Global Regulatory and Public Health Initiatives to Advance Pediatric Drug Development for Rare Diseases.

The literature thoroughly describes the challenges of pediatric drug development for rare diseases. This includes (1) generating interest from sponsors, (2) small numbers of children affected by a particular disease, (3) difficulties with study design, (4) lack of definitive outcome measures and assessment tools, (5) the need for additional safeguards for children as a vulnerable population, and (6) logistical hurdles to completing trials, especially with the need for longer term follow-up to establish safety and efficacy. There has also been an increasing awareness of the need to engage patients and their families in drug development processes and to address inequities in access to pediatric clinical trials. The year 2020 ushered in yet another challenge-the COVID-19 pandemic. The pediatric drug development ecosystem continues to evolve to meet these challenges. This article will focus on several key factors including recent regulatory approaches and public health policies to facilitate pediatric rare disease drug development, emerging trends in product development (biologics, molecularly targeted therapies), innovations in trial design/endpoints and data collection, and current efforts to increase patient engagement and promote equity. Finally, lessons learned from COVID-19 about building adaptable pediatric rare disease drug development processes will be discussed.

Clinical practice with steroid therapy for Duchenne muscular dystrophy: An expert survey in Asia and Oceania.

BACKGROUND: Several studies on clinical practice for Duchenne muscular dystrophy (DMD) have been conducted in Western countries. However, there have been only a few similar studies in Asia and Oceania. Here, we investigate the steroid therapy-related clinical practice for DMD among the local experts. In 2015, we conducted a DMD expert survey in Asia and Oceania to acquire information regarding patients with DMD and to assess current clinical practice with the cooperation of Asian and Oceanian Myology Centre, a neuromuscular disease research network. RESULTS: We obtained survey responses from 87 out of 148 clinicians (62%) from 13 countries and regions. In China, 1385 DMD patients were followed-up by 5 respondent neurologists, and 84% were between 0 and 9 years of age (15% were 10-19 years, 1% > 19 years). While in Japan, 1032 patients were followed-up by 20 clinicians, and the age distribution was similar between the 3 groups (27% were 0-9 years, 35% were 10-19 years, 38% were >19 years). Most respondent clinicians (91%) were aware of DMD standard of care recommendations. Daily prednisolone/prednisone administration was used most frequently at initiation (N = 45, 64%). Inconsistent opinion on steroid therapy after loss of ambulation and medication for bone protection was observed. CONCLUSIONS: Rare disease research infrastructures have been underdeveloped in many of Asian and Oceanian countries. In this situation, our results show the snapshots of current medical situation and clinical practice in DMD. For further epidemiological studies, expansion of DMD registries is necessary.

Characteristics of Japanese Patients with Becker Muscular Dystrophy and Intermediate Muscular Dystrophy in a Japanese National Registry of Muscular Dystrophy (Remudy): Heterogeneity and Clinical Variation.

BACKGROUND: Obtaining an adequate number of patients to conduct a natural history study for rare diseases such as Becker muscular dystrophy (BMD) is difficult. OBJECTIVES: The present study used data from Remudy, a national registry for neuromuscular diseases in Japan, to conduct a phenotypic analysis of BMD. METHODS: We analyzed Remudy data of participants with dystrophinopathy. All participants who were aged 17 and older and were ambulant at age 13 were included in this study. Participants were divided into two groups: those with BMD who were ambulant at age 17, and those with intermediate muscular dystrophy (IMD) who lost ambulation by age 17. Frequent mutations were analyzed by age at ambulation, cardiopulmonary function, and genotype. For clinical comparisons, participants who were administered steroids were excluded. RESULTS: From July 2009 through September 2015, 192 participants had registered with Remudy. Mean participant age was 34.80±13.3 (range, 17-78) years, and 52.1% of participants were ambulant. Of the entire study population, 50.5% had cardiomyopathy and 35.9% had respiratory failure. Three participants required invasive ventilation and 30 required non-invasive ventilation. Nineteen of the 30 non-invasive ventilator users were part-time users. In total, 138 (71.9%) had BMD and 54 (28.1%) had IMD. The most frequent mutation was ex45_ex47del (36 participants). Among participants with frequent in-frame mutations, those with the ex45-49del mutation lost their ambulation earlier than those with the ex45_ex47del mutation. A total of 67 different exon deletions and duplications were identified in the study population. CONCLUSION: We clarified the clinical phenotypes of Japanese patients with BMD/IMD using data from Remudy. Our results suggest that not only IMD but also BMD are associated with risk of respiratory dysfunction.

Social involvement issues in patients with Becker muscular dystrophy: A questionnaire survey of subjects from a patient registry.

BACKGROUND: Little is known about the relationship between Becker Muscular Dystrophy (BMD) and developmental problems, school life, employment, and mental problems. We aimed to clarify whether BMD is a risk factor for developmental disorders, problematic behavior, psychiatric diseases, and other social difficulties in school life and employment. METHODS: Adults with genetically or immunohistochemically confirmed BMD from the Registry of Muscular Dystrophy in Japan (REMUDY) were asked to complete a questionnaire regarding patient history, school life, employment, and mental problems. RESULTS: In total, 125 (68.3%) of 183 participants with BMD (median age, 37.2 years) completed the questionnaire. Of these, ten had developmental disorders (mental retardation, autism, and speech disturbance). Fifty-eight (44%) experienced bullying in school, and 39 felt the reason for bullying was physical handicap. Sixteen participants experienced problematic behavior such as cutting class, domestic violence, violent incidents, suicide attempts, or self-mutilation. Employment histories were noted by 92 (73%), of whom 15 could not continue to work due to physical handicaps. Fifteen participants had psychiatric disorders, with 5, 3 and 1 having neurosis, depression, and bipolar disorder, respectively. The other 6 participants with psychiatric disorders did not specify their diagnoses. Patients carrying a Dp140 expression change had significantly more incidences of developmental disorders, but not bullying, problematic behavior, workplace difficulties, or psychiatric disorders. CONCLUSIONS: Patients with BMD risk bullying and workplace difficulties, as well as developing psychiatric disorders. Parents, teachers, and supporters should be mindful of the daily environment of BMD patients and provide support to help them cope with stress.

A comparative study of care practices for young boys with Duchenne muscular dystrophy between Japan and European countries: Implications of early diagnosis.

Early diagnosis of Duchenne muscular dystrophy (DMD) is widely advocated to initiate proactive interventions and genetic counselling. Genetic testing now allows the diagnosis of DMD even prior to the onset of symptoms. However, little is known about care practices and their impact on young DMD boys and families after receiving an early diagnosis. We analysed 64 young boys (Japan, 19; the United Kingdom, 10; Germany, 18; Hungary, 6; Poland, 5; and the Czech Republic, 6) aged <5 years and diagnosed at ≤2 years old among the participants of the cross-sectional study about care practice in DMD. A combination of elevated serum creatine kinase and genetic testing usually led to the diagnosis (n = 31, 48%); 41 boys visited neuromuscular clinics more than once a year. Early diagnosis did not generally result in higher satisfaction among DMD families, and country-specific differences were observed. Psychosocial support following early diagnosis was perceived as insufficient in most countries, and deficits in access and uptake of genetic counselling resulted in lower satisfaction in the Japanese cohort. In conclusion, seamless and comprehensive support for DMD families following early diagnosis at presymptomatic stages should be taken into consideration if early genetic testing or newborn screening is made available more widely.

Trends in steroid therapy for Duchenne muscular dystrophy in Japan.

INTRODUCTION: We conducted a study to reveal trends in steroid prescription for Duchenne muscular dystrophy (DMD) patients in Japan. METHODS: We asked patients (ages 5-20 years) identified in the patient registry and their clinicians about steroid therapy experiences. Regimen, dose, and starting age were compared among 3 subgroups according to prednisolone initiation year (2000-2004, 2005-2009, and 2010-2013). RESULTS: Among 157 prednisolone users, 4 different regimens were used. Dose frequencies were: every other day (98 patients), daily (44 patients), 10 days on 20 days off (14 patients), and weekly (1 patient). Median starting age was 6 years, and median dose was 0.42 mg/kg/day. There was an increase in daily regimen use from 2005-2009 (n = 9, 16%) to 2010-2013 (n = 33, 36%). CONCLUSIONS: This study revealed a transition over time in steroid use from expert opinion to evidence-based recommendation. Clinical research should be encouraged to optimize medication worldwide. Muscle Nerve 54: 673-680, 2016.

[Update of steroid therapy for Duchenne muscular dystrophy].

Several novel therapies for Duchenne muscular dystrophy (DMD) have recently been developed. However, steroids are currently the only medication that has been objectively confirmed to have an effect on muscle weakness in DMD patients. Prednisolone has recently been approved for pharmaceutical use in DMD patients in Japan. Moreover, the domestic guidelines for DMD have been published, which may lead to an increase in the use of steroid therapy. The short-term effects of steroid therapy for improving motor function have already been confirmed. Subsequently, the long-term effects of steroid therapy, such as prolonging the time until loss of walking ability, delay of scoliosis, and preservation of cardio-pulmonary function, have also been recognized. However, the long-term side-effects, such as obesity and bone demineralization, remain a concern. Several clinical studies are currently ongoing, worldwide, to develop an optimal regimen of steroid therapy.

[Infrastructure for the clinical research of muscular dystrophies: remudy and MDCTN].

Remudy, operated by the NCNP, runs two national registries for Dystrophinopathy and GNE myopathy in Japan under the collaboration with the TREAT-NMD alliance. The aim is to construct the clinical research infrastructure and accelerate the clinical development research for these rare diseases. We successfully provide the data sets for the feasibility studies, send out the appropriate information of the clinical trials for the candidates to speed up the recruitment for trials, collaboration with the Muscular Dystrophy Clinical Trial Network: MDCTN, as well as present the natural history and epidemiological data of the rare diseases with a new 'registry based' research style. Remudy provides a prototype of the clinical research infrastructure to over come the rare and incurable diseases.

Prednisolone improves walking in Japanese Duchenne muscular dystrophy patients.

We evaluated the long-term efficacy of prednisolone (PSL) therapy for prolonging ambulation in Japanese patients with genetically confirmed Duchenne muscular dystrophy (DMD). There were clinical trials have shown a short-term positive effect of high-dose and daily PSL on ambulation, whereas a few study showed a long-term effect. Especially in Japan, "real-life" observation was lacking. We utilized the national registry of muscular dystrophy in Japan for our retrospective study. We compared the age at loss of ambulation (LOA) between patients in PSL group and those in without-PSL group. Out of 791 patients' in the Remudy DMD/BMD registry from July 2009 to June 2012, 560 were matched with inclusion criteria. Of the 560, all were genetically confirmed DMD patients, 245 (43.8 %) of whom were treated with PSL and 315 (56.2 %) without PSL. There was no difference between the two groups regarding their mutational profile. The age at LOA was significantly greater (11 month on average) in the PSL group than in the without-PSL group (median, 132 vs. 121 months; p = 0.0002). Although strictly controlled clinical trials have shown that corticosteroid therapies achieved a marked improvement in ambulation, discontinuation of the drug due to intolerable side effects led to exclusion of clinical trial participants, which is considered as unavoidable. In our study, patients were not excluded from the PSL group, even if they discontinued the medication shortly after starting it. The results of our study may provide evidence to formulate recommendations and provide a basis for realistic expectations for PSL treatment of DMD patients in Japan, even there are certain limitations due to the retrospectively captured data in the registry.

Extramuscular manifestations in children with severe congenital myopathy due to ACTA1 gene mutations.

We examined three patients with a severe infantile type of congenital myopathy due to dominant, missense ACTA1 mutations. In addition to muscle weakness, all three patients showed developmental delay in word comprehension during early childhood. All also showed frontal lobe hypoplasia and lateral ventricular dilatation. One patient in addition exhibited features of multiple congenital malformations including skeletal dysplasia, hepatomegaly and urinary tract stenosis. These findings may suggest a link between extramuscular expression of α-skeletal muscle actin and clinical symptoms in non-skeletal muscle tissues of patients with ACTA1 mutations, and probably a functional role of α-skeletal muscle actin during fetal development.