William M Pardridge1, Ruben J Boado2, Roberto Giugliani3,4, Mathias Schmidt2. 1. ArmaGen, Inc., Calabasas, CA, USA. wpardrid@ucla.edu. 2. ArmaGen, Inc., Calabasas, CA, USA. 3. Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 4. Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
Abstract
BACKGROUND: Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the α-L-iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy (ERT) with recombinant IDUA does not treat the CNS, due to the lack of transport of the enzyme across the blood-brain barrier (BBB). Human IDUA has been re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb domain binds the endogenous insulin receptor on the human BBB to trigger receptor-mediated transport across the BBB, and acts as a molecular Trojan horse to ferry the fused IDUA into the brain of patients with MPSI. METHODS: The present investigation describes the initial dosing, plasma pharmacokinetics, and plasma glucose response to the intravenous infusion of doses of valanafusp alpha ranging from 0.3 to 3 mg/kg in five adults and from 1 to 6 mg/kg in 13 pediatric subjects with MPSI. RESULTS: Valanafusp alpha plasma clearance is increased four-fold in children, and shows a linear pharmacokinetic response over the dose range of 0.3-3 mg/kg with a stable plasma elimination half-life (t½). The plasma pharmacokinetic parameters for valanafusp alpha overlapped with the same parameters previously reported for recombinant human IDUA (laronidase). The majority of the tested subjects had been receiving laronidase ERT for years, and some showed high levels of anti-drug antibodies (ADAs). However, the presence of these ADAs did not generally alter the rate of plasma clearance of valanafusp alpha in MPSI. The infusion of 0.3-6 mg/kg doses of valanafusp alpha had no effect on plasma glucose for up to 24 h after the drug infusion. CONCLUSION: The plasma clearance of valanafusp alpha is increased four-fold in children with MPSI compared with adult subjects at a dose of 1-3 mg/kg. The plasma pharmacokinetic profile of valanafusp alpha, at a dose of 1-3 mg/kg, is comparable to that of laronidase in children with MPSI.
BACKGROUND:Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the α-L-iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy (ERT) with recombinant IDUA does not treat the CNS, due to the lack of transport of the enzyme across the blood-brain barrier (BBB). HumanIDUA has been re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain is a monoclonal antibody (MAb) against the humaninsulin receptor (HIR). The HIRMAb domain binds the endogenous insulin receptor on the human BBB to trigger receptor-mediated transport across the BBB, and acts as a molecular Trojan horse to ferry the fused IDUA into the brain of patients with MPSI. METHODS: The present investigation describes the initial dosing, plasma pharmacokinetics, and plasma glucose response to the intravenous infusion of doses of valanafusp alpha ranging from 0.3 to 3 mg/kg in five adults and from 1 to 6 mg/kg in 13 pediatric subjects with MPSI. RESULTS:Valanafusp alpha plasma clearance is increased four-fold in children, and shows a linear pharmacokinetic response over the dose range of 0.3-3 mg/kg with a stable plasma elimination half-life (t½). The plasma pharmacokinetic parameters for valanafusp alpha overlapped with the same parameters previously reported for recombinant humanIDUA (laronidase). The majority of the tested subjects had been receiving laronidase ERT for years, and some showed high levels of anti-drug antibodies (ADAs). However, the presence of these ADAs did not generally alter the rate of plasma clearance of valanafusp alpha in MPSI. The infusion of 0.3-6 mg/kg doses of valanafusp alpha had no effect on plasma glucose for up to 24 h after the drug infusion. CONCLUSION: The plasma clearance of valanafusp alpha is increased four-fold in children with MPSI compared with adult subjects at a dose of 1-3 mg/kg. The plasma pharmacokinetic profile of valanafusp alpha, at a dose of 1-3 mg/kg, is comparable to that of laronidase in children with MPSI.
Authors: Wandong Zhang; Qing Yan Liu; Arsalan S Haqqani; Sonia Leclerc; Ziying Liu; François Fauteux; Ewa Baumann; Christie E Delaney; Dao Ly; Alexandra T Star; Eric Brunette; Caroline Sodja; Melissa Hewitt; Jagdeep K Sandhu; Danica B Stanimirovic Journal: Fluids Barriers CNS Date: 2020-07-22