DOCSLIB.ORG

A Phase 3, Double-Blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Phase 3, Double-Blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia CLINICAL TRIALS SECTION EDITOR: IRA SHOULSON, MD A Phase 3, Double-blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia David R. Lynch, MD, PhD; Susan L. Perlman, MD; Thomas Meier, PhD Objective: To assess the efficacy of idebenone on neu- (FARS) score, performance measures, and activities of rological function in patients with Friedreich ataxia. daily living were the secondary efficacy variables. Design: Randomized, double-blind, placebo- Results: Patients who received idebenone improved by controlled intervention trial. 2.5 points on mean ICARS score compared with base- line, while patients in the placebo group improved by 1.3 Setting: Children’s Hospital of Philadelphia and the Uni- points. Patients who took idebenone also improved by versity of California at Los Angeles. 1.6 points on the FARS, while patients taking placebo de- clined by 0.6 points. For both end points, the difference Participants: Seventy ambulatory pediatric patients (age, between the idebenone and placebo groups was not sta- 8-18 years) with a baseline International Cooperative tistically different. Ataxia Rating Scale (ICARS) score of 10 to 54. Conclusions: Idebenone did not significantly alter neu- Interventions: Participants were randomized into 1 of rological function in Friedreich ataxia during the 6-month 3 treatment arms: 450 or 900 mg of idebenone per day study. Larger studies of longer duration may be needed (in those with a body weight Յ or Ͼ45 kg, respectively; to assess the therapeutic potential of drug candidates on n=22); 1350 or 2250 mg of idebenone per day (n=24); neurological function in Friedreich ataxia. or placebo (n=24). Trial Registration: clinicaltrials.gov Identifier: Main Outcome Measures: Mean change from base- NCT00537680 line to week 24 in ICARS score was the primary efficacy variable. Mean change in Friedreich Ataxia Rating Scale Arch Neurol. 2010;67(8):941-947 RIEDREICH ATAXIA IS AN AU- the mitochondrial electron transport chain, tosomal recessive degenera- increasing the production of adenosine tri- tive disorder characterized by phosphate.8 In Friedreich ataxia, idebe- ataxia, areflexia, sensory loss, none may decrease cardiac hypertrophy and weakness, scoliosis, and car- improve cardiac function, with beneficial ef- diomyopathy. Diabetes mellitus, optic neu- fects observed at dose levels of 5 mg/kg per F 1,2 9-13 ropathy, and hearing loss are also seen. day. Data on neurological effects at this Most patients with Friedreich ataxia (97%) dose level are inconsistent.9-13 A 6-month, have expansions of a GAA repeat in the first double-blind, placebo-controlled phase 2 intron on both alleles of the gene encoding clinical trial (National Institutes of Health the mitochondrial protein frataxin,2,3 whose [NIH] Collaboration With Santhera in 4 Author Affiliations: expression is reduced in Friedreich ataxia. Ataxia [NICOSIA]) using higher doses of Departments of Neurology The size of the GAA-repeat expansion in- idebenone showed evidence of dose- and Pediatrics, University versely correlates with frataxin expression dependent improvement in secondary of Pennsylvania School and age at disease onset.3 Deficiency of fra- neurological end points compared with pla- of Medicine, and The Children’s taxin in cells leads to decreased activities of cebo.14 This was best noted on the Interna- Hospital of Philadelphia, iron-sulfur cluster–containing enzymes, ac- tional Cooperative Ataxia Rating Scale Philadelphia (Dr Lynch); cumulation of iron in the mitochondrial ma- (ICARS), with a similar pattern observed for Department of Neurology, trix, increased sensitivity to oxidative stress, the Activities of Daily Living and neuro- David Geffen School and impaired adenosine triphosphate pro- logical scales of the Friedreich’s Ataxia Rat- of Medicine, University 5-7 of California at Los Angeles, duction. ing Scale (FARS). Neurological improve- Los Angeles (Dr Perlman); and Idebenone, a synthetic analogue of co- ment was especially evident in ambulatory Santhera Pharmaceuticals, enzyme Q10, has potent antioxidant activ- patients with ICARS scores of 10 to 54 at Liestal, Switzerland (Dr Meier). ity and facilitates the flux of electrons along baseline. The trend to improvement was (REPRINTED) ARCH NEUROL / VOL 67 (NO. 8), AUG 2010 WWW.ARCHNEUROL.COM 941 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 vided as prepackaged kits marked with the appropriate treat- ment number. Group A received idebenone (150-mg idebe- 74 Screened 4 Excluded none tablets, Catena, Santhera Pharmaceuticals) at 450 mg per 3 ICARS score > 54 day (if Յ45-kg body weight at baseline) or 900 mg per day (if 1 Elevated liver Ͼ45-kg body weight at baseline); group B received idebenone function test result Յ Ͼ 70 Randomized at 1350 mg per day (if 45 kg) or 2250 mg per day (if 45 kg); and group C received placebo. These dosages correspond Center 1 Center 2 to doses in the range of approximately 10 to 20 mg/kg per day 12 Received placebo 12 Received placebo 11 Received 450 or 900 11 Received 450 or 900 (group A) and approximately 30 to 54 mg/kg per day (group mg/d of idebenone Allocation mg/d of idebenone B) for patients weighing 25 to 80 kg within each dose group. 12 Received 1350 or 2250 12 Received 1350 or 2250 The drug was administered in 3 divided doses with meals. mg/d of idebenone mg/d of idebenone 35 Completed treatment Follow-up 35 Completed treatment STUDY CONDUCT 35 Analyzed Analysis 35 Analyzed Within 8 weeks prior to randomization (at the baseline visit), pa- tients attended a screening visit where informed consent/assent was obtained and inclusion/exclusion criteria were assessed. They Figure 1. Participant flow diagram. ICARS indicates International underwent a physical and neurological examination, including Cooperative Ataxia Rating Scale. an assessment of vital signs and electrocardiography, and a preg- nancy test for female patients of childbearing potential. Thereaf- only evident at idebenone doses approximately 3- to 10- ter, neurological efficacy assessments were undertaken at base- fold higher than the previously used daily 5-mg/kg dose. line (day 1) and weeks 12 and 24 (end of therapy). Safety The present study, Idebenone Effects on Neurological assessments were performed at weeks 4, 12, 24, and 28 (follow- ICARS Assessments (IONIA), is a double-blind, random- up); no follow-up visit was undertaken in patients who enrolled ized, placebo-controlled intervention trial of 6 months’ du- into the open-label extension. Patients maintained a diary, with daily documentation of study medication intake and recording ration evaluating the safety and efficacy on neurological of adverse events and concomitant medications. function of idebenone in ambulatory pediatric patients with Friedreich ataxia. OUTCOME MEASURES AND OBJECTIVES METHODS The primary objective was to compare the efficacy of 24 weeks’ treatment with 2 different doses of idebenone with that of pla- STUDY DESIGN cebo on neurological impairment as assessed by the ICARS. Sec- ondary measures included the neurological examination of the The study was a double-blind, randomized, placebo- FARS; the Friedreich’s Ataxia Composite Test (FACT-Z3), de- controlled, parallel-group study investigating the safety, toler- rived from the Timed 25-Foot Walk test, the 9-hole peg test, ability, and efficacy of idebenone in the treatment of patients and the low-contrast letter acuity test; and the activities of daily with Friedreich ataxia conducted at 2 centers: Children’s Hos- living scale.15-18 pital of Philadelphia and the University of California at Los An- geles. Inclusion criteria included a diagnosis of Friedreich ataxia STATISTICAL ANALYSIS with confirmed GAA-expansion mutations (patients having point mutations were not eligible); age older than 7 and younger than The primary and secondary efficacy analyses were conducted 18 years at baseline evaluation; body weight above 25 kg; and in the intent-to-treat population, including all randomized pa- ability to walk at least 10 m without an accompanying person tients. The patients were analyzed as randomized regardless of (ICARS Walking Capacities score Յ6). Patients were ex- protocol deviations. The last observation carried forward method cluded if they had an ICARS score greater than 54 or less than was applied to impute missing data. Safety analysis included 10 at screening; were pregnant or breastfeeding; had clinically all randomized patients who received at least 1 dose of the trial significant abnormalities of hematology or biochemistry; or had medication and for whom safety assessments were available. participated in the previous phase 2 trial of idebenone.14 Pa- Unless specified, efficacy analyses for each group receiving tients being treated at screening with antioxidants (vitamin E, idebenone were compared against the placebo group using pair- coenzyme Q, and idebenone purchased from noncontrolled wise comparison based on an analysis of covariance model, with sources) were required to have a 1-month washout of these treatment as a factor and baseline value as a covariate testing a agents before the baseline visit. 2-sided alternative at a Bonferroni-adjusted ␣ level of 2.5%. With a minimum of 15 evaluable patients in each of the groups, an RANDOMIZATION anticipated effect size (difference between placebo and idebe- none) of more than 6.2 ICARS points, and a common SD of Of 74 patients who were screened, 4 did not qualify for enroll- 5.0 points, the study would provide 85% power to reject the ment (3 patients had ICARS scores Ͼ54 and 1 patient had an null hypothesis of no difference between any idebenone dose abnormal liver function test result) (Figure 1). Seventy pa- and placebo with regard to the change from baseline to week tients were randomized 1:1:1 to 1 of 3 treatment arms using a 24 in ICARS using a pairwise comparison test. This effect size central block randomization scheme. A list of randomization is based on results from subgroup analysis of NICOSIA14 and numbers and corresponding treatment numbers was com- is greater than the expected yearly decline in ICARS score for puter generated by a third party (Fischer Services, Allschwil, patients with Friedrich ataxia.
Load more

Recommended publications
  • Study Protocol
    EspeRare_RIM_001 Rimeporide in DMD patients Page 1 of 85 Clinical Study Protocol Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending oral doses of Rimeporide in patients with Duchenne Muscular Dystrophy Acronym: Rim4DMD Sponsor: EspeRare Foundation 14 Chemin des Aulx 1228 Plan-les-Ouates Switzerland Study Sponsor’s number: ESPERARE_RIM_001 EudraCT number: 2015-002530-50 Version: 2.1 Date: February 19th, 2016 Amendment number: 2 This document is a confidential communication of EspeRare. Acceptance of this document constitutes the agreement by the recipient that no unpublished information contained within will be published or disclosed without prior written approval, except as required to permit review by responsible Ethics Committees and Health Authorities or to obtain informed consent from potential patients. EudraCT Number 2015-002530-50 CONFIDENTIAL [Rim4DMD] – Final Version 2.1_ February 19th, 2016 EspeRare_RIM_001 Rimeporide in DMD patients Page 2 of 85 Investigator Agreement Protocol Number: EspeRare_RIM_001 EudraCT Number: 2015-002530-50 Protocol version and date: 2.1._ February 19th 2016 Sponsor: EspeRare Foundation Study drug: Rimeporide. Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending oral doses of rimeporide in patients with Duchenne Muscular Dystrophy. Acronym: Rim4DMD. Investigator endorsement: I, the undersigned, am responsible for the conduct of this study at this site and agree to conduct the study according to the protocol and any approved protocol amendments, study specific procedures, all applicable laws and regulatory authority requirements including but not limited to European directives, ICH Good Clinical Practice (GCP), the Ethical principles that have their origins in the Declaration of Helsinki and applicable privacy laws.
    [Show full text]
  • Idebenone Protects Against Acute Murine Colitis Via Antioxidant and Anti-Inflammatory Mechanisms
    International Journal of Molecular Sciences Article Idebenone Protects against Acute Murine Colitis via Antioxidant and Anti-Inflammatory Mechanisms Sonia Shastri 1,*, Tanvi Shinde 1,2 , Sukhwinder Singh Sohal 1, Nuri Gueven 3 and Rajaraman Eri 1,* 1 Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania 7250, Australia; [email protected] (T.S.); [email protected] (S.S.S.) 2 Centre for Food Safety and Innovation, Tasmanian Institute of Agriculture, University of Tasmania, Launceston, Tasmania 7250, Australia 3 Pharmacy, School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7005, Australia; [email protected] * Correspondence: [email protected] (S.S.); [email protected] (R.E.); Tel.: +61-4-4992-4236 (S.S.); +61-3-6226-5017 (R.E.) Received: 3 December 2019; Accepted: 9 January 2020; Published: 12 January 2020 Abstract: Oxidative stress is a key player of the inflammatory cascade responsible for the initiation of ulcerative colitis (UC). Although the short chain quinone idebenone is considered a potent antioxidant and a mitochondrial electron donor, emerging evidence suggests that idebenone also displays anti-inflammatory activity. This study evaluated the impact of idebenone in the widely used dextran sodium sulphate (DSS)-induced mouse model of acute colitis. Acute colitis was induced in C57BL/6J mice via continuous exposure to 2.5% DSS over 7 days. Idebenone was co-administered orally at a dose of 200 mg/kg body weight. Idebenone significantly prevented body weight loss and improved the disease activity index (DAI), colon length, and histopathological score.
    [Show full text]
  • Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy
    nanomaterials Review Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy Lucia Montenegro 1,* ID , Rita Turnaturi 2 ID , Carmela Parenti 3 and Lorella Pasquinucci 2 ID 1 Department of Drug Sciences, Pharmaceutical Technology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy 2 Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; [email protected] (R.T.); [email protected] (L.P.) 3 Department of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-095-738-4010 Received: 31 December 2017; Accepted: 30 January 2018; Published: 5 February 2018 Abstract: The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE’s unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro-emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification.
    [Show full text]
  • 213026Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213026Orig1s000 CLINICAL REVIEW(S) Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping CLINICAL REVIEW Application Type NME, original NDA Application Number(s) NDA 213,026 (IND 118,086) Priority or Standard Priority Submit Date(s) 1/10/20 (submission 1 [clinical, nonclinical]) 6/25/20 (submission 2 [quality, complete NDA]) Received Date(s) 1/10/20; 6/25/20 PDUFA Goal Date 2/25/21 Division/Office DN1 / ON / OND / CDER Reviewer Name(s) David Hosford, ; Xiang Ling (Biometrics); Thomas Biel, Ashutosh Rao (Office of Biotechnology Products [OBP]) Review Completion Date 2/15/21 Established/Proper Name Casimersen (Proposed) Trade Name Amondys 45 Applicant Sarepta Therapeutics, Inc. (Cambridge, MA) Dosage Form(s) concentrated solution in a single use-vial for IV infusion Applicant Proposed Dosing 30mg/kg weekly Regimen(s) Applicant Proposed For the treatment of Duchenne muscular dystrophy (DMD) in Indication(s)/Population(s) patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping Recommendation on Accelerated Approval Regulatory Action Recommended For the treatment of Duchenne muscular dystrophy (DMD) in Indication(s)/Population(s) patients who have a confirmed mutation of the DMD gene that (if applicable) is amenable to exon 45 skipping 1 Reference ID: 4751845 Clinical Review David Hosford, Xiang Ling, Thomas Biel, Ashutosh Rao NDA 213,026: casimersen for DMD amenable to exon 45 skipping Table of Contents Glossary ........................................................................................................................................11 1. Executive Summary...............................................................................................................14 1.1. Product Introduction......................................................................................................14 1.2.
    [Show full text]
  • Duchenne Clinical Trials Enrolling Or Soon to Be Enrolling
    Since 2001, Jett Foundation has met the needs of the Duchenne muscular dystrophy community. While we were founded out of one family’s desperate need to save their son, we have transformed dramatically. Once a non-profit dedicated to raising money for biomedical research, today we are meeting our families and young people where they are with direct service and educational programs that improve and enrich the lives of individuals impacted by Duchenne. We empower patients and families with the knowledge needed to be their own best advocates, spread awareness about Duchenne, and help accelerate research and development. We believe for Duchenne patients, education equals survival. Please use this sheet only as an outline when learning about potiential clinical trial options for you, your child, or your patient. DUCHENNE CLINICAL TRIALS ENROLLING OR SOON TO BE ENROLLING STUDY NAME & SPONSOR STUDY DESCRIPTION AGE CRITERIA AMBULATION METHOD STEROIDS RECRUITMENT WVE-210201 Phase 1 Clinical Trial -Exon-skipping 51 ≥ 5 and ≤ 18 years *Both Infusion Yes Enrolling (US) (WVE-DMDX51-001) -Phase 1 [Wave Life Sciences] -Double-blind, placebo controlled, single ascending dose Study of SRP-4045 and SRP-4053 in DMD Patients -Exon-skipping 45 and 53 ≥ 7 and ≤ 13 years Ambulatory Infusion Yes Enrolling (US) (ESSENCE) - NCT02500381 -Phase III [Sarepta Therapeutics, Inc.] -Double-blind, placebo-controlled Safety Study of Eteplirsen to Treat Early Stage -Exon-skipping 51 EXONDYS 51 ≥ 4 and ≤ 6 years Ambulatory Infusion Enrolling (US) Duchenne - NCT02420379 -Phase
    [Show full text]
  • Leber Hereditary Optic Neuropathy: Review of Treatment and Management
    MINI REVIEW published: 26 May 2021 doi: 10.3389/fneur.2021.651639 Leber Hereditary Optic Neuropathy: Review of Treatment and Management Rabih Hage* and Catherine Vignal-Clermont Neuro-ophthalmology Department, Hôpital Fondation Rothschild, Paris, France Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease that specifically targets the retinal ganglion cells by reducing their ability to produce enough energy to sustain. The mutations of the mitochondrial DNA that cause LHON are silent until an unknown trigger causes bilateral central visual scotoma. After the onset of loss of vision, most patients experience progressive worsening within the following months. Few of them regain some vision after a period of ∼1 year. Management of LHON patients has been focused on understanding the triggers of the disease and its pathophysiology to prevent the onset of visual loss in a carrier. Medical treatment is recommended once visual loss has started in at least one eye. Research evaluated drugs that are thought to be able to restore the mitochondrial electron transport chain of Edited by: Nitza Goldenberg-Cohen, the retinal ganglion cells. Significant advances were made in evaluating free radical cell Technion Israel Institute of scavengers and gene therapy as potential treatments for LHON. Although encouraging Technology, Israel the results of clinical trial have been mixed in stopping the worsening of visual loss. In Reviewed by: patients with chronic disease of over 1 year, efficient treatment that restores vision is yet to Marcela Votruba, Cardiff University, United Kingdom be discovered. In this review, we summarize the management strategies for patients with Marko Hawlina, LHON before, during, and after the loss of vision, explain the rationale and effectiveness University of Ljubljana, Slovenia of previous and current treatments, and report findings about emerging treatments.
    [Show full text]
  • Coenzyme Q10 and Idebenone Use in Friedreichs Ataxia
    • JOURNAL OF NEUROCHEMISTRY | 2013 | 126 (Suppl. 1) | 125–141 doi: 10.1111/jnc.12322 REVIEW Co-enzyme Q10 and idebenone use in Friedreich’s ataxia Michael H Parkinson,* Jorg€ B. Schulz† and Paola Giunti* *Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK †Department of Neurology, University Medical Centre, Aachen, Germany Abstract clinical trials have assessed the efficacy of antioxidant agents Friedreich’s ataxia is a debilitating progressive neurodegen- in this disease. This article reviews trials of the two most erative disease associated with cardiomyopathy and other important agents, namely co-enzyme Q10 and idebenone. features. The underlying cause is a deficiency of the mito- Keywords: clinical trials, co-enzyme Q10, Friedreich’s ataxia, chondrial protein frataxin which causes mitochondrial iron idebenone. deposition, increased oxidative stress and impaired adenosine J. Neurochem. (2013) 126 (Suppl. 1), 125–141. triphosphate production. Over the last 15 years, multiple Friedreich’s ataxia (FRDA) is a rare autosomal recessive increased oxidative stress (Schulz et al. 2000; Emond et al. degenerative disease usually of early onset which causes 2000; Piemonte et al. 2001), and impaired ATP production progressive neurological and non-neurological features. (Lodi et al. 1999). Individuals with FRDA have deficient Initial symptoms are typically gait ataxia and imbalance activity of the iron–sulfur cluster-containing subunits of but can progress to include impaired upper and lower limb mitochondrial electron transport complexes I, II, and III as coordination, dysarthria, dysphagia, eye movement abnor- well as aconitase, particularly in cardiac tissue (Rotig€ et al. malities, areflexia, sensory loss, and muscle weakness. 1997; Bradley et al.
    [Show full text]
  • ANNUAL REPORT 2017 Mission & Vision
    ANNUAL REPORT 2017 Mission & vision MISSION VISION At EspeRare, we address the translational A world in which patient representatives, gap in paediatric rare diseases by uncovering scientists, pharmaceutical experts and the potential of existing therapeutic inter- health authorities come together to address ventions to tackle unmet life-threatening the medical needs of children affected by medical needs. rare diseases, ultimately alleviating the healthcare burden of their conditions. As a non-profit organisation, we achieve this through a collaborative approach cen- tred on patient engagement with the aim of providing patients universal access to these therapies. Picture of EspeRare founders : Florence Porte-Thomé, Caroline Kant-Mareda & Béatrice Greco 2 EspeRare | Annual Report 2017 Message from the Co-founder and Chief Executive Officer 4 2017 highlights 6 Addressing rare diseases 8 Advancing rare disease treaments 10 The translational gap, a major roadblock for new treatments 12 Our alternative business model 14 Building our portfolio 16 Duchenne Muscular Dystrophy (DMD) 18 Rimeporide Programme 20 Focal Segmental Glomerulosclerosis (FSGS) 22 EspoiR-003 Programme 23 X-Linked Hypohidrotic Ectodemal Dysplasia (XLHED) 24 EspoiR-004 Programme 25 Congenital Heart Defects (CHD) 26 FloWatch Programme 27 Organisation 28 Financial view 34 How can I support EspeRare? 42 Established in Switzerland in 2013, EspeRare is a new nonprofit foundation with global reach, focused on accelerating the development of treatments for underserved patients affected with rare diseases. EspeRare | Annual Report 2017 3 Message from the Co-founder and Chief Executive Officer EspeRare was launched at the Inter- national Rare Diseases Research Consortium first Congress in Dublin in April 2013.
    [Show full text]
  • Treatment Strategies for Inherited Optic Neuropathies: Past, Present and Future
    OPEN Eye (2014) 28, 521–537 & 2014 Macmillan Publishers Limited All rights reserved 0950-222X/14 www.nature.com/eye P Yu-Wai-Man1,2,3,4, M Votruba5,6, AT Moore3,4 Treatment strategies REVIEW and PF Chinnery1,2 for inherited optic neuropathies: past, present and future Abstract Bilateral visual loss secondary to inherited Introduction optic neuropathies is an important cause of Hereditary optic nerve disorders result in registrable blindness among children and significant chronic visual morbidity, and the young adults. The two prototypal disorders minimum prevalence of affected individuals in seen in clinical practice are Leber hereditary the population has been estimated at 1 in 10 000.1 1Wellcome Trust Centre for optic neuropathy (LHON) and autosomal Leber hereditary optic neuropathy (LHON) and Mitochondrial Research, dominant optic atrophy (DOA). About 90% autosomal dominant optic atrophy (DOA) are Institute of Genetic of LHON cases are due to one of three Medicine, Newcastle the two classical paradigms for this group of mitochondrial DNA (mtDNA) point muta- University, Newcastle upon disorders, and they account for most of the tions: m.3460G4A, m.11778G4A, and Tyne, UK inherited optic atrophy cases seen in clinical m.14484T4C, which affect critical complex I practice. LHON is caused by mitochondrial 2Departments of Neurology subunits of the mitochondrial respiratory DNA (mtDNA) point mutations, whereas, in and Ophthalmology, Royal chain. The majority of patients with DOA DOA, the majority of cases are due to pathogenic Victoria Infirmary, Newcastle harbour pathogenic mutations within upon Tyne, UK mutations in the OPA1 gene, which codes for an OPA1, a nuclear gene that codes for a multi- 1,2 inner mitochondrial membrane protein.
    [Show full text]
  • 211970Orig1s000 CLINICAL REVIEW(S)
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211970Orig1s000 CLINICAL REVIEW(S) Office of Drug Evaluation-I: Decisional Memo Date August 19, 2019 From Ellis F. Unger, MD Director Office of Drug Evaluation-I Office of New Drugs Center for Drug Evaluation and Research (CDER) Subject Office Director Decisional Memo New Drug Application (NDA) # 211970 Applicant Name Sarepta Therapeutics Date of Submission December 19, 2018 PDUFA Goal Date August 19, 2019 Proprietary Name/ Vyondys 53 Established (USAN) Name Golodirsen intravenous solution Dosage Forms/Strengths 100 mg/2mL solution in a single-use vial 30 mg/kg administered weekly as IV infusion over 35-60 minutes Indication originally sought by Treatment of Duchenne muscular dystrophy (DMD) in applicant (see page 29 for final) pediatric and adult patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Action: Complete response Material Reviewed/Consulted - Action Package, including: Regulatory Project Manager Yuet (Fannie) Choy Medical Officer/Clinical Christopher Breder Bilal AbuAsal, Hobart Rogers, Atul Bhattaram, Christian Clinical Pharmacology/Pharmacometrics Grimstein, Sabarinath Sreedharan, Ramana Uppoor Biometrics (Statistical) Xiang Ling Nonclinical (Pharmacology Toxicology) Barbara Wilcox, Lois Freed, Paul Brown Office of Biotechnology Products Ashutosh Rao, Amy Rosenberg Rohit Tiwari, Su Tran, Rao Kambhampati, Wendy Wilson- Office of New Drug Quality Assessment Lee, Erin Kim, Nallaperumal Chidambaram, Jennifer Patro, Jesse Wells,
    [Show full text]
  • Prospects for Pharmacological Intervention in Alzheimer Disease
    NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Prospects for Pharmacological Intervention in Alzheimer Disease Ge´rard Emilien, PhD; Konrad Beyreuther, PhD; Colin L. Masters, MD; Jean-Marie Maloteaux, MD, PhD lzheimer disease (AD) involves neuronal degeneration with impaired cholinergic trans- mission in the cerebral cortex and hippocampus in areas of the brain particularly as- sociated with memory and higher intellectual functioning. Other neurotransmitter defi- cits also occur, but the mechanisms underlying the widespread impairment of synaptic Afunctions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves ap- proaches to retarding, halting, or preventing the formation or accumulation of b-amyloid (Ab) plaques. Estrogen is believed to have antioxidant or other anti-Ab effects, as hormonal replace- ment therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Ab deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Ab drugs will work in the trans- genic models of AD is eagerly awaited with the expectation that they will eventually prove suc- cessful in humans.
    [Show full text]
  • Molecular Effects of Olecular Effects of Idebenone Idebenone
    MMMolecularMolecular Effects of Idebenone Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Roman Hans Haefeli aus Wetzikon, ZH Winterthur, 2012 Molecular Effects of Idebenone 1 Table of Content Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Markus Rüegg PD Dr. Thomas Meier PD Dr. Dirk Fischer Basel, den 20. September 2011 Prof. Dr. Martin Spiess Dekan 2 Molecular Effects of Idebenone Table of Contents Table of Contents Table of Contents .................................................................................................................................................................................................. 3 1 Abstract ................................................................................................................................................................................................... 7 2 Introduction .......................................................................................................................................................................................... 9 2.1 Mitochondria-Related Diseases ............................................................................................................................................... 9 2.1.1 Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Syndrome (MELAS) ................. 10 2.1.2 Leber’s Hereditary Optic Neuropathy (LHON) .........................................................................................................
    [Show full text]