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Buyse G.M.,University Hospitals Leuven | Voit T.,Institut Universitaire de France | Schara U.,Universitatsklinikum | Straathof C.S.M.,Leiden University | And 8 more authors.
The Lancet | Year: 2015

Background Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. Methods In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884. Findings 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3·05%p [95% CI -7·08 to 0·97], p=0·134, vs placebo -9·01%p [-13·18 to -4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (-2·57%p [-6·68 to 1·54], p=0·215, vs -8·84%p [-12·73 to -4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients). Interpretation Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. Funding Santhera Pharmaceuticals. © 2015 Elsevier Ltd.


News Article | November 22, 2016
Site: www.prnewswire.co.uk

ReportsnReports.com adds "Muscular Dystrophy - Pipeline Review, H2 2016" to its store, providing comprehensive information on the therapeutics under development for Muscular Dystrophy, complete with analysis by stage of development, drug target, mechanism of action (MoA), route of administration (RoA) and molecule type. The report also covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Additionally, the report provides an overview of key players involved in therapeutic development for Muscular Dystrophy and features dormant and discontinued projects. Muscular dystrophy is a group of diseases in which muscle fibers are unusually susceptible to damage. These damaged muscles become progressively weaker. Symptoms usually appear before age 6 and may appear as early as infancy. They may include fatigue, learning difficulties, intellectual disability, muscle weakness and progressive difficulty walking. Complete report on Global Muscular Dystrophy Market Research with 44 market data tables and 15 figures, spread across 144 pages is available at http://www.reportsnreports.com/reports/755879-muscular-dystrophy-pipeline-review-h2-2016.html . Company Analysis and Positioning discussed in this research are Acceleron Pharma, Inc., AMO Pharma Limited, Asahi Kasei Pharma Corp., aTyr Pharma, Inc., Benitec Biopharma Limited, Bio Blast Pharma Ltd., Biophytis SAS, Corcept Therapeutics Incorporated, Evotec AG, F. Hoffmann-La Roche Ltd., Genethon, Ionis Pharmaceuticals, Inc., Marina Biotech, Inc., Medestea Research & Production S.p.A., Novogen Limited, Pfizer Inc., Prothelia, Inc., SanBio, Inc., Santhera Pharmaceuticals Holding AG, Sarepta Therapeutics, Inc., Selecta Biosciences, Inc., Strykagen Corporation, Takeda Pharmaceutical Company Limited and WAVE Life Sciences Ltd. Drug Profiles mentioned in this research are  ACE-083, Antisense Oligonucleotide to Inhibit DM1 Protein Kinase for Myotonic Dystrophy, Antisense RNAi Oligonucleotides for Myotonic Dystrophy, ATYR-1940, baliforsen, BIO-103, domagrozumab, Drugs for Merosin-Deficient Congenital Muscular Dystrophy Type 1A, elcatonin, Gene Therapy for Muscular Dystrophy and Liver Diseases, Gene Therapy to Activate Dysferlin for Duchenne and Limb Girdle Muscular Dystrophies, Gene Therapy to Activate Dysferlin for Dysferlinopathies, Gene Therapy to Activate Dystrophin for Muscular Dystrophy, IUCT-169, IUCT-290, IUCT-309, ketoprofen, LR-08, MED-1101, mexiletine hydrochloride, Oligonucleotide 1 to Target Dystrophia Myotonica Protein Kinase for Myotonic Dystrophy, Oligonucleotides to Inhibit DM1 Protein Kinase for Myotonic Dystrophy, omigapil, Pabparna, poloxamer, PRT-01, Recombinant Protein to Activate Utrophin for Muscular Dystrophies, RNAi Gene Therapy to Inhibit Myotilin for LGMD, RP-33, SB-308, SIWA-318, Small Molecule to Inhibit DUX4 for Muscular Dystrophy, Small Molecule to Target CUG RNA for Myotonic Dystrophy 1, Small Molecule to Target RNA for Myotonic Dystrophy, Small Molecules for Dysferlinopathies, Small Molecules for Facioscapulohumeral Muscular Dystrophy, Small Molecules for Myotonic Dystrophy, Small Molecules for Myotonic Dystrophy Type 1, Small Molecules to Activate SMCHD1 for Facioscapulohumeral Dystrophy, Small Molecules to Antagonize Glucocorticoid Receptor II for Muscular Dystrophy, Small Molecules to Inhibit MBNL1 for Myotonic Dystrophy Type I, Small Molecules to Target RNA for Myotonic Dystrophy, SRT-149, SRT-152, Stem Cell Therapy for Muscular Dystrophy, Stryka-232, Stryka-234, Stryka-425, Stryka-533, Stryka-978, tideglusib, trehalose, TXA-127, VAL-0411 and VAL-1205. The Muscular Dystrophy (Musculoskeletal Disorders) pipeline guide also reviews of key players involved in therapeutic development for Muscular Dystrophy and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Phase III, Phase II, Phase I, Preclinical and Discovery stages are 1, 5, 2, 24 and 14 respectively. Similarly, the Universities portfolio in Phase II, Phase I, Preclinical and Discovery stages comprises 1, 1, 3 and 4 molecules, respectively.Muscular Dystrophy. Muscular Dystrophy (Musculoskeletal Disorders) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from Global Markets Direct’s proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources. Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. ReportsnReports.com is your single source for all market research needs. Our database includes 500,000+ market research reports from over 100+ leading global publishers & in-depth market research studies of over 5000 micro markets. With comprehensive information about the publishers and the industries for which they publish market research reports, we help you in your purchase decision by mapping your information needs with our huge collection of reports. Connect With Us on:


Liestal, Switzerland, November 8, 2016 - Santhera Pharmaceuticals (SIX: SANN) announces that the Swiss Agency for Therapeutic Products (Swissmedic) has accepted for review Santhera's Marketing Authorization Application (MAA) for Raxone® (idebenone) for the treatment of Duchenne muscular dystrophy (DMD) in patients with respiratory function decline not taking concomitant glucocorticoids. Raxone was granted Orphan Drug Designation for DMD in Switzerland in 2012. Santhera submitted a MAA to Swissmedic for Raxone in DMD in October 2016. Swissmedic has now confirmed that the dossier is sufficiently complete to permit substantive review. The standard assessment time is typically 15-18 months. The MAA for Raxone is already under review for the same indication by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). "This submission reflects our continued efforts to make Raxone available to patients and physicians beyond the European Union," said Thomas Meier, PhD, CEO of Santhera. "We look forward to Swissmedic's review of our application and to the approval of Raxone in Switzerland for DMD patients with respiratory function loss." The intended indication for Raxone is for patients with DMD in whom respiratory function has started to decline and who are currently not taking concomitant glucocorticoids. This indication would include patients who were previously treated with glucocorticoids or in whom glucocorticoid treatment is not desired, not tolerated or is contraindicated. As part of the Swiss MAA, Santhera submitted data from its phase II (DELPHI) program and the successful pivotal phase III (DELOS) study, the results of which have been further substantiated by a comparative natural history study. Data from all studies demonstrate that Raxone slows the rate of respiratory function decline compared to untreated patients to a degree that is of major clinical relevance for patients with DMD. Raxone (900 mg/day) was safe and well tolerated with adverse event rates comparable to placebo. In parallel to the already ongoing MAA reviews in Europe, Santhera continues to prepare for further discussions with the United States' Food and Drug Administration on the most appropriate regulatory pathway to approval in the US. About Raxone® (Idebenone) in Duchenne Muscular Dystrophy Duchenne muscular dystrophy (DMD) is one of the most common and devastating types of muscle degeneration and results in rapidly progressive muscle weakness. DMD is characterized by a loss of the protein dystrophin, leading to cell damage, impaired calcium homeostasis, elevated oxidative stress and reduced energy production in muscle cells. This results in progressive muscle weakness and wasting and early morbidity and mortality due to respiratory failure. Idebenone is a synthetic short-chain benzoquinone and a cofactor for the enzyme NAD(P)H:quinone oxidoreductase (NQO1) capable of stimulating mitochondrial electron transport, reducing and scavenging reactive oxygen species (ROS) and supplementing cellular energy levels. DELOS was a phase III, double-blind, placebo-controlled trial which randomized 64 patients, not taking concomitant glucocorticoids, to receive either Raxone (900 mg/day) or matching placebo. The trial met its primary endpoint and demonstrated that Raxone can slow the loss of respiratory function and reduces bronchopulmonary complications. The statistically significant and clinically relevant outcomes of the phase III DELOS study were published: Buyse et al., The Lancet 2015, 385:1748-1757; McDonald et al. Neuromuscular Disorders 2016, 26: 473-480 and Buyse et al., Pediatric Pulmonology 2016: http://dx.doi.org/10.1002/ppul.23547. About Santhera Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative pharmaceutical products for the treatment of orphan mitochondrial and neuromuscular diseases. Santhera's lead product Raxone is authorized in the European Union, Norway, Iceland and Liechtenstein for the treatment of Leber's hereditary optic neuropathy (LHON). For Duchenne muscular dystrophy (DMD), the second indication for Raxone, Santhera has filed a Marketing Authorization Application (MAA) in the European Union. In collaboration with the US National Institute of Neurological Disorders and Stroke (NINDS) Santhera is developing Raxone in a third indication, primary progressive multiple sclerosis (PPMS), and omigapil for congenital muscular dystrophy (CMD), all areas of high unmet medical need. For further information, please visit the Company's website www.santhera.com. Disclaimer / Forward-looking statements This communication does not constitute an offer or invitation to subscribe for or purchase any securities of Santhera Pharmaceuticals Holding AG. This publication may contain certain forward-looking statements concerning the Company and its business. Such statements involve certain risks, uncertainties and other factors which could cause the actual results, financial condition, performance or achievements of the Company to be materially different from those expressed or implied by such statements. Readers should therefore not place undue reliance on these statements, particularly not in connection with any contract or investment decision. The Company disclaims any obligation to update these forward-looking statements.


Liestal, Switzerland, December 23, 2016 - Santhera Pharmaceuticals (SIX: SANN) announces that it has been informed that the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) designated Raxone® (idebenone) for the treatment of Duchenne muscular dystrophy (DMD) in patients with respiratory function decline not taking concomitant glucocorticoids as Promising Innovative Medicine (PIM) and as a suitable candidate for entry into Step II of the EAMS process. In the UK the Early Access to Medicines Scheme aims to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorization when there is a clear unmet medical need. "We are delighted about MHRA's decision designating Raxone as a candidate for further consideration under the Early Access to Medicines Scheme as this underscores the high unmet medical need in DMD and acknowledges the innovative treatment approach of Raxone," said Thomas Meier, PhD, CEO of Santhera. Nic Bungay, Director of Campaigns, Care and Information at Muscular Dystrophy UK, commented: "We welcome this very encouraging news that Raxone has been considered suitable for the second step of the EAMS process, especially as this is the first muscular dystrophy drug to reach this stage. This demonstrates that the introduction of the EAMS, which Muscular Dystrophy UK had called for, could help to fast track emerging treatments. We urge the Government to continue to support the use of EAMS by pharmaceutical companies to bring through potentially promising treatments." The European Medicines Agency (EMA) and Swissmedic (the Swiss Agency for Therapeutic Products) are currently reviewing marketing authorization applications for Raxone for DMD patients in whom respiratory function has started to decline and who are not taking concomitant glucocorticoids. This indication would include patients who were previously treated with glucocorticoids or in whom glucocorticoid treatment is not desired, not tolerated or is contraindicated. About the UK Early Access to Medicines Scheme (EAMS) The UK's industry-sponsored EAMS aims to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorization when there is a clear unmet medical need. The EAMS is a two-step process: Step I is the Designation as a Promising Innovation Medicine (PIM). The PIM designation is an early indication that a medicinal product is a promising candidate for EAMS and gives reassurance that its clinical development is on track by having an early review of its data by the medicines regulator. Step II is the Scientific Opinion by the Medicines and Healthcare products Regulatory Agency (MHRA, UK regulatory agency). The Scientific Opinion describes the benefits and risks of the medicine and supports the prescriber and patient to make a decision on using the medicine before its license is approved. About Santhera Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative pharmaceutical products for the treatment of orphan mitochondrial and neuromuscular diseases. Santhera's lead product Raxone is authorized in the European Union, Norway, Iceland and Liechtenstein for the treatment of Leber's hereditary optic neuropathy (LHON). For Duchenne muscular dystrophy (DMD), the second indication for Raxone, Santhera has filed a Marketing Authorization Application (MAA) in the European Union and Switzerland. In collaboration with the US National Institute of Neurological Disorders and Stroke (NINDS) Santhera is developing Raxone in a third indication, primary progressive multiple sclerosis (PPMS), and omigapil for congenital muscular dystrophy (CMD), all areas of high unmet medical need. For further information, please visit the Company's website www.santhera.com. Disclaimer / Forward-looking statements This communication does not constitute an offer or invitation to subscribe for or purchase any securities of Santhera Pharmaceuticals Holding AG. This publication may contain certain forward-looking statements concerning the Company and its business. Such statements involve certain risks, uncertainties and other factors which could cause the actual results, financial condition, performance or achievements of the Company to be materially different from those expressed or implied by such statements. Readers should therefore not place undue reliance on these statements, particularly not in connection with any contract or investment decision. The Company disclaims any obligation to update these forward-looking statements.


BURLINGTON, Mass. & LIESTAL, Switzerland--(BUSINESS WIRE)--Santhera Pharmaceuticals, a Swiss specialty pharmaceutical company focused on the development of innovative treatments for rare mitochondrial and neuromuscular diseases, announced that it will be establishing U.S. operations in Burlington, Mass. Santhera’s U.S. operations are being led by Todd Bazemore, Chief Operating Officer of Santhera Pharmaceuticals (USA), Inc. The U.S. operations will initially be staffed to focus on regulatory and clinical operations support, medical affairs, patient advocacy liaison and commercial strategy. “A strong presence in the U.S. is an important next step in our mission to advance novel treatments for Duchenne muscular dystrophy and other rare neuromuscular and mitochondrial diseases,” said Todd Bazemore, COO of Santhera U.S. “We chose the metropolitan Boston area for our U.S. operations because it is one of the main centers for the biotech and pharma business globally with a unique confluence of academia, life science companies, and clinical expertise.” Duchenne muscular dystrophy (DMD) is one of the most common and devastating types of muscle degeneration and leads to progressive muscle weakness starting at an early age. DMD is a genetic, degenerative disease that occurs almost exclusively in males with an incidence of up to 1 in 3,500 live male births worldwide.1 DMD is characterized by a loss of the protein dystrophin, ultimately resulting in muscle weakness and wasting and early morbidity and mortality due to respiratory failure. In DMD, the progressive respiratory muscle weakness results in respiratory symptoms such as inability to cough and clear mucus, frequent airway infections, sleep-disordered breathing and the need for assisted ventilation. Addressing the progressive loss of respiratory function is a hallmark in DMD and an urgent unmet medical need for these patients. In a Phase III clinical trial (DELOS) conducted in DMD patients not taking glucocorticoids, Santhera’s lead therapeutic candidate, idebenone, demonstrated a clinically significant slowing in the loss of respiratory function, regardless of the underlying genetic mutation. Santhera is now enrolling patients in a new Phase III trial (SIDEROS) in 60 centers across the United States and Europe to confirm the efficacy of idebenone in 266 patients who are currently taking a stable dose of glucocorticoids. The first patient was enrolled at the University of Kansas Medical Center (KUMC), Department of Neurology in September with Jeffrey Statland, MD. In the U.S., the SIDEROS trial will be conducted in 24 study centers with the goal of having this trial fully enrolled by end of 2017. If successful, this study will provide data that supports the use of idebenone in all DMD patients experiencing respiratory decline irrespective of their glucocorticoid use or genetic mutation. “Idebenone is generating a significant interest among researchers, physicians and the patient community. In slowing the loss of respiratory function in all patients irrespective of their mutational status, this drug candidate has the potential to expand the current treatment paradigm for DMD,” said Thomas Meier, PhD, CEO of Santhera. “Our presence here in the U.S. will enable us to expand our engagement with physicians, their patients, and families as the SIDEROS trial moves forward while we continue our efforts to find a regulatory path for early approval.” “There is high interest from investigators and the patient community in therapies that hold the promise of maintaining respiratory function in patients with DMD,” added Oscar Henry Mayer, MD, Medical Director of the Pulmonary Function Testing Laboratory at the Children’s Hospital of Philadelphia and Lead SIDEROS Investigator for the U.S. “A patient and caregiver survey conducted by Parent Project Muscular Dystrophy clearly demonstrated that the DMD community highly values treatment options for respiratory complications.” SIDEROS is a phase III, double-blind, randomized, placebo-controlled trial with idebenone in approximately 266 DMD patients receiving concomitant glucocorticoids. Patients with declining respiratory function on any stable glucocorticoid treatment scheme and irrespective of the underlying dystrophin mutation or ambulatory status will be eligible. Study participants will receive either idebenone (900 mg/day; given as 2 tablets 3 times a day with meals) or placebo for 78 weeks (18 months). The primary endpoint of the trial is the change from baseline to week 78 in forced vital capacity % predicted (FVC%p). Secondary endpoints include changes from baseline in % predicted peak expiratory flow (PEF%p), time to first 10% decline in FVC and change from baseline in inspiratory flow reserve. Patients completing the trial will be offered the opportunity to enroll in an open label extension study in which all patients receive idebenone. The study will be conducted at about 60 centers in the United States and Europe. Patients wishing to enroll in the study should contact their neuromuscular clinic physician. Further information about the study is available under www.clinicaltrials.gov. Duchenne muscular dystrophy (DMD) is one of the most common and devastating types of muscle degeneration and results in rapidly progressive muscle weakness. DMD is characterized by a loss of the protein dystrophin, leading to cell damage, impaired calcium homeostasis, elevated oxidative stress and reduced energy production in muscle cells. This results in progressive muscle weakness and wasting and early morbidity and mortality due to respiratory failure. Idebenone is a synthetic short-chain benzoquinone and a cofactor for the enzyme NAD(P)H:quinone oxidoreductase (NQO1) capable of stimulating mitochondrial electron transport, reducing and scavenging reactive oxygen species (ROS) and supplementing cellular energy levels. DELOS was a phase III, double-blind, placebo-controlled trial which randomized 64 patients, not taking concomitant glucocorticoids, to receive either idebenone (900 mg/day) or matching placebo. The trial met its primary endpoint and demonstrated that idebenone can slow the loss of respiratory function and reduces bronchopulmonary complications. The statistically significant and clinically relevant outcomes of the phase III DELOS study were published: Buyse et al., The Lancet 2015, 385:1748-1757; McDonald et al., Neuromuscular Disorders 2016, 26: 473–480 and Buyse et al., Pediatric Pulmonology 2016: http://dx.doi.org/10.1002/ppul.23547. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) and the Swiss regulatory authorities Swissmedic are currently assessing a Marketing Authorization Application (MAA) for idebenone under the name RAXONE® in DMD patients with respiratory function decline who are not taking concomitant glucocorticoids. The indication would include patients who previously were treated with glucocorticoids or in whom glucocorticoid treatment is not desired, not tolerated or is contraindicated. Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative pharmaceutical products for the treatment of orphan mitochondrial and neuromuscular diseases. Santhera's lead product RAXONE® (idebenone) is authorized in the European Union, Norway, Iceland and Liechtenstein for the treatment of Leber's hereditary optic neuropathy (LHON). For Duchenne muscular dystrophy (DMD), the second indication for RAXONE®, Santhera has filed a Marketing Authorization Application (MAA) in the European Union and Switzerland. In collaboration with the U.S. National Institute of Neurological Disorders and Stroke (NINDS) Santhera is developing RAXONE® in a third indication, primary progressive multiple sclerosis (PPMS), and omigapil for congenital muscular dystrophy (CMD), all areas of high unmet medical need. For further information, please visit the Company's website www.santhera.com. This communication does not constitute an offer or invitation to subscribe for or purchase any securities of Santhera Pharmaceuticals Holding AG. This publication may contain certain forward looking statements concerning the Company and its business. Such statements involve certain risks, uncertainties and other factors which could cause the actual results, financial condition, performance or achievements of the Company to be materially different from those expressed or implied by such statements. These statements could be affected by, among other things, risks and factors referred to in the Risk Factors section on Santhera’s web site (http://www.santhera.com/investors-and-media/investor-toolbox/risk-factors). Readers should therefore not place undue reliance on these statements, particularly not in connection with any contract or investment decision. The Company disclaims any obligation to update these forward-looking statements. 1 National Institutes of Health, U.S. National Library of Medicine, Genetics Home Reference, Duchenne and Becker muscular dystrophy, https://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy#statistics


Meier T.,Santhera Pharmaceuticals Holding | Perlman S.L.,University of California at Los Angeles | Rummey C.,Santhera Pharmaceuticals Holding | Coppard N.J.,Santhera Pharmaceuticals Holding | Lynch D.R.,Children's Hospital of Philadelphia
Journal of Neurology | Year: 2012

The aim of this study was to investigate the efficacy of idebenone on neurological function as assessed by ICARS and FARS neurological rating scales in pediatric Friedreich's ataxia (FRDA) patients. Sixty-eight pediatric patients were enrolled in an open-label extension study (IONIA-E) where patients received idebenone (Catena ®, 150 mg film-coated tablets) at a weight-adjusted dose of 1,350/2,250 mg/day for 12 months after patients had completed a double-blind, randomized, placebo-controlled study (IONIA) receiving either idebenone at a weight-adjusted dose of 450/900 or 1,350/2,250 mg/day or placebo for 6 months. Changes in ICARS and FARS total scores and subscores were recorded for the 12-month IONIA-E study and for the 18-month combined IONIA and IONIA-E study period. Data analyzed by a mixed-model repeated-measures ANCOVA relative to baseline resulted in least square means for the change in ICARS for the IONIA-E study of +0.98 points (SEM 0.73; p = 0.180), indicating a trend for worsening. However, combined with the IONIA study the change was -1.03 ± 0.68 points (p = 0.132), indicating a trend for improvement in neurological function over the 18-month period. Importantly, patients who received idebenone 1,350/2,250 mg/day over this period significantly improved in neurological function (change in ICARS: -3.02 ± 1.22, p = 0.014). The improvement in neurological function over time was best seen when the posture and stance subscore was excluded from the analysis. Comparable data were obtained with the FARS. The findings of the open-label IONIA-E study combined with the double-blind IONIA study indicate that idebenone at a dose of 1,350/2,250 mg/day may offer a therapeutic benefit to pediatric FRDA patients by stabilizing the overall neurological function and improving fine motor skills and speech. © 2011 Springer-Verlag.


Lynch D.R.,Children's Hospital of Philadelphia | Perlman S.L.,University of California at Los Angeles | Meier T.,Santhera Pharmaceuticals Holding
Archives of Neurology | Year: 2010

Objective: To assess the efficacy of idebenone on neurological function in patients with Friedreich ataxia. Design: Randomized, double-blind, placebocontrolled intervention trial. Setting: Children's Hospital of Philadelphia and the University of California at Los Angeles. Participants: Seventy ambulatory pediatric patients (age, 8-18 years) with a baseline International Cooperative Ataxia Rating Scale (ICARS) score of 10 to 54. Interventions: Participants were randomized into 1 of 3 treatment arms: 450 or 900 mg of idebenone per day (in those with a body weight ≤ or >45 kg, respectively; n=22); 1350 or 2250 mg of idebenone per day (n=24); or placebo (n=24). Main Outcome Measures: Mean change from baseline to week 24 in ICARS score was the primary efficacy variable. Mean change in Friedreich Ataxia Rating Scale (FARS) score, performance measures, and activities of daily living were the secondary efficacy variables. Results: Patients who received idebenone improved by 2.5 points on mean ICARS score compared with baseline, while patients in the placebo group improved by 1.3 points. Patients who took idebenone also improved by 1.6 points on the FARS, while patients taking placebo declined by 0.6 points. For both end points, the difference between the idebenone and placebo groups was not statistically different. Conclusions: Idebenone did not significantly alter neurological function in Friedreich ataxia during the 6-month study. Larger studies of longer duration may be needed to assess the therapeutic potential of drug candidates on neurological function in Friedreich ataxia. Trial Registration: clinicaltrials.gov Identifier: NCT00537680. ©2010 American Medical Association. All rights reserved.


Buyse G.M.,University Hospitals Leuven | Goemans N.,University Hospitals Leuven | Van Den Hauwe M.,University Hospitals Leuven | Meier T.,Santhera Pharmaceuticals Holding
Pediatric Pulmonology | Year: 2013

In Duchenne muscular dystrophy (DMD) progressive weakness of respiratory muscles leads to a restrictive pulmonary syndrome that contributes to early morbidity and mortality. Currently no curative treatment exists for DMD. In a Phase II randomized placebo-controlled study (DELPHI) in 21 DMD boys at age 8-16 years, idebenone (450 mg/d) showed trends of efficacy for cardiac and respiratory endpoints. Since the DELPHI study population comprised both glucocorticoid-naïve subjects and glucocorticoid-users, we now report a post-hoc analysis investigating the effects of glucocorticoids and idebenone on markers of respiratory weakness, particularly peak expiratory flow (PEF) percent predicted (PEF%p). Baseline values of PEF%p correlated well with the percent predicted values for maximal inspiratory mouth pressure (MIP%p), forced vital capacity (FVC%p), and forced expired volume in 1 sec (FEV1%p). Baseline PEF%p and FVC%p were significantly higher in patients on concomitant glucocorticoids compared to glucocorticoid-naïve patients. In the latter subgroup, idebenone caused a 8.0 ± 12.1% improvement in PEF%p, whilst patients on placebo declined by -12.3 ± 17.9% (P < 0.05) in the course of the 12 month study. In patients receiving concomitant glucocorticoids, PEF%p remained stable (-0.4 ± 14.6%) in the idebenone group compared to a decline by -6.2 ± 12.4% (P = 0.24) in the placebo group. Idebenone showed a trend for efficacy on FVC%p only in glucocorticoid-naïve patients. Because of the study limitations, these data are exploratory and preclude any firm conclusions. In conclusion, PEF appears to be a sensitive respiratory function parameter that could be a valid and clinically relevant endpoint in intervention studies in DMD. In DELPHI the effect size of idebenone on PEF%p was significantly larger in steroid-naive patients, possibly indicating a maximum treatment effect reached by steroids or steroid-mediated suppression of idebenone's effects. The impact of standard care glucocorticoids on respiratory function will have to be considered in the planning of future interventional trials in DMD. Pediatr Pulmonol. 2013; 48:912-920. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.


Meinen S.,University of Basel | Lin S.,University of Basel | Thurnherr R.,University of Basel | Erb M.,Santhera Pharmaceuticals Holding | And 2 more authors.
EMBO Molecular Medicine | Year: 2011

Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin ('mini-agrin') or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients. © 2011 EMBO Molecular Medicine.


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