In DMD, progressive weakness of respiratory muscles leads to life-threatening respiratory complications. In a randomized placebo-controlled, Phase 3 clinical trial (DELOS) in 64 DMD patients aged 10–18 years and not taking concomitant glucocorticoids, idebenone (900 mg/day) significantly reduced the rate of respiratory function decline, as measured by peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) – as percent predicted (%p). In a post hoc analysis of the DELOS trial, we compared the efficacy of idebenone vs placebo on PEF%p, FVC%p and FEV1%p using two different analysis methods. Method 1: Change from baseline to last visit (month 12), and to other study visits (months 3, 6, and 9), were analyzed by mixed model for repeated measures, with treatment group, visit and treatment group by visit interaction as fixed factors and the baseline as a covariate. Method 2: The slope across all visits was analyzed using a random coefficient regression model. Using method 1, the estimated difference between idebenone and placebo for PEF%p was 6.3%p (p = 0.031) at last visit. The differences at months 3, 6 and 9 were 3.9%p (p = 0.104), 8.3%p (p < 0.001) and 7.6%p (p = 0.016), respectively. The estimated difference at last visit for FVC%p was 3.3%p (p = 0.082), with month 3, 6 and 9 differences of 3.3%p (p = 0.021), 4.7%p (p < 0.002) and 5.0%p (p = 0.019), respectively. For FEV1, the results were 6.4% at the last visit, with month 3, 6 and 9 differences of 5.2%p (p = 0.010,), 9.3%p (p < 0.001,) and 6.9%p (p = 0.016), respectively. Using method 2, the estimated annual slope difference across all visits was 5.8%p (p = 0.007) for PEF%p, 4.1%p (p < 0.001) for FVC%p and 6.8%p (p = 0.0160) for FEV1%p. Based on results from two different analyses for PEF%p, FVC%p and FEV1%p data, idebenone significantly slowed the rate of respiratory function decline compared with placebo.

Patients with DMD experience respiratory function decline that is accelerated once patients become non-ambulatory. The ability of idebenone to slow respiratory function decline in patients with DMD has been investigated in two randomized, placebo-controlled trials (the phase II DELPHI trial and phase III DELOS trial). DELPHI included patients (aged 8 to 16 yrs) irrespective of baseline respiratory function status, while DELOS required patients (aged 10 to 18 yrs) to be in the respiratory decline phase. DELPHI allowed the randomization of steroid-using patients, while DELOS included only steroid non-users. Raw data from both trials were pooled and analyzed for treatment effects on peak expiratory flow and forced vital capacity, expressed as a percentage of predicted (PEF%p and FVC%p). Patients were excluded if they were not in the respiratory function decline phase (baseline PEF%p of >80%p). Change in PEF%p and FVC%p from baseline to month 6 and 12 were analyzed using a mixed model for repeated measures, with study as a random effect. In total, 76 patients (DELPHI: 12; DELOS: 64) were in the respiratory function decline phase (PEF%p < 80%), of which 72 were not using steroids. Across all patients, the difference between the idebenone and placebo groups in PEF%p from baseline to month 12 was 8.0%p (p = 0.003). When omitting steroid users, this difference was 7.7%p (p = 0.005). For FVC%p, the treatment difference was 3.6%p (p = 0.046) in all patients, with a comparable difference of 3.5%p (p = 0.051) when omitting steroid users. Results from a meta-analysis with data from two randomized, placebo-controlled trials (DELPHI and DELOS) demonstrate that idebenone slows respiratory function decline in patients with DMD.

Pulmonary function loss in patients with Duchenne muscular dystrophy (DMD) is progressive and leads to pulmonary insufficiency. The purpose of this study in 10-18 year old patients with DMD is the assessment of the inter-correlation between pulmonary function tests (PFN, their reliability and the association with the general disease stage measured by the Brooke score. Dynamic PFTs (peak expiratory flow [PEF], forced vital capacity [FVC],, forced expiratory volume in one second [FEV1]) and maximum static airway pressures (MIP, MEP) were prospectively collected from 64 DMD patients enrolled in the DELOS trial (ClinicalTrials.gov, number NCT01027884). Baseline PEF percent predicted (PEF%p) was <80% and patients had stopped taking glucocorticoids at least 12 months prior to study start. At baseline PEF%p, FVC%p and FEV1%p correlated well with each other (Spearman's rho: PEF%p FVC%p: 0.54; PEF%p FEV1%p: 0.72; FVC%p FEV1%p: 0.91). MIP%p and MEP%p correlated well with one another (MIP%p MEP%p: 0.71) but less well with PEF%p (MIP%p PEF%p: 0.40; MEP%p-PEF%p: 0.41) and slightly better with FVC%p (MIP%p FVC%p: 0.59; MEP%p FVC%p: 0.74). The within-subject coefficients of variation (CV) for successive measures were 6.97% for PEF%p, 6.69% for FVC%p and 11.11% for FEV1%p, indicating that these parameters could be more reliably assessed compared to maximum static airway pressures (CV for MIP%p: 18.00%; MEP%p: 15.73%). Yearly rates of PFT decline (placebo group) were larger in dynamic parameters (PEF%p: 8.9% [SD 2.0]; FVC%p: 8.7% [SD 1.1]; FEV1%p: 10.2% [SD 2.0]) than static airway pressures (IvIIP%p: 4.5 [SD 1.3]; MEP%p: 2.8 [SD 1.1]). A considerable drop in dynamic pulmonary function parameters was associated with loss of upper limb function (transition from Brooke score category 4 to category 5). In conclusion, these findings expand the understanding of the reliability, correlation and evolution of different pulmonary function measures in DMD patients who are in the pulmonary function decline phase. (C) 2017 The Authors. Published by Elsevier B.V.

Respiratory failure causes morbidity and early mortality in Duchenne muscular dystrophy (DMD). Standard of care guidelines recommend routine monitoring of respiratory function. Here we report the use of a hand-held device for home-based frequent monitoring of respiratory flow and volume parameters. Respiratory function data were prospectively collected from 64 DMD patients 10–18 (mean 14.3) years participating in the multi-center, phase III DELOS trial. Standard spirometry was conducted at baseline and 3-monthly intervals for a period of 52 weeks during hospital visits using a Spirotrac V device. Patients were also asked to measure peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) using the portable ASMA-1 device (Vitalograph) once every week at home. Patients were either treated with idebenone (Raxone, 900 mg/d) or placebo. For each assessment, subjects recorded several test maneuvers, and the highest value was used for analysis according to ATS/ETS guidelines. On average patients provided ASMA-1 data during 41.4 (SD: 14.7) weeks of the 52 week study, corresponding to 79.6% compliance. PEF, PEF%p, FEV1 and FEV1%p collected during hospital-based spirometry or by the ASMA-1 device at home correlated well at baseline (Spearman's R for PEF: 0.89; PEF%p: 0.80; FEV1: 0.73; FEV1%p: 0.83) and for the change from baseline to Week 52 (Spearman's R for PEF: 0.78; PEF%p: 0.67; FEV1: 0.74 and FEV1%p: 0.60). This is the first demonstration that frequent, home-based respiratory function testing is possible in young DMD patients. The hand-held ASMA-1 device provides reliable respiratory function data in pediatric and adolescent patients with DMD. Portable home-based respiratory function testing could be a valuable tool for routine measuring and monitoring, especially in patients at risk of respiratory function decline.

Reliable natural history data of respiratory function changes in patients with DMD are still limited and available data sets are frequently confounded by heterogeneity in the use of glucocorticoid steroids (GCS). Here we report respiratory function data prospectively collected from 33 patients, 10–18 (mean 15.0, SD 2.5) years of age, enrolled in the placebo group of the multi-center, phase III DELOS trial. Patients had stopped taking GCS at least 12 months prior to enrollment and during the 52 week follow up time. Spirometry was conducted at baseline and 3-monthly intervals during hospital visits. Data for peak expiratory flow (PEF) and lung volumes (FVC and FEV1) were converted to corresponding percent of predicted (%p) by standard formulae. DELOS eligible patients had to have a PEF%p of <80 at baseline. Baseline values for PEF%p, FEV%p and FEV1%p were comparable at 54.2 (SD: 13.2), 50.4 (20.0) and 49.7 (18.3) respectively. The annual rate of change was −8.84 (SE 1.95; p < 0.001) for PEF%p, −8.95 (SE 1.26; p < 0.001) for FVC%p and −10.68 (SE 2.56; p < 0.001) for FEV1%p. In patients who previously had taken GCS but stopped on average 4.3 (SD: 2.2) years prior to enrollment, the annual rate of decline in all respiratory function data was slightly less than in GCS-naïve patients (previous GCS users: PEF%p: −7.95, FVC%p: −8.72, FEV1%p: −10.17; GCS naïve: PEF%p: −9.95, FVC%p: −9.09, FEV1%p: −12.37). Baseline values for all respiratory function parameters were higher in the subgroup of patients below the median (≤14 years) compared to patients > 14 years and the annual rate of decline was slightly higher in the subgroup of younger patients. Our findings provide a set of natural history data for respiratory function in a well-defined group of DMD patients not using GCS.

Decline in pulmonary function in Duchenne Muscular Dystrophy (DMD) contributes to significant morbidity and reduced longevity. Spirometry is a widely used and fairly easily performed technique to assess lung function, and in particular lung volume; however, the acceptability criteria from the American Thoracic Society (ATS) may be overly restrictive and inappropriate for patients with neuromuscular disease. We examined prospective spirometry data (Forced Vital Capacity [FVC] and peak expiratory flow [PEF]) from 60 DMD patients enrolled in a natural history cohort study (median age 10.3 years, range 5–24 years). Expiratory flow‐volume curves were examined by a pulmonologist and the data were evaluated for acceptability using ATS criteria modified based on the capabilities of patients with neuromuscular disease. Data were then analyzed for change with age, ambulation status, and glucocorticoid use. At least one acceptable study was obtained in 44 subjects (73%), and 81 of the 131 studies (62%) were acceptable. The FVC and PEF showed similar relative changes in absolute values with increasing age, i.e., an increase through 10 years, relative stabilization from 10–18 years, and then a decrease at an older age. The percent predicted, FVC and PEF showed a near linear decline of approximately 5% points/year from ages 5 to 24. Surprisingly, no difference was observed in FVC or PEF by ambulation or steroid treatment. Acceptable spirometry can be performed on DMD patients over a broad range of ages. Using modified ATS criteria, curated spirometry data, excluding technically unacceptable data, may provide a more reliable means of determining change in lung function over time. Pediatr Pulmonol. 2015; 50:487–494. © 2015 Wiley Periodicals, Inc.

Purpose LHON is an inherited mitochondrial orphan disease leading to rapid, irreversible vision loss in the majority patients. This survey reports the clinical course of vision loss and recovery in patients with LHON based on a large retrospective data collection. Methods Visual acuity (VA) data from 383 individual patients were collected by chart review conducted in 11 clinical centres under local ethics approval using a standardized VA report form. Change of VA with time since onset of symptoms was analysed using cross sectional and longitudinal data analyses. Mutation dependent rates for spontaneous clinically relevant recovery (off-to-on-chart or at least 2 lines on chart) of VA were established from 774 individual observations available from 74 patients for whom relevant longitudinal VA data were available for up to 31 months. Results The data confirm the expected rapid loss of VA with 73% of eyes deteriorating beyond the threshold for legal blindness within 3 months of onset. The VA nadir was typically reached within less than 6 months from onset and for observations available between 12 and 24 months from onset, 78% of eyes remained legally blind. The time to VA recovery and proportion of patients with recovery from nadir varied with the LHON-associated mtDNA mutation carried. A total of 31.1% patients presented with spontaneous clinically relevant recovery G11778A: 25%, G3460A: 50%, T14484C: 43%). Conclusion These data demonstrate that in patients with LHON vision loss is rapidly progressive and severe. The great majority of patients do not regain VA but remain legally blind. Commercial interest

Purpose LHON is an orphan mitochondrial disorder affecting the retinal ganglion cells leading to permanent blindness from which recovery is rare. Here we report visual acuity outcomes for patients with recent onset who received Raxone® (idebenone) under an ongoing global Expanded Access Program (EAP). Methods Visual acuity was measured in 3-monthly intervals. Clinically relevant recovery was defined as (i) improvement from nadir by at least 10 letters on the ETDRS chart or (ii) improvement from “off-chart” at nadir to being able to read at least 5 letters on-chart. Results Currently there are 61 LHON patients enrolled, of which 48 patients have been treated for an average of 11 months. So far, 24 of 48 patients (50%) have experienced a clinically relevant and stable recovery in VA (89% for T14484C, 70% for G3460A and 31% for G11778A). The average treatment effect size in patients with recovery was 29 letters and 84 % recovered within 12 months of the initiation of the EAP. Conclusion A high proportion of LHON patients treated with idebenone under a global EAP experienced a clinically meaningful recovery of vision, further demonstrating the therapeutic potential of idebenone in the treatment of LHON. Commercial interest

Purpose To establish the long term benefit of oral idebenone 900mg/day in the treatment of Leber's Hereditary Optic Neuropathy (LHON). Methods Patients who participated in a 24-week, multi-centre (3 sites), double-masked, randomized, placebo controlled trial (RHODOS) were re-assessed at a single visit by means of Visual Acuity (VA) using ETDRS charts. Results Eighty-five patients were enrolled in the RHODOS study: 55 treated with idebenone (900mg/day) and 30 with placebo. At the end of the 24 week treatment period, the VA for patients randomized to placebo deteriorated. In contrast, in patients treated with 900mg/day idebenone, VA was preserved. In addition, in severely affected patients with off-chart vision at Baseline, only idebenone treated patients improved sufficiently to read at least 1 full line on the ETDRS chart (Klopstock et al., 2011). VA was repeated at a follow-up visit conducted 2.5 years (median) after treatment discontinuation. The difference in VA between placebo and idebenone treated patients was maintained. Specifically, in patients who during RHODOS received idebenone and who on average were protected from vision loss, VA did not deteriorate upon discontinuation of treatment. Conclusion These findings support the original conclusion that in selected patients with LHON, idebenone has significant therapeutic potential in preventing further vision loss and facilitating vision recovery. Commercial interest

Leber’s Hereditary Optic Neuropathy (LHON) is caused by mtDNA mutations affecting subunits of Complex I of the mitochondrial electron transport chain. Affected mutation carriers suffer from rapidly progressing and mostly irreversible bilateral vision loss. An increasing body of evidence indicates that idebenone has therapeutic potential for the treatment of LHON. Data from a randomized placebo-controlled study (RHODOS) and from a number of case reports and retrospective cohort studies demonstrate that patients with established vision loss may benefit from idebenone treatment and recover visual acuity. Early treatment start (e.g. within one year from onset of symptoms) appears to be associated with better outcome, which is supported by the cellular pathology of LHON. Data from a currently on-going named patient program (NPP), where LHON patients receive 900 mg/day Raxone® under routine clinical care, will be presented and an update on the regulatory status of Raxone® provided. Commercial interest

Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G > A, m.11778G > A, and m.14484T > C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

A 12-month double-blind, randomized, placebo-controlled phase II study in 21 patients with DMD (DELPHI study) has indicated that idebenone (Catena®) may improve cardiac and respiratory function in 8–16 year old patients with DMD. Patients completing the DELPHI study were eligible to enroll into the open label extension study (DELPHI-E) of 24 months duration to further investigate the long-term safety and efficacy of idebenone. Patients were enrolled into DELPHI-E and received Catena® at 450 mg/d (patients ⩽ 45 kg body weight) or 900 mg/d (patients >45 kg body weight). Efficacy was assessed as change from baseline to month 6, 12, 18 and 24 for respiratory function tests (including peak expiratory flow (PEF), forced vital capacity (FVC), maximum mouth pressures). Cardiac function tests were conducted by echocardiography and Tissue Doppler Myocardial Imaging, particularly by assessment of the peak systolic radial strain of the left ventricular inferolateral wall, the region of the heart that is the earliest and most severely affected in DMD. Nineteen patients at age 15.1 ± 2.6 years (mean ± SD) were enrolled and completed the 24 months study period of DELPHI-E. Eleven patients were taking concomitant glucocorticoids. Catena® was safe and generally well tolerated. Baseline respiratory function data for the entire study cohort were: FVC: 2.20 ± 0.85 l, FVC percent predicted: 68.8 ± 25.6%, PEF: 269.4 ± 93.6 l/min, PEF percent predicted: 66.1 ± 22.3%. The change over time in respiratory as well as cardiac function data will be presented. Data from this long-term open label study will inform on the usefulness of different respiratory and cardiac efficacy outcome measures for intervention trials in DMD. The study also will provide additional data to assess the safety and therapeutic potential of idebenone (Catena®) in patients with DMD. Study sponsored by Santhera Pharmaceuticals.

Decline in skeletal muscle function in Duchenne Muscular Dystrophy (DMD) contributes to restrictive lung disease, chronic respiratory failure, poor cough and increased risk of pneumonia. These pulmonary complications cause the early morbidity and mortality in patients with DMD. Consequently, pulmonary function data in DMD patients provides important information and may provide clinically relevant measures for intervention studies testing the efficacy of emerging therapies for DMD. A decline in forced vital capacity (FVC) is observed in the second decade in DMD often leading the decline in pulmonary status and the initiation of non-invasive ventilation and assisted airway clearance devices. However, there is still a shortage of natural history data that describe and correlate the evolution of pulmonary function parameters beyond FVC, such as peak expiratory flow (PEF). Methods: Pulmonary function test (PFT) data was obtained prospectively from 62 DMD patients (age range 5–24 years) enrolled in an IRB-approved natural history study at the Children’s Hospital of Philadelphia from 2005 to 2009. Data was collected by trained physical therapists. Spirometry flow-loops from all subjects was reviewed by a pediatric pulmonologist (OHM) and only data that met American Thoracic Society guidelines was included in the analysis. Both cross-sectional and longitudinal data were analyzed. Statistical analysis will be performed to describe and correlate the evolution of PEF and FVC as absolute values and as a percent of predicted. Use of steroid medication was also analyzed. Results: A predictable decline in both FVC and PEF % predicted was demonstrated from age 13 years onward. PEF % predicted was generally lower than the FVC % predicted up to age 13 years. Conclusion: Data from this study will assist in the selection of pulmonary function parameters that may capture an early decline in DMD and may serve as efficacy endpoints in clinical studies.