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.
Highlights
Mucopolysaccharidosis (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
In addition to the morbidity and mortality associated with HCST, there remains a significant portion of MPS Type I (MPSI) patients that are permanently cognitively impaired following Hematopoietic stem cell transplant (HSCT) [6, 7]
The present study reports on a phase I-II clinical trial of the treatment of MPSI adults and children with valanafusp alpha
Summary
Mucopolysaccharidosis (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. 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 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. Mucopolysaccharidosis (MPS) Type I (MPSI) can present as severe MPSI (Hurler syndrome) or attenuated MPSI (Hurler-Scheie, or Scheie syndrome), and is caused by mutations in the gene encoding the lysosomal enzyme α-L-iduronidase (IDUA) [1]. In addition to the morbidity and mortality associated with HCST, there remains a significant portion of MPSI patients that are permanently cognitively impaired following HSCT [6, 7]
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