Aromatic ʟ-amino acid decarboxylase (AADC) deficiency is a rare pediatric neurotransmitter disorder that typically necessitates lifelong care, and that carries a risk of childhood mortality. Eladocagene exuparvovec gene therapy is designed to restore AADC production. Study GT-002 (NCT04903288) is a phase 2, multicenter, open-label trial assessing the pharmacodynamics, safety, and efficacy of eladocagene exuparvovec administered to the putamen bilaterally in pediatric patients with AADC deficiency using a magnetic resonance (MR)-compatible cannula. Patients received eladocagene exuparvovec at 1.8 × 1011 vector genomes via the SmartFlow MR-compatible cannula in a single operative session. Endpoints include the change from baseline in cerebrospinal fluid homovanillic acid levels, motor milestone achievement, and safety. Here we report results from 48 weeks of follow-up. Mean (SD) cerebrospinal fluid homovanillic acid levels increased from baseline (22.5 [32.3] nmol/L; n = 13) to week 48 (55.3 [45.6] nmol/L; change from baseline: 28.3 [13.7] nmol/L; p = 0.0003; n = 9), indicating de novo dopamine production. At baseline (n = 13), all patients showed severe motor developmental delay; at week 48 (n = 12), nine achieved full head control, four could sit unassisted, two could stand with support, and two could walk independently to a toy. Overall, 260 treatment-emergent adverse events were reported in 13 patients; 259 were deemed unrelated and one likely unrelated to the MR-compatible cannula. No treatment-emergent adverse events led to study withdrawal and no deaths occurred. This study provides further evidence of the favorable pharmacodynamic, efficacy, and safety profile of eladocagene exuparvovec in children with AADC deficiency; intraputaminal administration using an MR-compatible cannula was well tolerated. Study GT-002 (NCT04903288) provides further evidence of the favourable pharmacodynamic, efficacy and safety profile of eladocagene exuparvovec gene therapy in children with AADC deficiency over 48 weeks and demonstrates that intraputaminal administration using an MR-compatible cannula was well tolerated, allowing for real-time MRI confirmation of cannula placement and infusate coverage, and for accurate dosing to the putamen.

Background Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare genetic disorder characterized by movement disorders, motor and autonomic dysfunction, and developmental delays. The gene therapy eladocagene exuparvovec has become available in some regions; pooled clinical trial results demonstrate continuous long-term improvement in motor development and cognitive function. We sought to characterize clinically meaningful change in motor function, as measured by Total Peabody Developmental Motor Scales-Second Edition (PDMS-2) score, and assess correlations with cognition and language domains of the Bayley-III and motor milestone (MM) achievement. Methods Data from N = 30 patients from three single-arm clinical studies of eladocagene exuparvovec were analyzed. Anchor-based estimation of the meaningful score difference (MSD) of Total PDMS-2 score was conducted using mean-difference and receiver operating characteristic curve (ROC) approaches. MM achievement served as the anchor defining meaningful change. Results An MSD of 40 points for Total PDMS-2 score was selected for analysis as it yielded specificity > 0.95 using the ROC approach, and generally aligned with the mean-difference approach. Cumulative incidence analysis reflected that 50% of patients treated with eladocagene exuparvovec may achieve the MSD of 40-point change in Total PDMS-2 score at 6 months, and 86% at 18 months. Correlations between measures were of large magnitude and improved over time (Month 6: r = 0.599 [p = 0.0032]; Month 18: r = 0.796 [p = 0.0002]; Month 60: r = 0.861 [p = 0.0007]). Conclusions The MSD of 40 points for Total PDMS-2 score enables the interpretation of changes observed in patients with AADCd, and suggests that treatment with eladocagene exuparvovec leads to significant improvements in motor and cognitive function.

Background: The main objective of this prospective, multicenter study (REVEAL-CP) was to test children with cerebral palsy-like signs and symptoms for raised 3-O-methyldopa (3-OMD) blood levels, a biomarker for aromatic L-amino acid decarboxylase deficiency (AADCd). A secondary objective was to characterize the molecular basis for the defective aromatic L-amino acid decarboxylase (AADC) gene product. Methods: Patients were identified in pediatric secondary and tertiary care hospitals through database searches and personal communication. 3-OMD concentrations from Guthrie card tests were determined using liquid chromatography/mass spectrometry. If 3-OMD was raised, cerebrospinal fluid analysis and dopa decarboxylase (DDC) gene sequencing were performed. An in-silico mutagenesis analysis was carried out to model altered AADC enzymes. Results: In total, 166 patients were enrolled in this study. The median age was 8 years. Sixty-six patients (39.8%) had a diagnosis of cerebral palsy, with the most common type being "mixed" (n = 42; 25.3%). One patient (0.6%), an 11-month-old boy from Italy, was diagnosed with AADCd caused by a homozygous, pathogenic DDC variant (c.749C>T; p.Ser250Phe). Three-dimensional modeling of the Ser250Phe AADC enzyme variant revealed its destabilization. Conclusions: A Guthrie card test for 3-OMD is a recognized screening technique for AADCd. If universal newborn screening for this metabolic disease is not available, children with signs and symptoms of a movement disorder should be investigated for AADCd.

Aim: To report the efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) from the phase III, 72-week, placebo-controlled period of Study 041. Materials & methods: Inclusion criteria: boys with nmDMD aged ≥5 years, on a stable corticosteroid regimen for ≥12 months, and baseline 6-minute walk distance (6MWD) ≥150 m. Randomization: 1:1, ataluren (40 mg/kg/day):placebo. Primary end point: slope of 6MWD change (average rate of change). Secondary end points: changes in 6MWD, time to 10% persistent worsening in 6MWD, North Star Ambulatory Assessment score, timed function tests and safety. Study populations: intention-to-treat; patients aged ≥7 to ≤16 years with baseline 6MWD ≥300 m and stand from supine ≥5 s; patients with baseline 6MWD 300–400 m. Results: In the intention-to-treat population (n = 359), over 72 weeks, ataluren reduced the rate of 6MWD decline by 21% (p = 0.0248), reduced the average 6MWD change (p = 0.0248), delayed time to 10% persistent worsening in 6MWD (p = 0.0078), and reduced North Star Ambulatory Assessment total score decline (p = 0.0235), change in 10 m walk/run time (p = 0.0422) and change in time to climb four stairs (p = 0.0293) versus placebo. In the 6MWD 300–400 m subgroup (n = 169), ataluren reduced the rate of 6MWD decline by 30% (p = 0.0310) versus placebo. Ataluren treatment benefits were seen in secondary end points in this subgroup, except for change in time to descend four stairs. In the 6MWD ≥300 m and time to stand from supine ≥5s subgroup (n = 185), there was a 9% slower rate of 6MWD decline for ataluren versus placebo over 72 weeks (p = 0.3626). Ataluren reduced change in time to climb four stairs (p = 0.0179) versus placebo in this subgroup; no treatment benefits were seen for other secondary end points. Ataluren was well tolerated (serious adverse events: ataluren, 7.1%; placebo, 6.8%); no deaths occurred. Conclusion: Long-term ataluren treatment has a favorable benefit–risk profile, slowing motor function decline in the largest phase III nmDMD study to date.

Abstract Background Duchenne muscular dystrophy (DMD) is a rare disease that causes progressive muscle degeneration resulting in life-threatening cardiac complications. The objective of this systematic literature review was to describe and grade the published evidence of predictors of cardiac disease in DMD. Methods The review encompassed searches of Embase, MEDLINE ALL, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of cardiac disease in DMD. The certainty of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Results We included 33 publications encompassing 9,232 patients with DMD. We found moderate- to high-quality evidence that cardiac medication (i.e., ACE inhibitors [enalapril and perindopril], β-blockers [carvedilol], and mineralocorticoid receptor antagonists [eplerenone]) are significantly associated with preserved left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular circumferential strain (LVCS). DMD mutations in exons 51 and 52 were found to be significantly associated with lower risk of cardiomyopathy; deletions treatable by exon 53 skipping and mutations in the Dp116 coding region with improved LVEF and prolonged cardiac dysfunction-free survival; and exons 45–50 and 52 with early left ventricular systolic dysfunction (low/very low-quality evidence). We found high-quality evidence that glucocorticoids (deflazacort) are significantly associated with preserved LVEF and improved fractional shortening (FS), and low-quality evidence that glucocorticoids (deflazacort, prednisone, and/or prednisolone) are associated with improved ejection fraction (EF) and lower risk of cardiomyopathy, ventricular dysfunction, and heart failure-related mortality. Full-time mechanical ventilation was found to be significantly correlated with LVEF (low-quality evidence), muscle strength with FS (low-quality evidence), and genetic modifiers (i.e., LTBP4 rs10880 and ACTN3) with LVEF, lower risk of cardiomyopathy and left ventricular dilation (low-quality evidence). Conclusion Several sources of cardiac disease heterogeneity are well-studied in patients with DMD. Yet, the certainty of evidence is generally low, and little is known of the contribution of non-pharmacological interventions, as well as the impact of different criteria for initiation of specific treatments. Our findings help raise awareness of prevailing unmet needs, shape expectations of treatment outcomes, and inform the design of future research.

BACKGROUND:Despite advances in the medical management of the disease, respiratory involvement remains a significant source of morbidity and mortality in children and adults with Duchenne muscular dystrophy (DMD).OBJECTIVE:The objective of this systematic literature review was to synthesize and grade published evidence of factors associated with respiratory health and function in DMD.METHODS:We searched MEDLINE, Embase, and the Cochrane Library for records of studies published from January 1, 2000 (to ensure relevance to current care practices), up until and including December 31, 2022, reporting evidence of prognostic indicators and predictors of disease progression in DMD. The quality of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework.RESULTS:The bibliographic search strategy resulted in the inclusion of 29 articles. In total, evidence of 10 factors associated with respiratory health and function in patients with DMD was identified: glucocorticoid exposure (high- to very low-quality evidence), DMD mutations (low-quality evidence), DMD genetic modifiers (low-quality evidence), other pharmacological interventions (i.e., ataluren, eteplirsen, idebenone, and tamoxifen) (moderate- to very low-quality evidence), body mass index and weight (low-quality evidence), and functional ability (low-quality evidence).CONCLUSIONS:In conclusion, we identified a total of 10 factors associated with respiratory health in function in DMD, encompassing both pharmacological therapies, genetic mutations and modifiers, and patient clinical characteristics. Yet, more research is needed to further delineate sources of respiratory heterogeneity, in particular the genotype-phenotype association and the impact of novel DMD therapies in a real-world setting. Our synthesis and grading should be helpful to inform clinical practice and future research of this heavily burdened patient population.

To assess the effects of ataluren in clinically meaningful milestones in Duchenne muscular dystrophy (DMD).

DMD is an X-linked neuromuscular disease characterized by progressive muscle weakness. While LoA is commonly reported, disease burden is less well-characterized. This study aimed to characterize disease progression in boys with DMD according to ambulatory status and age at LoA (AaLoA).

Objective: The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD). Methods: This systematic review and meta-analysis included searches of MEDLINE ALL, Embase, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of loss of ambulation in DMD. Search terms included "Duchenne muscular dystrophy" as a Medical Subject Heading or free text term, in combination with variations of the term "predictor". Risk of bias was assessed using the Newcastle-Ottawa Scale. We performed metaanalysis pooling of hazard ratios of the effects of glucocorticoids (vs. no glucocorticoid therapy) by fitting a common-effect inverse-variance model. Results: The bibliographic searches resulted in the inclusion of 45 studies of children and adults withDMDfrom 17 countries across Europe, Asia, and North America. Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40-0.48]) (n = 25 studies). Earlier onset of first signs or symptoms, earlier loss of developmental milestones, lower baseline 6MWT (i.e.,<350 vs. =350 metres and <330 vs. =330 metres), and lower baseline NSAA were associated with earlier loss of ambulation (n = 5 studies). Deletion of exons 3-7, proximal mutations (upstream intron 44), single exon 45 deletions, and mutations amenable of skipping exon 8, exon 44, and exon 53, were associated with prolonged ambulation; distal mutations (intron 44 and downstream), deletion of exons 49-50, and mutations amenable of skipping exon 45, and exon 51 were associated with earlier loss of ambulation (n= 13 studies). Specific single-nucleotide polymorphisms in CD40 gene rs1883832, LTBP4 gene rs10880, SPP1 gene rs2835709 and rs11730582, and TCTEX1D1 gene rs1060575 (n = 7 studies), as well as race/ethnicity and level of family/patient deprivation (n = 3 studies), were associated with loss of ambulation. Treatment with ataluren (n = 2 studies) and eteplirsen (n = 3 studies) were associated with prolonged ambulation. Magnetic resonance biomarkers (MRI and MRS) were identified as significant predictors of loss of ambulation (n = 6 studies). In total, 33% of studies exhibited some risk of bias. Conclusion: Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population.

[This corrects the article DOI: 10.1371/journal.pone.0265879.].

The value of real-world registries in informing long-term treatment benefits is increasingly recognized, particularly in rare diseases. Strategic Targeting of Registries and International Database of Excellence (STRIDE; NCT02369731) is an international, observational registry evaluating long-term safety and effectiveness of ataluren in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in real-world clinical practice. Propensity score matching (PSM) was performed to identify Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (NCT00468832) patients who were comparable to STRIDE patients for the following established predictors of disease progression: age at first symptom onset, age at first corticosteroid use and duration of corticosteroid use. Here we assess the robustness of the PSM methodology using sensitivity analyses. Sensitivity analyses were performed to address potential sources of bias in PSM patient populations, including standard of care, severity of underlying disease, age and functional status at study entry as covariates. Sensitivity analyses also included alternative propensity score methods, using all CINRG patients, with propensity scores as weights and as covariates to detect potential bias. As of January 2023, STRIDE had enrolled >300 boys with nmDMD. In the primary analysis, ataluren treatment in STRIDE patients was associated with a 3.5-year delay in loss of ambulation (LoA) compared with CINRG counterparts (Hazard Ratio [HR] 0.46; p<0.0001). HRs of sensitivity analyses were 0.43–0.49, demonstrating stability of the PSM algorithm of the primary matching and the robustness of the primary result, when using propensity-matched STRIDE and CINRG patients. Sensitivity analyses confirmed that major identified potential sources of bias of PSM were addressed, suggesting the observed delay in LoA in patients with nmDMD in STRIDE to be reliably attributed to ataluren.

Strategic Targeting of Registries and International Database of Excellence (STRIDE; NCT02369731) is an international, observational registry evaluating the long-term safety and effectiveness of ataluren in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in real-world clinical practice. This study investigated whether patients in the STRIDE Registry experienced a slower decline in upper limb function versus patients with DMD receiving standard of care (SoC) alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (NCT00468832). Data were extracted on 31 January 2023. Upper limb function was assessed using the PUL module in the STRIDE Registry and the Brooke Scale in the CINRG cohort. Kaplan–Meier analyses estimated the age at loss of upper limb function (loss of overhead reach, loss of hand-to-mouth function and loss of distal hand function). The mean age at the last assessment was 14.0 years and 15.2 years in propensity score-matched STRIDE and CINRG cohorts (N=277 per cohort), respectively. The median (95% CI) ages at loss of overhead reach (STRIDE vs CINRG) were 15.8 (12.1, 19.2) and 12.7 (10.3, 14.3) years, respectively (HR [95% CI], 0.412 [0.220, 0.771]; p=0.0095). In CINRG patients, the median (95% CI) age at loss of hand-to-mouth function was 20.5 years (17.1, NC) and the median age at loss of distal hand function was 30.1 years (27.6, NC). These outcomes were not yet estimable for STRIDE Registry patients. These results indicate that treatment with ataluren plus SoC in routine clinical practice may help preserve upper limb function in patients with advanced nmDMD.

Objective: To assess performance of upper limb (PUL) function in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) receiving ataluren plus standard of care (SoC) in Study 041 (NCT03179631) and in the STRIDE Registry (NCT02369731). Background: DMD is a severe neuromuscular disorder caused by a lack of functional dystrophin. Ataluren promotes read through of an in-frame premature stop codon to produce full-length dystrophin and is indicated for the treatment of patients with nmDMD. Study 041 (NCT03179631) is a phase 3, double-blind, placebo-controlled 72-week trial. The STRIDE Registry (NCT02369731) is an ongoing, long-term, real-world evidence study. Design/Methods: In Study 041, boys with nmDMD aged ≥5 years, on a stable corticosteroid regimen, and with a 6-minute walk distance (6MWD) ≥150m were randomized 1:1, ataluren:placebo. The intention-to-treat (ITT) population comprised randomized boys who received at least one dose of study treatment (N=359; mean age 8.1 years); a key subgroup included those with baseline 300–400m 6MWD (n=169). STRIDE patients were propensity-score matched to patients receiving SoC alone in CINRG DNHS (NCT00468832), yielding a comparable population (N=261). Kaplan-Meier analyses estimated age at loss of upper limb function. Results: Least-squares mean PUL total score change from baseline to week 72 (by MMRM analysis) numerically favored ataluren versus placebo (0.44, p=0.1059) in the Study 041 ITT population and was significant in the 300–400m 6MWD subgroup (1.02, p=0.0165). In matched STRIDE versus CINRG patients (mean last assessment age, 13.1 versus 14.6), ataluren preserved hand-to-mouth function by 3.4 years (p=0.0046) as assessed by entry level items of PUL versus Brooke Scale, respectively. Median age at loss of overhead reach numerically favored STRIDE, consistent with the overall trend (15.8 versus 12.6; p=0.2872). Median age at loss of distal hand function was non-estimable for STRIDE patients. Conclusions: These results indicate that ataluren may help preserve upper limb function in patients with advanced nmDMD. Disclosure: Dr. McDonald has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sarepta Therapeutics. Dr. McDonald has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for PTC Therapeutics. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astellas. Dr. McDonald has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Capricor Therapeutics. Dr. McDonald has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Catabasis. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Epirium Bio. Dr. McDonald has received personal compensation in the range of $0-$499 for serving as a Consultant for Italfarmaco. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Santhera Pharmaceuticals. Dr. McDonald has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta Therapeutics. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC Therapeutics. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Capricor. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Catabasis Pharmaceuticals. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Santhera Pharmaceuticals. The institution of Dr. McDonald has received research support from Sarepta Therapeutics. The institution of Dr. McDonald has received research support from PTC Therapeutics. The institution of Dr. McDonald has received research support from Santhera Pharmaceuticals. The institution of Dr. McDonald has received research support from Astellas. The institution of Dr. McDonald has received research support from Capricor Therapeutics. The institution of Dr. McDonald has received research support from Catabasis. The institution of Dr. McDonald has received research support from Epirium Bio. The institution of Dr. McDonald has received research support from Italfarmaco. Dr. McDonald has received research support from NS Pharma. The institution of Dr. McDonald has received research support from Pfizer. The institution of Dr. McDonald has received research support from NIH (NINDS). The institution of Dr. McDonald has received research support from NIDILRR. The institution of Dr. McDonald has received research support from Department of Defense. The institution of Dr. McDonald has received research support from Parent Project Muscular Dystrophy. The institution of Dr. McDonald has received research support from Muscular Dystrophy Association. Dr. McDonald has received personal compensation in the range of $500-$4,999 for serving as a Member National Advisory Board for Medical Rehabilitation Research with NIH. Eugenio Mercuri has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta, Santhera, PTC, Pfizer, Roche, Biogen, Avexis Novartis, Scholar Rock, Cytokinetics. Eugenio Mercuri has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sarepta, Santhera, PTC, Pfizer, Roche, Biogen, Avexis Novartis. The institution of Eugenio Mercuri has received research support from biogen. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sarepta. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Pfizer. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Avexis. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. The institution of Dr. Muntoni has received research support from European Commission. The institution of Dr. Muntoni has received research support from Medical Research Council. The institution of Dr. Muntoni has received research support from Biogen. The institution of Dr. Muntoni has received research support from Muscular Dystrophy UK. The institution of Dr. Muntoni has received research support from MDA USA. The institution of Dr. Muntoni has received research support from Sarepta. The institution of Dr. Muntoni has received research support from Association Francoise Myopathies. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving as a Clinical expert with UK NICE Committee. Heather Gordish-Dressman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AGADA BioSciences. Heather Gordish-Dressman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TRiNDS, LLC. Heather Gordish-Dressman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Solid Biosciences. An immediate family member of Heather Gordish-Dressman has received intellectual property interests from a discovery or technology relating to health care. Ms. Morgenroth has received personal compensation for serving as an employee of TRiNDS. Ms. Morgenroth has stock in TRiNDS. Maria Bernadete Dutra de Resende has nothing to disclose. Shuizhen Zhou has nothing to disclose. Dr. Neeharika has nothing to disclose. Dr. Haginoya has nothing to disclose. Dr. Ramos-Platt has received personal compensation for serving as an employee of MDA. Dr. Ramos-Platt has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. The institution of Dr. Ramos-Platt has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Ramos-Platt has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cure sma. Mrs. Williams has nothing to disclose. Vinay Penematsa has nothing to disclose. Connie Chou has stock in PTC Therapeutics. Dr. Lin has received personal compensation for serving as an employee of PTC Therapeutics. Ms. Johnson has received personal compensation for serving as an employee of PTC Therapeutics Inc. Ms. Johnson has stock in PTC Therapeutics. Dr. Koladicz has received personal compensation for serving as an employee of PTC Therapeutics. Nick Mastrandrea has received personal compensation for serving as an employee of PTC Therapeutics. Nick Mastrandrea has stock in PTC Therapeutics. Christian Werner has nothing to disclose. Panayiota Trifillis has received personal compensation for serving as an employee of PTC Therapeutics. Panayiota Trifillis has received stock or an ownership interest from PTC Therapeutics, Inc.. Panayiota Trifillis has received intellectual property interests from a discovery or technology relating to health care.

Age at loss of ambulation (AALoA) and respiratory symptoms for nmDMD have been compared between patients receiving ataluren from the STRIDE registry and standard of care (SoC) from the CINRG study. A 4-year delay in loss of ambulation (LoA) was demonstrated for ataluren-treated patients. However, estimating treatment effects on respiratory function is challenging due to data limitations. This study aimed to assess the association between LoA and respiratory function - defined by predicted forced vital capacity (pFVC).