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

In Hunter syndrome (mucopolysaccharidosis II [MPS-II]),systemic accumulation of glycosaminoglycans (GAGs) dueto a deficiency of iduronate-2-sulfatase (IDS), caused by mu-tations in theIDSgene, leads to multiple somatic manifesta-tions and in patients with the severe (neuronopathic)phenotype, also to central nervous system (CNS) involve-ment. These symptoms cannot be effectively treated withcurrent enzyme-replacement therapies, as they are unableto cross the blood-brain barrier (BBB). Pabinafusp alfa, anovel IDS fused with an anti-human transferrin receptorantibody, was shown to penetrate the BBB and to addressneurodegeneration in preclinical studies. Subsequent phase1/2 and 2/3 clinical studies in Japan have shown markedreduction of GAG accumulation in the cerebrospinalfluid(CSF), along with favorable clinical responses. A 26-week,open-label, randomized, parallel-group phase 2 study wasconducted in Brazil to further evaluate the safety and efficacyof intravenously administered pabinafusp alfa at 1.0, 2.0,and 4.0 mg/kg/week in MPS-II patients. The safety profilesin the three dosage groups were similar. Neurodevelopmentalevaluation suggested positive neurocognitive signals despite arelatively short study period. The 2.0-mg/kg group, whichdemonstrated marked reductions in substrate concentrationsin the CSF, serum, and urine, was considered to provide thebest combination regarding safety and efficacy signals