Mika Leinonen

A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy

Abstract 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.

Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe

Purpose A meta-analysis was conducted to estimate the prevalence of patients with molecularly confirmed Leber hereditary optic neuropathy (LHON) carrying any of the 3 primary mtDNA mutations (m.11778G>A, m.14484T>C, m.3460G>A) which cause this inherited form of blindness. Methods A literature search was conducted to identify primary reports with LHON prevalence data reported for Europe. The overall prevalence of LHON with molecularly confirmed diagnosis was evaluated by weighting the prevalence estimates of the individual studies by the inverse of their variance. Results Based on this meta-analysis of 5 European studies providing appropriate information, the estimated prevalence of LHON disease associated with the combined m.11778G>A, m.14484T>C, m.3460G>A mutations was ∼1:45,000 (2.23×10-5; 95% confidence interval [CI] 2.01-2.44×10–5). Patients with LHON carrying either the m.11778G>A or the m.3460G>A mutation have a more severe clinical presentation and a much lower chance of spontaneous recovery from vision loss compared to patients with the m.14484T>C mutation. The estimated prevalence for patients with LHON in Europe carrying either of these severe mutations (m.11778G>A or m.3460G>A) was ∼1:65,000 (1.54×10–5; 95% CI 1.33-1.74×10–5). Conclusions Although this meta-analysis summarizes the existing prevalence data for the primary, disease-causing mitochondrial DNA mutations of LHON in Europe, there is still a clear lack of reliable primary epidemiologic data for this devastating ophthalmologic disease.

Effects of Idebenone on Color Vision in Patients With Leber Hereditary Optic Neuropathy

Background:The authors investigated the correlation of protan and tritan color vision with disease characteristics in Leber hereditary optic neuropathy (LHON). The authors also characterized the therapeutic potential of idebenone in protecting patients from developing dyschromatopsia in LHON. Methods:Color contrast data of 39 LHON patients participating in a randomized, double-blind placebo-controlled intervention study were evaluated. Patients reported disease onset <5 years before enrolment and were genetically confirmed. Protan and tritan color contrast sensitivity was measured using a computer graphics method in patients receiving idebenone (Catena; 900 mg/d; N = 28) or placebo (N = 11) for 6 months. Results:Mean age of patients was 28.1 years, 87.2% were men, 76.9% carried the m11778G>A mutation, and mean duration since onset was 2 years. Assessing protan and tritan color vision at baseline revealed a high degree of color confusion even in young patients (<25 years) and with a short history of disease (<1 year). Treatment with idebenone improved tritan color vision compared with placebo (P = 0.008 at week 24); a similar trend was seen for protan. The effect of idebenone was most prominent in patients with discordant visual acuity (interocular difference of logMAR >0.2). In this subgroup, the treatment effect at week 24 was 20.4% (P = 0.005) in favor of idebenone for the tritan color domain and 13.5% (P = 0.067) for the protan domain. Conclusion:This study confirms that protan and tritan color confusion is an early symptom in LHON. Treatment with idebenone can protect from loss of color vision, particularly in patients who are at imminent risk of further vision loss.

Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy.

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10-18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900u2009mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated by patient (HR 0.33, pu2009=u20090.0187) and for all BAEs (HR 0.28, pu2009=u20090.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics.

Treatment effect of idebenone on inspiratory function in patients with Duchenne muscular dystrophy.

Assessment of dynamic inspiratory function may provide valuable information about the degree and progression of pulmonary involvement in patients with Duchenne muscular dystrophy (DMD). The aims of this study were to characterize inspiratory function and to assess the efficacy of idebenone on this pulmonary function outcome in a large and well‐characterized cohort of 10–18 year‐old DMD patients not taking glucocorticoid steroids (GCs) enrolled in the phase 3 randomized controlled DELOS trial. We evaluated the effect of idebenone on the highest flow generated during an inspiratory FVC maneuver (maximum inspiratory flow; VI,max(FVC)) and the ratio between the largest inspiratory flow during tidal breathing (tidal inspiratory flow; VI,max(t)) and the VI,max(FVC). The fraction of the maximum flow that is not used during tidal breathing has been termed inspiratory flow reserve (IFR). DMD patients in both treatment groups of DELOS (idebenone, nu2009=u200931; placebo: nu2009=u200933) had comparable and abnormally low VI,max(FVC) at baseline. During the study period, VI,max(FVC) further declined by −0.29u2009L/sec in patients on placebo (95%CI: −0.51, −0.08; Pu2009=u20090.008 at week 52), whereas it remained stable in patients on idebenone (change from baseline to week 52: 0.01u2009L/sec; 95%CI: −0.22, 0.24; Pu2009=u20090.950). The between‐group difference favoring idebenone was 0.27u2009L/sec (Pu2009=u20090.043) at week 26 and 0.30u2009L/sec (Pu2009=u20090.061) at week 52. In addition, during the study period, IFR improved by 2.8% in patients receiving idebenone and worsened by −3.0% among patients on placebo (between‐group difference 5.8% at week 52; Pu2009=u20090.040). Although the clinical interpretation of these data is currently limited due to the scarcity of routine clinical practice experience with dynamic inspiratory function outcomes in DMD, these findings from a randomized controlled study nevertheless suggest that idebenone preserved inspiratory muscle function as assessed by VI,max(FVC) and IFR in patients with DMD. Pediatr Pulmonol. 2017;52:508–515.

Characterization of pulmonary function in 10–18 year old patients with Duchenne muscular dystrophy

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 (PFTs), 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 (Spearmans 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 (MIP%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.

Efficacy of Idebenone to Preserve Respiratory Function above Clinically Meaningful Thresholds for Forced Vital Capacity (FVC) in Patients with Duchenne Muscular Dystrophy

Background: Patients with DMD experience progressive restrictive respiratory disease and eventual respiratory failure. Standard of care guidelines command changes in disease management when forced vital capacity percent of predicted (FVC% p) falls below clinically relevant thresholds. The Phase 3 DELOS trial in patients with DMD demonstrated that idebenone reduces the loss of peak expiratory flow and FVC compared to placebo (Buyse GM, et al.; Lancet 2015; 385u200a:u200a1748-57). Objective: Post-hoc analyses were conducted to assess whether treatment with idebenone could reduce the risk of patients dropping below clinically meaningful thresholds of FVC% p. Methods: The DELOS trial enrolled DMD patients 10–18 years of age not using glucocorticoids to receive idebenone (Nu200a=u200a31) or placebo (Nu200a=u200a33) for 12 months. Change from baseline in FVC and FVC% p was assessed by hospital spirometry and analyzed by mixed model of repeated measures and slope analysis and proportions of patients falling below clinically meaningful thresholds of FVC% p were compared. Results: The change over 1 year in FVC and FVC% p showed a consistent pattern in favor of idebenone treatment across multiple analysis methods and fewer patients in the idebenone group declined by a margin of 10% or more in FVC and FVC% p compared to placebo. There were also fewer patients in the idebenone group (15%) with a decline below FVC% p of 50% compared to the placebo group (25%) and fewer patients in the idebenone group (28%) showed a decline below FVC% p of 50% or 40% or 30% compared to the placebo group (43%). Conclusions: These data added to the consistency and clinical meaningfulness of findings from the DELOS trial showing that idebenone can slow the loss of pulmonary function in patients with DMD.

Correlation of respiratory function parameters in 10–18 year old patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common and severe type of muscular dystrophy. Respiratory involvement, which accounts for early morbidity and mortality in this patient population, is characterized by progressive respiratory muscle weakness and ineffective cough, nocturnal hypoventilation, sleep disordered breathing, recurrent chest infections and atelectasis, leading to respiratory failure. 1,2