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

Background: 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. 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.

Results: Drug 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.

Conclusion: Clinical 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 registration: Clinical Trials.Gov, NCT03053089 . Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341 . Registered 6 March, 2017.

Keywords: Blood-brain barrier; Efficacy; Iduronidase; Insulin receptor; Mucopolysaccharidosis Type I; Open label clinical trial; Safety.

Conflict of interest statement

Ethics approval and consent to participate

All patients were treated and evaluated at the HCPA-Hospital das Clinical de Porto Alegre, Brazil. The clinical protocol was reviewed and approved by the local Institutional Review Board, the National Ethics Committee (CONEP) and the National Health Surveillance Agency (ANVISA) in Brazil. Written informed consent was read, understood, and signed by a parent or guardian before each patient enrolled in the study.

Consent for publication

Not applicable.

Competing interests

MS and RJB are employees of ArmaGen, and RG, IN, SC, and WMP have received consulting fees from ArmaGen. The other authors declare no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Trial design

Fig. 2

Concentration of heparan sulfate (HS, panel a) and dermatan sulfate (DS, panel b) in CSF of Stage 2 patients at baseline and at 26 weeks (wks) of treatment in comparison to HS and DS levels in CSF of 10 non-MPSI human pediatric subjects. The mean ± SE values for HS in CSF are 685 ± 112, 779 ± 78, and 91 ± 18 ng/mL for the MPSI patients at baseline, for the MPSI patients at 26 weeks, and for the pediatric controls, respectively. The mean ± SE values for DS in CSF are 436 ± 85, 490 ± 87, and 38 ± 8 ng/mL for the MPSI patients at baseline, for the MPSI patients at 26 weeks, and for the pediatric controls, respectively

Fig. 3

Urinary GAGs (Mean±SEM) are plotted vs weeks of treatment. The horizontal lines are the mean±SEM of urinary GAGs in 12 MPSI children after 12 months of laronidase therapy, with a range of 177-269 ug GAG/mg creatinine [4]