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.

Hunter syndrome (mucopolysaccharidosis II [MPS II]), a deficiency of iduronate-2-sulfatase (IDS), causes an accumulation of glycosaminoglycans, giving rise to multiple systemic and CNS symptoms. The currently available therapies, idursulfase and idursulfase beta, are ineffective against the CNS symptoms because they cannot pass the blood-brain barrier (BBB). A novel IDS fused with anti-human transferrin receptor antibody (JR-141) has been shown to penetrate the BBB and ameliorate learning deficits in model mice. This first-in-human study evaluated the pharmacokinetics, safety, and potential efficacy of JR-141 in 14 patients with MPS II. In a dose-escalation study performed in two patients, JR-141 plasma concentrations were dose dependent and peaked at 3 hr after initiation of each infusion, and no or only mild adverse reactions were exhibited. In a subsequent 4-week evaluation at two dose levels, the plasma concentration profiles were similar between the first and final administration, indicating no drug accumulation. Levels of heparan sulfate (HS) and dermatan sulfate (DS) were suppressed in both plasma and urine and HS levels were significantly decreased in cerebrospinal fluid. Two patients experienced some amelioration of neurocognitive and motor symptoms. These results suggest that the drug successfully penetrates the BBB and could have CNS efficacy.

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.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, finding ways to increase drug delivery into the brain across the BBB remains a crucial challenge for researchers and clinicians in the field. Attempts have been made to boost brain uptake of enzymes by targeting various receptors (e.g., insulin and transferrin), and several other administration routes have also been tested. This review summarizes the available information on clinical trials (completed, ongoing, and planned) of novel therapeutic agents with efficacy against CNS symptoms in neuropathic MPS and also discusses the common associated challenges and pitfalls, some of which may help elucidate the pathogenesis of the neurodegeneration leading to the manifold CNS symptoms. A summary of current knowledge pertaining to the neuropathological progression and resultant neuropsychiatric manifestations is also provided, because it should be useful to ERT researchers looking for better approaches to treating CNS lesions in MPS.

Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood–brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious to the therapeutic benefits of ERT, although ERT via intrathecal and intracerebroventricular routes can be used for some neuronopathic LSDs (in particular, mucopolysaccharidoses). However, the considerable practical issues involved make these routes unsuitable for long-term treatment. Efforts have been made to modify enzymes (e.g., by fusing them with antibodies against innate receptors on the cerebrovascular endothelium) so that they can cross the BBB via receptor-mediated transcytosis (RMT) and address neuronopathy in the CNS. This review summarizes the various scientific and technological challenges of applying RMT to the development of safe and effective enzyme therapeutics for neuronopathic mucopolysaccharidoses; it then discusses the translational and methodological issues surrounding preclinical and clinical evaluation to establish RMT-applied ERT.