WHAT IS KNOWN ABOUT THE PHARMACOLOGY OF INTRAMUSCULAR THERAPEUTICS IN DUCHENNE MUSCULAR DYSTROPHY? A SYSTEMATIC REVIEW

2Clinical Research Facility, Alder Hey Children’s HospitalIntroductionIn 2018 the Centers for Disease Control published updated Standards of Care for Duchenne Muscular Dystrophy – newly included was the recommendation for all patients with DMD who received steroids to receive prescriptions for intramuscular (IM) hydrocortisone for emergency administration at home.The aim of this systematic review was to assess the current understanding of the pharmacodynamics and kinetics of intramuscular therapies in patients affected by DMD.MethodsA systematic review was conducted according to Cochrane methodology. Medline, EMBASE and PubMed databases were searched. Two independent reviewers reviewed the abstract of each identified paper. Where there was any discrepancy in the decision to include or exclude a paper, a third reviewer arbitrated.ResultsThe search returned a total of 98 papers. 96 papers were excluded: 61 described animal or in-vitro studies, whilst the remaining studies did not study an intramuscular pharmacological intervention or were review articles.Of the two included articles, one compared the immunogenicity of intramuscular and subcutaneous administration of influenza vaccination, and the other studied ten patients with DMD who were injected with two different doses of plasmidic DNA. Neither study reported on the pharmacodynamics or kinetics of the interventions.ConclusionsThere is very limited evidence into the pharmaco-kinetics and -dynamics of IM therapies for children affected by muscular dystrophy. Given the recognised changes in the muscle structure and function, studies to explore if this causes clinically significant changes in boys with DMD are required.</jats:sec

WHAT IS KNOWN ABOUT THE PHARMACOLOGY OF INTRAMUSCULAR THERAPEUTICS IN DUCHENNE MUSCULAR DYSTROPHY? A SYSTEMATIC REVIEW

IntroductionOff-label use is still inevitable for paediatric drug treatment. The aim of this study was to analyse the licensing status of drug prescriptions in German paediatric (specialised) outpatient clinics and to determine changes over a 10-year time course.MethodsCross-sectional, retrospective, monocentric studies were conducted in 2009 and 2019 to assess drug prescriptions regarding their licensing status in 10 (one general and nine specialised) outpatient clinics in Germany. Prevalence and relative frequency of off-label prescriptions were calculated, reasons for off-label prescribing analysed and logistic regression performed to determine influencing factors.Results751 prescriptions of 296 patients in 2009 and 1438 prescriptions of 786 patients in 2019 were examined and classified according to their licensing status. Relative frequency of off-label prescriptions was around 45% without significant change over that decade. Prevalence of off-label prescriptions was 60.1% in 2009 and 53.1% in 2019 and therefore significantly higher in 2009 (p=0.037). The number of prescriptions per patient was significantly higher in 2009 (2.5 ± 2.3 vs. 1.8 ± 1.5, p&lt;0.000), too. Comparison revealed the same high-ranking reasons in every study: off-label use due to indication, overdosing and missing paediatric information.ConclusionsOff-label prescribing still plays an important role in clinical daily routine in paediatrics. Despite numerous regulatory efforts and incentives, no substantial reduction in off-label prescribing could be determined since 2009. Further efforts are needed to generate more evidence-based knowledge about paediatric pharmacotherapy and to treat children as best as possible.</jats:sec

Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading

Introduction Phenytoin has complex pharmacokinetics. The intravenous loading dose of phenytoin for children in status epilepticus has recently been increased from 18 to 20mg/kg. There are no data on the clinical effectiveness and safety of this new dose. Methods The use of intravenous loading doses of phenytoin was audited over 27 months to evaluate the pharmacokinetic, clinical and toxic effects of the new dose in clinical practice. Serum phenytoin concentrations were compared with both dose (weight-adjusted) and time. Results Serum phenytoin concentrations were measured on 48 occasions from 41 children (39 retrospective and 9 prospective), of which 24 were within 60-180 (median 105) minutes following completion of infusion of the loading dose. Use of estimated weights meant patients received between 15.5 and 27.5mg/kg (78-138% expected dose). Supra-therapeutic serum concentrations (>20µg/ml were present in 5/24 (20.1%) (after doses based on actual weight in three, and estimated weight in two patients). Three adverse effects consistent with phenytoin toxicity were noted in children with supra-therapeutic concentrations. Two errors in dose prescriptions were found. Conclusion The majority of serum phenytoin concentrations were in the therapeutic range. Estimating weight in children for the 20mg/kg intravenous loading dose of phenytoin is often clinically necessary but inaccurate, resulting in up to 138% of the expected and recommended dose in this cohort

Risdiplam in Spinal Muscular Atrophy: Safety Profile and Use Through The Early Access to Medicine Scheme for the Paediatric Cohort in Great Britain

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2-splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021. OBJECTIVE: To describe the largest paediatric European real-world set of data on patients' characteristics and short-term safety for risdiplam in Great Britain through EAMS. METHODS: We collated data from SMA REACH UK a national clinical and research network for all patients enrolled onto EAMS and assessed all submitted adverse events. RESULTS: Of the 92 patients; 78% were Type 2 SMA, mean age 10.9 years, range 0-17 years. 56 were treatment naïve, 33 previously treated; of these 25 had received nusinersen, 3 previous treatment unknown. Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life-threatening events were reported with 2 deaths and permanent cessation of risdiplam in 3 patients.Overall, 38/60 AEs were considered unrelated to risdiplam, 10/60 related to risdiplam and for 12/60 causality not specified. CONCLUSIONS: This study found a safety profile similar to clinical trials with no new safety concerns identified. With the restricted eligibility of onasemnogene abeparvovec and complications of nusinersen administration, EAMS allowed access or continued treatment to naïve patients or patients no longer suitable for approved medications. Collection of longitudinal data for this complex population is needed, to provide greater insights into risdiplam's role in addressing patients' needs into the future

Pain experience, expression and coping in boys and young men with Duchenne muscular dystrophy – a pilot study using mixed methods

Introduction: There is limited research exploring the pain experience of boys and young men with Duchenne Muscular Dystrophy. Methods: We conducted a mixed-methods pilot study to assess the feasibility of using particular measures of pain, pain coping and quality of life within semi-structured interviews with boys and young men with Duchenne Muscular Dystrophy and a postal survey of their parents. Non-probability, convenience sampling was used. Results: Twelve young men aged 11 to 21 years (median 15 years), three of whom were still ambulant, and their parents / guardians were recruited. The measures used were acceptable to the young men and demonstrated potential to provide useful data. Two-thirds of young men suffered from significant daily pain which was associated with reduced quality of life. Pain complaints were largely kept within the family. Young men's pain-coping strategies were limited by their restricted physical abilities. Statistical power based on these preliminary results suggests a study of approximately 50 boys/young men which appears feasible. Conclusions: Further study is needed to explore acceptable and effective methods of pain management in this population and ways of enhancing pain-coping strategies. In clinical practice, assessment of pains and discomfort should form part of all routine consultations

Pathogenic Variants in MT-ATP6: A United Kingdom-Based Mitochondrial Disease Cohort Study

Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-31

Development of a consensus core dataset in juvenile dermatomyositis for clinical use to inform research

Objectives This study aimed to develop consensus on an internationally agreed dataset for juvenile dermatomyositis (JDM), designed for clinical use, to enhance collaborative research and allow integration of data between centres. Methods A prototype dataset was developed through a formal process that included analysing items within existing databases of patients with idiopathic inflammatory myopathies. This template was used to aid a structured multistage consensus process. Exploiting Delphi methodology, two web-based questionnaires were distributed to healthcare professionals caring for patients with JDM identified through email distribution lists of international paediatric rheumatology and myositis research groups. A separate questionnaire was sent to parents of children with JDM and patients with JDM, identified through established research networks and patient support groups. The results of these parallel processes informed a face-to-face nominal group consensus meeting of international myositis experts, tasked with defining the content of the dataset. This developed dataset was tested in routine clinical practice before review and finalisation. Results A dataset containing 123 items was formulated with an accompanying glossary. Demographic and diagnostic data are contained within form A collected at baseline visit only, disease activity measures are included within form B collected at every visit and disease damage items within form C collected at baseline and annual visits thereafter. Conclusions Through a robust international process, a consensus dataset for JDM has been formulated that can capture disease activity and damage over time. This dataset can be incorporated into national and international collaborative efforts, including existing clinical research databases

A Phase 1b Trial to Assess the Pharmacokinetics of Ezutromid in Pediatric Duchenne Muscular Dystrophy Patients on a Balanced Diet.

Ezutromid (SMT C1100) is a small-molecule utrophin modulator that was developed to treat Duchenne muscular dystrophy (DMD). Previous clinical trials of this agent revealed lower exposure in DMD patients compared with healthy volunteers, which may reflect differences in diet. This study evaluated the pharmacokinetics of ezutromid in patients with DMD who followed a balanced diet. This was a multicenter, double-blind, placebo-controlled, ascending single and multiple oral dose study. Twelve pediatric patients were randomly allocated to 1 of 3 treatment sequences within which were 3 treatment periods of 2 weeks each. Each patient received, in a dose-escalating fashion, 1250 mg and 2500 mg twice daily (BID) of ezutromid administered orally as a microfluidized suspension (F3) with placebo in the other treatment period. Throughout the study, patients followed a balanced diet including recommended proportions of major food groups and administration of drug accompanied with 100 mL of full-fat milk. This approach improved the absorption of ezutromid, resulting in higher systemic exposure, with considerable variability in exposure between patients at each dose level. Single and multiple oral doses of 1250 mg and 2500 mg BID were considered safe and well tolerated. No severe or serious adverse events and no study discontinuations due to adverse events were reported. This study provides assurance that, with the formulation tested (F3) and instructions regarding food (balanced diet and whole-fat milk), 2500 mg BID of ezutromid achieves plasma concentrations that, based on preclinical studies, should be able to modulate utrophin expression in future clinical trials

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy.

PURPOSE SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. METHODS This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A-C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. RESULTS Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. CONCLUSIONS SMT C1100 was well tolerated in pediatric DMD patients. TRIAL REGISTRATION ClinicalTrials.gov NCT02383511

Preventing Cardiomyopathy in DMD: A Randomized Placebo-Controlled Drug Trial.

Objective To determine whether a combination of 2 heart medications would be tolerated and could prevent/delay the onset of cardiomyopathy in boys with Duchenne muscular dystrophy (DMD) compared with placebo. Methods This multicenter, parallel group, 1:1 patient randomized, placebo-controlled study of prophylactic perindopril and bisoprolol recruited boys with DMD aged 5-13 years, with normal ventricular function. Repeat assessments of left ventricular (LV) function, electrocardiogram, and adverse event reporting were performed 6 monthly. The primary outcome was change in ejection fraction between arms after 36 months. The study was approved by the National Research Ethics Service Committee East Midlands-Derby. Results Eighty-five boys were recruited (76% on steroid therapy) and randomized to combination heart drugs or matched placebo. Group change in left ventricular ejection fraction (LVEF%) at 36 months from baseline was -2.2% ± 6.0% and -2.9% ± 6.1% in active and placebo arms (adjusted mean difference: -2.1, 95% CI -5.2 to 1.1). There was no difference between treatment arms over repeated assessments (analysis of variance) up to 36 months (trial arms = 0.53); arm-over-time ( = 0.44). Four participants on placebo but none on active therapy were withdrawn due to deteriorations in LV function. Secondary outcomes did not differ between arms either. Thirty-six serious adverse events occurred none due to cardiac events or trial medication. Conclusions Combination therapy was well tolerated. Consistent with the previous prophylactic perindopril heart study, there was no evidence of group benefit after 36-month treatment. Classification of Evidence This study provides Class I evidence that combination perindopril-bisoprolol therapy was well tolerated but did not change decline in LVEF significantly in boys with DMD