidosis Type I in Patients With Articular Manifestations of the Disease?

“…Несмотря на эффективность ФЗТ, остаются ткани и органы с низкой биодоступностью для ферментных препаратов -это костная и хрящевая ткань, сердце, центральная нервная система, ткани глаза и роговица [43]. В настоящий момент ведутся разработки по преодолению гематоэнцефалического барьера с помощью специальных растворимых рецепторов, что может расширить возможности ФЗТ при тяжелых формах МПС I [44].…”