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2017 ANNUAL REPORT | Translating SCIENCE • Transforming LIVES OUR COMMITMENT Make Every Day Count at PTC, Patients Are at the Center of Everything We Do
20 YEARS OF COMMITMENT 2017 ANNUAL REPORT | Translating SCIENCE • Transforming LIVES OUR COMMITMENT Make every day count At PTC, patients are at the center of everything we do. We have the opportunity to support patients and families living with rare disorders through their journey. We know that every day matters and we are committed to making a difference. OUR SCIENCE Our scientists are finding new ways to regulate biology to control disease We have several scientific research platforms focused on modulating protein expression within the cell that we believe have the potential to address many rare genetic disorders. OUR PEOPLE Care for each other, our community, and for the needs of our patients At PTC, we are looking at drug discovery and development in a whole new light, bringing new technologies and approaches to developing medicines for patients living with rare disorders and cancer. We strive every day to be better than we were the day before. At PTC Therapeutics, it is our mission to provide access to best-in-class treatments for patients who have an unmet need. We are a science-led, global biopharmaceutical company focused on the discovery, development and commercialization of clinically-differentiated medicines that provide benefits to patients with rare disorders. Founded 20 years ago, PTC Therapeutics has successfully launched two rare disorder products and has a global commercial footprint. This success is the foundation that drives investment in a robust pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need. As we celebrate our 20th year of bringing innovative therapies to patients affected by rare disorders, we reflect on our unwavering commitment to our patients, our science and our employees. -
Duchenne Muscular Dystrophy (DMD) Agents
Therapeutic Class Overview Duchenne muscular dystrophy (DMD) Agents INTRODUCTION • Duchenne muscular dystrophy (DMD) is 1 of 4 conditions known as dystrophinopathies, which are inherited, X-linked myopathic disorders due to a defect in the dystrophin gene that results in the primary pathologic process of muscle fiber degradation. The hallmark symptom is progressive weakness (Darras 2018[a], Darras 2018[b], Muscular Dystrophy Association [MDA] 2019). The other 3 conditions include: Becker muscular dystrophy (BMD), which is a mild form of DMD; an intermediate presentation between BMD and DMD; and DMD-associated dilated cardiomyopathy, which has little or no clinical ○ skeletal or muscle disease (MDA 2019). • DMD symptom onset is in early childhood, usually between the ages of 2 and 3 years old. The proximal muscles are affected first, followed by the distal limb muscles. Generally, the lower external muscles will be affected before the upper. The affected child may have difficulties jumping, walking, and running (MDA 2019). • The prevalence of DMD ranges from 1 to 2 per 10,000 live male births; female-manifesting carriers are rarer, but can present with a range of symptoms that vary in their severities (Birnkrant et al 2018, Darras 2018[a], Emflaza Food and Drug Administration [FDA] Medical Review 2017). • The clinical course and lifespan of patients with DMD is relatively short. Individuals are usually confined to a wheelchair by age 13, and many die in their late teens or twenties from respiratory insufficiency or cardiomyopathy. Although survival until adulthood is more common now, very few patients survive past the 3rd decade (Darras 2018[a]). -
Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New
biomolecules Review Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New Andrea Barp 1,* , Amanda Ferrero 1, Silvia Casagrande 1,2 , Roberta Morini 1 and Riccardo Zuccarino 1 1 NeuroMuscular Omnicentre (NeMO) Trento, Villa Rosa Hospital, Via Spolverine 84, 38057 Pergine Valsugana, Italy; [email protected] (A.F.); [email protected] (S.C.); [email protected] (R.M.); [email protected] (R.Z.) 2 Department of Neurosciences, Drug and Child Health, University of Florence, Largo Brambilla 3, 50134 Florence, Italy * Correspondence: [email protected] Abstract: The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less “time-consuming”. In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics Citation: Barp, A.; Ferrero, A.; (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss Casagrande, S.; Morini, R.; Zuccarino, the application of biochemical biomarkers (both validated and emerging) in the most common NMDs R. -
The Use of Ataluren in the Effective Management of Duchenne Muscular Dystrophy
Review Neuromuscular Diseases Early Diagnosis and Treatment – The Use of Ataluren in the Effective Management of Duchenne Muscular Dystrophy Eugenio Mercuri,1 Ros Quinlivan2 and Sylvie Tuffery-Giraud3 1. Catholic University, Rome, Italy; 2. Great Ormond Street Hospital and National Hospital for Neurology and Neurosurgery, London, UK; 3. Laboratory of Genetics of Rare Diseases (LGMR), University of Montpellier, Montpellier, France DOI: https://doi.org/10.17925/ENR.2018.13.1.31 he understanding of the natural history of Duchenne muscular dystrophy (DMD) is increasing rapidly and new treatments are emerging that have the potential to substantially improve the prognosis for patients with this disabling and life-shortening disease. For many, Thowever, there is a long delay between the appearance of symptoms and DMD diagnosis, which reduces the possibility of successful treatment. DMD results from mutations in the large dystrophin gene of which one-third are de novo mutations and two-thirds are inherited from a female carrier. Roughly 75% of mutations are large rearrangements and 25% are point mutations. Certain deletions and nonsense mutations can be treated whereas many other mutations cannot currently be treated. This emphasises the need for early genetic testing to identify the mutation, guide treatment and inform genetic counselling. Treatments for DMD include corticosteroids and more recently, ataluren has been approved in Europe, the first disease-modifying therapy for treating DMD caused by nonsense mutations. The use of ataluren in DMD is supported by positive results from phase IIb and phase III studies in which the treatment produced marked improvements in the 6-minute walk test, timed function tests such as the 10 m walk/run test and the 4-stair ascent/descent test compared with placebo. -
Mechanisms of Action of Antiepileptic Drugs
Review Mechanisms of action of antiepileptic drugs Epilepsy affects up to 1% of the general population and causes substantial disability. The management of seizures in patients with epilepsy relies heavily on antiepileptic drugs (AEDs). Phenobarbital, phenytoin, carbamazepine and valproic acid have been the primary medications used to treat epilepsy for several decades. Since 1993 several AEDs have been approved by the US FDA for use in epilepsy. The choice of the AED is based primarily on the seizure type, spectrum of clinical activity, side effect profile and patient characteristics such as age, comorbidities and concurrent medical treatments. Those AEDs with broad- spectrum activity are often found to exert an action at more than one molecular target. This article will review the proposed mechanisms of action of marketed AEDs in the US and discuss the future of AEDs in development. 1 KEYWORDS: AEDs anticonvulsant drugs antiepileptic drugs epilepsy Aaron M Cook mechanism of action seizures & Meriem K Bensalem-Owen† The therapeutic armamentarium for the treat- patients with refractory seizures. The aim of this 1UK HealthCare, 800 Rose St. H-109, ment of seizures has broadened significantly article is to discuss the past, present and future of Lexington, KY 40536-0293, USA †Author for correspondence: over the past decade [1]. Many of the newer AED pharmacology and mechanisms of action. College of Medicine, Department of anti epileptic drugs (AEDs) have clinical advan- Neurology, University of Kentucky, 800 Rose Street, Room L-455, tages over older, so-called ‘first-generation’ First-generation AEDs Lexington, KY 40536, USA AEDs in that they are more predictable in their Broadly, the mechanisms of action of AEDs can Tel.: +1 859 323 0229 Fax: +1 859 323 5943 dose–response profile and typically are associ- be categorized by their effects on the neuronal [email protected] ated with less drug–drug interactions. -
Horizon Scanning Status Report June 2019
Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the horizon scanning system has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions. A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the horizon scanning system. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions. Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflicts with the material presented in this report. Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. -
8Th European Congress on Epileptology, Berlin, Germany, 21 – 25 September 2008
Epilepsia, 50(Suppl. 4): 2–262, 2009 doi: 10.1111/j.1528-1167.2009.02063.x 8th ECE PROCEEDINGS 8th European Congress on Epileptology, Berlin, Germany, 21 – 25 September 2008 Sunday 21 September 2008 KV7 channels (KV7.1-5) are encoded by five genes (KCNQ1-5). They have been identified in the last 10–15 years by discovering the caus- 14:30 – 16:00 ative genes for three autosomal dominant diseases: cardiac arrhythmia Hall 1 (long QT syndrome, KCNQ1), congenital deafness (KCNQ1 and KCNQ4), benign familial neonatal seizures (BFNS, KCNQ2 and VALEANT PHARMACEUTICALS SATELLITE SYM- KCNQ3), and peripheral nerve hyperexcitability (PNH, KCNQ2). The fifth member of this gene family (KCNQ5) is not affected in a disease so POSIUM – NEURON-SPECIFIC M-CURRENT K+ CHAN- far. The phenotypic spectrum associated with KCNQ2 mutations is prob- NELS: A NEW TARGET IN MANAGING EPILEPSY ably broader than initially thought (i.e. not only BFNS), as patients with E. Perucca severe epilepsies and developmental delay, or with Rolando epilepsy University of Pavia, Italy have been described. With regard to the underlying molecular pathophys- iology, it has been shown that mutations in KCNQ2 and KCNQ3 Innovations in protein biology, coupled with genetic manipulations, have decrease the resulting K+ current thereby explaining the occurrence of defined the structure and function of many of the voltage- and ligand- epileptic seizures by membrane depolarization and increased neuronal gated ion channels, channel subunits, and receptors that are the underpin- firing. Very subtle changes restricted to subthreshold voltages are suffi- nings of neuronal hyperexcitability and epilepsy. Of the currently cient to cause BFNS which proves in a human disease model that this is available antiepileptic drugs (AEDs), no two act in the same way, but all the relevant voltage range for these channels to modulate the firing rate. -
For Cystic Fibrosis (Review)
Cochrane Database of Systematic Reviews Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis (Review) Aslam AA, Higgins C, Sinha IP, Southern KW Aslam AA, Higgins C, Sinha IP, Southern KW. Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD012040. DOI: 10.1002/14651858.CD012040.pub2. www.cochranelibrary.com Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER....................................... 1 ABSTRACT ...................................... 1 PLAINLANGUAGESUMMARY . 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . ..... 4 BACKGROUND .................................... 7 OBJECTIVES ..................................... 8 METHODS ...................................... 8 RESULTS....................................... 12 Figure1. ..................................... 13 Figure2. ..................................... 16 DISCUSSION ..................................... 20 AUTHORS’CONCLUSIONS . 22 ACKNOWLEDGEMENTS . 22 REFERENCES ..................................... 23 CHARACTERISTICSOFSTUDIES . 26 DATAANDANALYSES. 33 Analysis 1.1. Comparison 1 Ataluren versus placebo, Outcome 1 FEV - mean relative change from baseline. 35 Analysis 1.2. Comparison 1 -
Ataluren Stimulates Ribosomal Selection of Near-Cognate Trnas to Promote Nonsense Suppression
Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression Bijoyita Roya,b,1, Westley J. Friesenb,1, Yuki Tomizawab, John D. Leszykc, Jin Zhuob, Briana Johnsonb, Jumana Dakkab, Christopher R. Trottab, Xiaojiao Xueb,d,e, Venkateshwar Mutyame,f, Kim M. Keelingd,e, James A. Mobleyg, Steven M. Rowee,f, David M. Bedwelld,e, Ellen M. Welchb, and Allan Jacobsona,2 aDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655-0122; bPTC Therapeutics Inc., South Plainfield, NJ 07080; cDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655-0122; dDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; eGregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294; fDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and gDepartment of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294 Edited by Rachel Green, Johns Hopkins University, Baltimore, MD, and approved September 6, 2016 (received for review April 1, 2016) A premature termination codon (PTC) in the ORF of an mRNA promote therapeutic nonsense suppression (1, 3). To date, ataluren generally leads to production of a truncated polypeptide, accelerated has been shown to restore function to more than 20 different degradation of the mRNA, and depression of overall mRNA ex- disease-specific or reporter nonsense alleles in systems ranging in pression. Accordingly, nonsense mutations cause some of the most complexity from in vitro translation to cell culture to mouse models severe forms of inherited disorders. The small-molecule drug ataluren and human patients (1, 3–14). -
Ganaxolone (Epilepsy) – Forecast and Market Analysis to 2022
Ganaxolone (Epilepsy) – Forecast and Market Analysis to 2022 Reference Code: GDHC1071DFR Publication Date: February 2013 Executive Summary Epilepsy: Key Metrics in the Epilepsy Markets The below figure illustrates ganaxolone sales for the US 2022 Market Sales and 5EU during the forecast period. US $43.17m Sales for Ganaxolone by Region, 2022 5EU $4.64m Total $47.81m 10% 2012 Total: $47.81m Key Events (2012–2022) Level of Impact Launch of ganaxolone in the US in 2019 ↑↑↑ US Launch of ganaxolone in the 5EU in 2019 ↑↑↑ 5EU Source: GlobalData Sales for Ganaxolone in the Epilepsy Market GlobalData expects Marinus Pharmaceuticals to launch 90% ganaxolone in the US and EU in 2019. We estimate that 2022 sales of ganaxolone will reach $47.81m across Source: GlobalData these markets. Key factors affecting the uptake of ganaxolone will include: What Do the Physicians Think? Novel mechanism of action and good tolerability Overall physicians expressed a need for more AEDs profile and favorable opinions of those in pipeline Efficacy profile is not significantly different from that development. of other marketed anti-epileptic drugs (AEDs) “Among intractable epilepsy patients, any drug that helps Ganaxolone is still in early development; possible treat an additional segment of them will be used, and lack of funding to conduct Phase III trials necessary because we don’t have a basis for using one or another, for commercialization if it’s attractive, it will be used more.” [US] key opinion leader, November 2012 Heavy competition in the market “Brivaracetam is an interesting concept because it’s supposed to be “Super Keppra,” the follow-on from Keppra. -
Molecular Mechanisms of Antiseizure Drug Activity at GABAA Receptors
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Seizure 22 (2013) 589–600 Contents lists available at SciVerse ScienceDirect Seizure jou rnal homepage: www.elsevier.com/locate/yseiz Review Molecular mechanisms of antiseizure drug activity at GABAA receptors L. John Greenfield Jr.* Dept. of Neurology, University of Arkansas for Medical Sciences, 4301W. Markham St., Slot 500, Little Rock, AR 72205, United States A R T I C L E I N F O A B S T R A C T Article history: The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at Received 6 February 2013 GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by Received in revised form 16 April 2013 the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, Accepted 17 April 2013 actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible Keywords: antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, Inhibition led to the development of ganaxolone. Other agents modulate GABAergic ‘‘tone’’ by regulating the Epilepsy synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane Antiepileptic drugs chloride gradient, which changes during development and in chronic epilepsy. This may provide an GABA receptor Seizures additional target for ‘‘GABAergic’’ ASDs. GABAAR subunit changes occur both acutely during status Chloride channel epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs. -
Effect of Ganaxolone on Seizure Frequency Across Subpopulations of Patients with CDKL5 Deficiency Disorder: Subgroup Analyses of the Marigold Study Elia M
Effect of Ganaxolone on Seizure Frequency Across Subpopulations of Patients With CDKL5 Deficiency Disorder: Subgroup Analyses of the Marigold Study Elia M. Pestana-Knight1; Alex Aimetti2; Joseph Hulihan2 1Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA; 2Marinus Pharmaceuticals, Inc., Radnor, PA, USA Table 1. Patient Baseline Demographics, Clinical Characteristics, Baseline allopregnanolone-sulfate (Allo-S) concentration Geographic region Introduction and Enrollment Location • Preliminary data from previous open-label clinical trials of GNX in genetic pediatric epilepsies • Ganaxolone performed directionally better than placebo across geographic regions analyzed suggest that lower plasma Allo-S concentrations may predict favorable antiseizure response (Figure 6) • CDKL5 deficiency disorder (CDD) is a rare, X-linked, epileptic encephalopathy with an estimated Placebo Ganaxolone a • No correlations between baseline Allo-S and response were observed in enrolled patients with − Ganaxolone demonstrated 36.7% MMSF difference in relation to placebo in the United States incidence of 1:40,000 to 1:60,000 live births1,2 (n = 51) (n = 49) CDD (Figure 3) (95% CI, 62.8%-7.2%) • Clinical phenotype of CDD is heterogenous but often includes early-onset refractory epilepsy, Age, n (%) − Future data from other clinical indications aim to provide further insights into the potential − Ganaxolone demonstrated 29.9% MMSF difference in relation to placebo in Australia, France, hypotonia, intellectual and gross motor impairment, and sleep disturbances 2-4 15 (29.4) 21 (42.9) 5-9 17 (33.3) 15 (30.6) utility of plasma Allo-S levels to predict response Israel, Italy, and the United Kingdom (95% CI, 82.2% to −12.6%) • The Marigold Study (NCT03572933) is the first phase 3, randomized, placebo-controlled trial to 10-19 19 (37.3) 13 (26.5) − Ganaxolone demonstrated 16.9% MMSF difference in relation to placebo in Russia and Poland evaluate adjunctive investigational ganaxolone (GNX) in patients with refractory epilepsy associated Gender, n (%) Figure 3.