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Clinical Trial
. 2021 Feb 3;29(2):671-679.
doi: 10.1016/j.ymthe.2020.09.039. Epub 2020 Sep 30.

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II

Torayuki Okuyama  1 , Yoshikatsu Eto  2 , Norio Sakai  3 , Kimitoshi Nakamura  4 , Tatsuyoshi Yamamoto  5 , Mariko Yamaoka  5 , Toshiaki Ikeda  5 , Sairei So  5 , Kazunori Tanizawa  5 , Hiroyuki Sonoda  5 , Yuji Sato  6
Affiliations
Clinical Trial

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II

Torayuki Okuyama et al. Mol Ther. .

Abstract

Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.

Keywords: Hunter syndrome; anti-human transferrin receptor antibody; blood brain barrier; central nervous system; enzyme-replacement therapy; heparan sulfate; iduronate-2-sulfatase; mucopolysaccharidosis II; neurocognitive development; neurocognitive impairment; neurodegeneration; pabinafusp alfa.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Time Courses of the HS and DS Concentrations in the CSF The data are represented as means ± SD.
Figure 2
Figure 2
Time Courses of the HS Concentrations in the CSF According to the Subtypes of MPS-II
Figure 3
Figure 3
Changes of Gradients by Chronological and Developmental Ages According to Phenotypic Subtypes
Figure 4
Figure 4
Serum HS and DS Concentrations in Patients with Prior ERT (Left) and Those Without (Right) at 0, 26, and 52 Weeks of Treatment with Pabinafusp Alfa The data are represented as means ± SD.
See this image and copyright information in PMC

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