Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. OBJECTIVE: Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. METHODS: An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. RESULTS: Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. CONCLUSIONS: The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete. FINDINGS: Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. INTERPRETATION: Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. FUNDING: Italfarmaco.

Practical Considerations for Delandistrogene Moxeparvovec Gene Therapy in Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four through five years with a confirmed Duchenne muscular dystrophy (DMD)-causing mutation in the DMD gene. This therapy was developed to address the underlying cause of DMD through targeted skeletal, respiratory, and cardiac muscle expression of delandistrogene moxeparvovec micro-dystrophin, an engineered, functional dystrophin protein. METHODS: Drawing on clinical trial experience from Study 101 (NCT03375164), Study 102 (NCT03769116), and ENDEAVOR (Study 103; NCT04626674), we outline practical considerations for delandistrogene moxeparvovec treatment. RESULTS: Before infusion, the following are recommended: (1) screen for anti-adeno-associated virus rhesus isolate serotype 74 total binding antibody titers <1:400; (2) assess liver function, platelet count, and troponin-I; (3) ensure patients are up to date with vaccinations and avoid vaccine coadministration with infusion; (4) administer additional corticosteroids starting one day preinfusion (for patients already on corticosteroids); and (5) postpone dosing patients with any infection or acute liver disease until event resolution. Postinfusion, the following are recommended: (1) monitor liver function weekly (three months postinfusion) and, if indicated, continue until results are unremarkable; (2) monitor troponin-I levels weekly (first month postinfusion, continuing if indicated); (3) obtain platelet counts weekly (two weeks postinfusion), continuing if indicated; and (4) maintain the corticosteroid regimen for at least 60 days postinfusion, unless earlier tapering is indicated. CONCLUSIONS: Although the clinical safety profile of delandistrogene moxeparvovec has been consistent, monitorable, and manageable, these practical considerations may mitigate potential risks in a real-world clinical practice setting.

Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR).

OBJECTIVE: Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103; NCT04626674) is a single-arm, open-label study to evaluate delandistrogene moxeparvovec micro-dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec. METHODS: In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.33 × 1014 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro-dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber-localized micro-dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score-weighted external natural history control. RESULTS: The 1-year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro-dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score-weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001. INTERPRETATION: Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955-968.

Pamrevlumab, a Fully Human Monoclonal Antibody Targeting Connective Tissue Growth Factor, for Non-Ambulatory Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases. METHODS: MISSION (Study 079; NCT02606136) was an open-label, Phase II, single-arm trial of pamrevlumab in 21 non-ambulatory patients with DMD (aged≥12 years, receiving corticosteroids) who received 35-mg/kg intravenous infusions every 2 weeks for 2 years. The primary endpoint was change from baseline in percent predicted forced vital capacity (ppFVC). Secondary endpoints included other pulmonary function tests, upper limb function and strength assessments, and changes in upper arm fat and fibrosis scores on magnetic resonance imaging. RESULTS: Fifteen patients completed the trial. Annual change from baseline (SE) in ppFVC was -4.2 (0.7) (95% CI -5.5, -2.8). Rate of decline in ppFVC in pamrevlumab-treated patients was slower than observed in historical published trials of non-ambulatory patients. MISSION participants experienced slower-than-anticipated muscle function declines compared with natural history and historical published trials of non-ambulatory patients with DMD. Pamrevlumab was well-tolerated. Treatment-emergent adverse events were mild to moderate, and none led to study discontinuation. CONCLUSIONS: nti-CTGF therapy with pamrevlumab represents a potential treatment for DMD. The lack of internal control group limits the results.

Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). OBJECTIVE: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. METHODS: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. RESULTS: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. CONCLUSIONS: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.

Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG).

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing. OBJECTIVE: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients. METHODS: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls. RESULTS: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01). CONCLUSIONS: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Evaluation of rAAVrh74 gene therapy vector seroprevalence by measurement of total binding antibodies in patients with Duchenne muscular dystrophy.

Background: Adeno-associated virus (AAV) vectors are a promising platform for in vivo transfer of transgenes designed to treat diseases. Pre-existing humoral immunity to these vectors can potentially impact the safety and efficacy of gene therapies. Consequently, individuals with pre-existing antibodies to the specific AAV serotypes used may be excluded from clinical trials and treatments. Recombinant AAV serotype rh74 (rAAVrh74), a vector originally isolated from rhesus monkeys and potentially less immunogenic than other serotypes isolated from humans (e.g. AAV2, AAV5, and AAV9), efficiently transduces muscle and is being investigated for use in gene therapy for Duchenne muscular dystrophy (DMD). Objective: To evaluate prevalence of total binding antibodies (neutralizing and non-neutralizing) against rAAVrh74 in patients with DMD. Methods: Eligible individuals (N = 107) were ⩾ 4 to < 18 years old with genetically confirmed DMD and were excluded from the study if they lived with a person who had known exposure to rAAVrh74 or other gene transfer therapy, or if they received prior treatment with gene transfer therapy. A single blood sample was obtained from each participant, and anti-rAAVrh74 total binding antibodies were measured by enzyme-linked immunosorbent assay. Total binding antibody level < 1:400 was defined as not elevated or seronegative. Primary endpoint was the percentage of subjects with elevated total antibody titers to rAAVrh74. Results: A large preponderance (86.1%) of patients with DMD in this data set was seronegative for anti-rAAVrh74 total binding antibodies. These patients would potentially meet the antibody status eligibility criterion for entry into rAAVrh74-based gene therapy clinical trials. Conclusion: Measuring total binding antibodies is a more comprehensive approach to assess pre-existing immune response versus measuring neutralizing antibodies alone. The low seroprevalence of total binding antibodies against rAAVrh74 shown here supports the broad applicability of rAAVrh74-based gene transfer therapy for patients with DMD and potentially other neuromuscular diseases.

Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial.

SPR1NT ( NCT03505099 ) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening.

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial.

Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group. OBJECTIVE: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy. METHODS: This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. RESULTS: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations. CONCLUSIONS: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.

Laboratory monitoring of nusinersen safety.

INTRODUCTION: This retrospective study reports our tertiary care center's experience with intrathecal nusinersen administration in children and adults with spinal muscular atrophy (SMA). METHODS: We reviewed safety monitoring laboratory results and need for procedural sedation and fluoroscopy-guidance in all SMA patients receiving nusinersen between February 2017 and March 2020. RESULTS: Fifty-eight patients ages 1 mo- 56 y received 494 nusinersen doses. There were 166 laboratory abnormalities in 45 patients. Most were either mild (145 [87.3%]) or were transient proteinuria (18 [10.8%]). None altered nusinersen treatment. Twenty-eight patients required either general anesthesia (75 doses) or anxiolysis with oral midazolam (133 doses, including 6 patients [23 doses] with SMA type I). Eight patients with complicated spines (45 doses) required fluoroscopic guidance. One treatment-related serious adverse event (emesis leading to intubation) occurred during general anesthesia. Two children had asymptomatic increased intracranial pressure. No patients discontinued treatment due to adverse events. DISCUSSION: Intrathecal nusinersen is generally safe and well-tolerated, including in patients requiring oral anxiolysis, general sedation, and fluoroscopic guidance. Frequent serial laboratory monitoring did not identify any persistent significantly abnormal findings or alter treatment.

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.

BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy. METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed). FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus). INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1. FUNDING: Novartis Gene Therapies.

The Spinal Muscular Atrophy Health Index: A novel outcome for measuring how a patient feels and functions.

INTRODUCTION: The Spinal Muscular Atrophy Health Index (SMA-HI) is a multifaceted, disease-specific, patient-reported outcome to measure an SMA patient's perception of their disease burden. In preparation for upcoming therapeutic trials, we examine the validity, reliability, and usability of the SMA-HI in adults, teenagers, and children with SMA. METHODS: Using data from a cross-sectional study of 359 international adult patients with SMA, we identified the most relevant symptoms to include in the SMA-HI. We utilized factor analysis, patient interviews with adults and minors (age 8-15 years), known-group validity testing, and test-retest reliability assessments to evaluate and refine the SMA-HI. RESULTS: The SMA-HI measures overall disease burden and 15 areas of SMA health. Fifteen adult patients and five patients, age 8 to 15 years, participated in semistructured qualitative interviews and found the SMA-HI to be comprehensive, easily completed, and to have clear meaning. The final SMA-HI and its subscales demonstrated good internal consistency (Cronbach α = 0.77-0.96), high test-retest reliability (intraclass correlation coefficient = 0.60-0.96), and an ability to differentiate between SMA groups with different disease severities affecting areas such as employment and ambulation (P < .0001 for both). DISCUSSION: This research provides evidence that the SMA-HI is a valid, relevant, and reliable outcome measure to assess multifaceted patient-reported disease burden in older children, teenagers, and adults with SMA. The SMA-HI provides an opportunity for researchers and clinicians to measure a SMA patient's perception of their health and determine relevant changes in response to therapeutic intervention or disease progression.

Medical management of muscle weakness in Duchenne muscular dystrophy.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens. METHODS: A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach. RESULTS: Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid. DISCUSSION: The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects.

Pulse oral corticosteroids in pediatric chronic inflammatory demyelinating polyneuropathy.

Childhood onset chronic inflammatory demyelinating polyneuropathy (CIDP) often requires long-term immunomodulatory therapy. We report a comprehensive review of our treatment of pediatric CIDP with a focus on high-dose weekly corticosteroids ("pulse oral corticosteroids"), a treatment method that is not commonly reported. We retrospectively reviewed medical records of pediatric patients with CIDP treated at our center between 2000 and 2018 for whom we had at least 12 mo follow-up. Here, we describe the demographics, disease course, treatment regimens, and long-term outcomes of these patients. Twenty-five patients were identified for analysis. Pulse oral corticosteroid monotherapy was the predominant maintenance treatment in 56% of patients. Patients were followed for a median of 4 y. Side effects were seen in a minority of patients. The probability of a normal exam or being off treatment at last follow-up was similar regardless of predominant maintenance therapy. Pulse oral corticosteroid therapy is a safe and effective long-term treatment option in children with CIDP.

Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A Phase 2 Randomized Clinical Trial.

Importance: An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease. Objective: To evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping. Design, Setting, and Participants: This phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019. Interventions: Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion. Main Outcomes and Measures: Primary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants' biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function. Results: Of the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit. Conclusions and Relevance: Systemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed. Trial Registration: ClinicalTrials.gov Identifier: NCT02740972.

Intramuscular blood flow in Duchenne and Becker Muscular Dystrophy: Quantitative power Doppler sonography relates to disease severity.

OBJECTIVE: Absent or truncated dystrophin in Duchenne (DMD) and Becker (BMD) muscular dystrophies results in impaired vasodilatory pathways and exercise induced muscle ischemia. Here, we used power Doppler sonography to quantify changes in intramuscular blood flow immediately following exercise in boys with D/BMD. METHOD: We quantified changes in intramuscular blood flow following exercise using power Doppler sonography in 14 boys with D/BMD and compared changes in muscle blood flow to disease severity and to historic controls. RESULT: Post exercise blood flow change in the anterior forearm muscles is lower in (1) DMD (median 0.25%; range -0.47 to 2.19%) than BMD (2.46%; 2.02-3.38%, p < 0.05) and historical controls (6.59%; 2.16-12.40%, p < 0.01); (2) in non-ambulatory (0.04%; -0.47 to 0.10%) than ambulatory DMD boys (0.71%; 0.07-2.19%, p < 0.05); and (3) in muscle with higher echointensity (rs = -0.7253, p = 0.005). The tibialis anterior showed similar findings. We estimate that a single sample clinical trial would require 19 subjects to detect a doubling of blood flow to the anterior forearm after the intervention. CONCLUSION: Post-exercise blood flow is reduced in D/BMD and relates to disease severity. SIGNIFICANCE: Our protocol for quantifying post-exercise intramuscular blood flow is feasible for clinical trials in D/BMD.