JCR Pharmaceuticals (Japan)

Whereas significant strides have been made in the treatment of lysosomal storage diseases (LSDs), the neuronopathy associated with these diseases remains impervious mainly because of the blood-brain barrier (BBB), which prevents delivery of large molecules to the brain. However, 100 years of research on the BBB since its conceptualization have clarified many of its functional and structural characteristics, spurring recent endeavors to deliver therapeutics across it to treat central nervous system (CNS) disorders, including neuronopathic LSDs. Along with the BBB, the cerebrospinal fluid (CSF) also functions to protect the microenvironment of the CNS, and it is therefore deeply involved in CNS disorders at large. Recent research aimed at developing therapeutics for neuronopathic LSDs has uncovered a number of critical roles played by the CSF that require further clarification. This review summarizes the most up-to-date understanding of the BBB and the CSF acquired during the development of therapeutics for neuronopathic LSDs, and highlights some of the associated challenges that require further research.

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.

Enzyme replacement therapy (ERT) improves the 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 intend to achieve CNS effects, but the burdens on patients are inimical to long-term multiple administrations. However, after pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in mice 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 effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the hitherto obtained preclinical and clinical evidence associated with this drug, and discusses the preclinical, translational and clinical challenges of evaluating, ameliorating and preventing the neurodegeneration in patients with MPS-II.

We investigated whether the basic concepts of ICH guideline Q8 “ Pharmaceutical Development” relating to the effective and efficient control of quality in drug development can be applied as a means for the effective and efficient implementation of audits carried out as a part of the quality assurance program for clinical trials in clinical development. We divided the clinical trial into 12 processes. Pharmaceuticals and Medical Devices Agency (PMDA) Inquiries from GCP On-site Inspections and Document-based Conformity Inspections, obtained from the PMDA on the basis of the information disclosure system, were categorized into the 12 processes. As our analysis targets, we chose the “ Revision of written informed consent form with regard to serious adverse events (SAEs)” process, which relates to patient safety, and the “ Examination/Observation/Assessment” process, which generates the highest number of inquiries. These two processes were further divided into several sub-processes. The inquiries were analyzed to tabulate the number of harms in each sub-process and to identify the nature of those events. We then identified the process parameters (PPs) of each process as well as deviations from said PPs (hazards), and tabulated the number of these incidences. We found that the number of harms attributable to said two processes were localized in specific sub-processes. Localization was likewise observed in the nature of the harms, the PPs relating to said harms, and deviations from said PPs. We also identified which sub-processes, the nature of harms,the PPs relating to said harms, and deviations from said PPs require management. Our findings suggest that the basic concepts of the ICH-Q8 guidelines can be applied to the quality assurance programs for clinical trials for the effective and efficient implementation of audits.

.The efficacy and safety of recombinant human GH (rhGH) treatment were assessed inJapanese children with small-for-gestational-age short stature. A total of 88 patientswere enrolled in the comparative and extension studies. At the end of the comparativestudy (24 mo), the mean height SD score for chronological age had significantly increasedin the 0.23 mg/kg/wk and 0.47 mg/kg/wk groups with increments of 0.84 ± 0.42 and 1.50 ±0.44 SD, respectively. In the extension study, the dose could be increased based on thepre-defined growth criteria. Increments in height SD scores over the 24 to 36 mo period atdoses of 0.23 mg/kg/wk, 0.23 to 0.47 mg/kg/wk, and 0.47 mg/kg/wk were 0.25 ± 0.28, 0.46 ±0.21, and 0.28 ± 0.16 SD, respectively. The growth effect increased following doseescalation even in the low responders in the initial 2-yr treatment at 0.23 mg/kg/wk,indicating the effectiveness of dose escalation in accordance with the Japaneseguidelines. rhGH at 0.47 mg/kg/wk provided a greater degree of growth promotion after 24mo. The safety profile appeared to be tolerable and was similar in all groups. Consideringthe increased insulin resistance, the recommendations of the regulatory authorities shouldbe followed to minimize the risks of rhGH treatment.