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Clinical Trial
. 2021 Jul 7;29(7):2378-2386.
doi: 10.1016/j.ymthe.2021.03.019. Epub 2021 Mar 27.

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil

Roberto Giugliani  1 , Ana Maria Martins  2 , Sairei So  3 , Tatsuyoshi Yamamoto  3 , Mariko Yamaoka  3 , Toshiaki Ikeda  3 , Kazunori Tanizawa  3 , Hiroyuki Sonoda  3 , Mathias Schmidt  3 , Yuji Sato  4
Affiliations
Clinical Trial

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil

Roberto Giugliani et al. Mol Ther. .

Abstract

In Hunter syndrome (mucopolysaccharidosis II [MPS-II]), systemic accumulation of glycosaminoglycans (GAGs) due to a deficiency of iduronate-2-sulfatase (IDS), caused by mutations in the IDS gene, leads to multiple somatic manifestations and in patients with the severe (neuronopathic) phenotype, also to central nervous system (CNS) involvement. These symptoms cannot be effectively treated with current enzyme-replacement therapies, as they are unable to cross the blood-brain barrier (BBB). Pabinafusp alfa, a novel IDS fused with an anti-human transferrin receptor antibody, was shown to penetrate the BBB and to address neurodegeneration in preclinical studies. Subsequent phase 1/2 and 2/3 clinical studies in Japan have shown marked reduction of GAG accumulation in the cerebrospinal fluid (CSF), along with favorable clinical responses. A 26-week, open-label, randomized, parallel-group phase 2 study was conducted in Brazil to further evaluate the safety and efficacy of intravenously administered pabinafusp alfa at 1.0, 2.0, and 4.0 mg/kg/week in MPS-II patients. The safety profiles in the three dosage groups were similar. Neurodevelopmental evaluation suggested positive neurocognitive signals despite a relatively short study period. The 2.0-mg/kg group, which demonstrated marked reductions in substrate concentrations in the CSF, serum, and urine, was considered to provide the best combination regarding safety and efficacy signals.

Keywords: Hunter syndrome; JR-141; anti-human transferrin receptor antibody; blood-brain barrier; enzyme-replacement therapy; heparan sulfate; iduronate-2-sulfatase; mucopolysaccharidosis II; neurocognitive impairment; pabinafusp alfa.

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Conflict of interest statement

Declaration of interests R.G. has been an investigator, consultant, and/or speaker within the last 12 months for Abeona, Allevex, Amicus, BioMarin, Chiesi, Denali, Idorsia, Inventiva, JCR, Lysogene, Novartis, PassageBio, PTC, RegenxBio, Sanofi-Genzyme, Sigilon, Sobi, Takeda, and Ultragenyx. A.M.M. has received honors and support for travels and congresses from BioMarin, Sanofi Genzyme, Takeda, and Ultragenyx. A.M.M. has received research fundings from Alexion, BioMarin, Sanofi Genzyme, and Takeda.

Figures

None
Graphical abstract
Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Time courses of mean plasma concentrations of pabinafusp alfa at weekly dosages of 1.0, 2.0, and 4.0 mg/kg at weeks 1 and 26 (A) Week 1. (B) Week 26). The data represent mean ± SD.
Figure 3
Figure 3
HS and DS concentrations in the CSF The data represent mean ± SD.
Figure 4
Figure 4
Age-equivalent scores and developmental quotients against chronological age as determined with BSID-III (A) Age-equivalent scores. (B) Developmental quotients. All patients belong to a severe (neuronopathic) subtype. The curves with asterisks denote the patients naive to ERT.
Figure 5
Figure 5
Age-equivalent scores and developmental quotients against chronological age as determined with KABC (A) Age-equivalent scores. (B) Developmental quotients. All patients belong to the attenuated subtype. The curves with asterisks denote the patients naive to ERT.
Figure 6
Figure 6
Changes seen over 52 weeks in three subdomains in VABS-II in the MPS-II patients The patients include both attenuated and severe subtypes.
See this image and copyright information in PMC

References

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