2/13/2020 Disclosures I have nothing to disclose New ALS diagnostics and Treatment Prevalence and Impact on Patients and Caregivers Catherine Lomen-Hoerth, MD, PhD Professor of Clinical Neurology, UCSF Recent Advances in Neurology 2020 1 2 Overview of ALS in 2020 Steps in the Management Case for making an earlier diagnosis Making the diagnosis and breaking the news Importance and ethics of genetic testing Starting treatments that slow the disease process (Riluzole, Edaravone, TUDCA) Designer gene therapies Managing respiratory insufficiency Update on biomarkers Managing dysphagia / preventing malnutrition New clinical trial approaches Treating symptoms that reduce quality of life Latest news on stem cell therapy AAN Practice Guidelines Neurology 1999;52:1311; 2009; 73: 1227-1239 3 4 1
2/13/2020 Treatable symptoms in ALS Clinical Features of ALS • Upper motor neuron findings • Slow speech • Brisk gag and jaw jerk, brisk limb reflexes • Spasticity • Lower motor neuron findings • Atrophy • Fasciculations • weakness Mayo Clin Proc. 2018 Nov;93(11):1617-1628. 5 6 El Escorial Criteria to diagnose ALS ALS-Mimic Syndromes Radiculopathies UMN degeneration by clinical exam CNS disorders (Stroke, Brain tumor, Parkinson’s disease, MS) LMN degeneration by clinical exam or EMG Post-poliomyelitis syndrome Progressive spread of signs within a region or into other spinal or brainstem regions Multifocal motor neuropathy Endocrinopathies Absence of evidence of other diseases by EMG or imaging to hyperparathyroidism and hyperthyroidism explain the findings Lead intoxication Infections Lyme disease and HIV/AIDS Paraneoplastic syndromes - lymphoma, MGUS 7 8 2
2/13/2020 ALS is Heterogeneous Benefits of an earlier ALS diagnosis The diagnosis is clinical and a process of exclusion Ability to take newly approved ALS therapies Patients vary in: Option to participate in clinical trials Rate of progression Regions affected during the disease course Access to multidisciplinary care Family history of degenerative disease Connection to ALS satellite clinics and telemedicine Accurate categorization of patients into clinical categories is of utmost importance in facilitating research into targeted therapies Quicker genetic testing A key aspect of disease heterogeneity is cognitive-behavioral CONSIDER REFERRAL TO AN ALS CENTER FOR involvement including frontotemporal dementia ALL CASES OF PROGRESSIVE WEAKNESS OF UNCLEAR ETIOLOGY 9 10 New potential ALS therapy Free genetic testing and counseling ALS GAP provides clinical genetics services to pALS who are under the care of a registered NEALS clinician https://www.neals.org/als-trials/news/als-gap-update Eur J Neurol. 2016 Jan;23(1):45-52. 11 12 3
2/13/2020 Designer DNA therapy for ALS ALS biomarker update Antisense oligonucleotide therapies for familial ALS Viral therapies such as designed for SMA Gene therapy studies targeting sporadic ALS https://www.frontiersin.org/articles/10.3389/f Curr Opin Neurol. 2018 Oct;31(5):648-654. neur.2019.00291/full 13 14 Potential biomarkers for ALS New ALS clinical trial guidelines Revised Airlie House consensus Neurophysiological-MUNE/MUNIX/EIM/TMS guidelines for design and implementation Neuroimaging-DTI, fMRI, VBM, iron sensitive sequences of ALS clinical trials. Serum creatinine van den Berg LH 1 , Sorenson E 2 , Gronseth G 2 , Macklin EA 2 , Andrews J 2 , Uric acid level Baloh RH 2 , Benatar M 2 , Berry JD 2 , Chio A 2 , Corcia P 2 , Genge A 2 , Gubitz AK 2 , Lomen-Hoerth C 2 , McDermott CJ 2 , Pioro EP 2 , Rosenfeld J 2 , Silani Urinary extracellular cleavage domain of neurotrophin receptor P75 V 2 , Turner MR 2 , Weber M 2 , Brooks BR 2 , Miller RG 2 , Mitsumoto H 2 ; Airlie House ALS Clinical Trials Guidelines Group. CSF and plasma light and heavy chain neurofilament proteins Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS. Goyal NA, Berry JD, Windebank A, Staff NP, Maragakis NJ, van den Berg LH, Neurology. 2019 Apr 2;92(14):e1610-e1623. Genge A, Miller R, Baloh RH, Kern R, Gothelf Y, Lebovits C, Cudkowicz M. Muscle Nerve. 2020 Jan 3. 15 16 4
2/13/2020 New ALS clinical trial guidelines Changes in clinical trial design Preclinical studies Biomarkers Biological and Clinical trial phases phenotypic Beyond traditional trial heterogeneity designs Outcome measures Statistical Disease modifying considerations and symptomatic interventions Recruitment and retention Neurology. 2019 Apr 2;92(14):e1610- Park, J.J.H., Siden, E., Zoratti, M.J. et al. Systematic review of basket trials, umbrella trials, and platform trials: e1623. a landscape analysis of master protocols. Trials 20, 572 (2019). 17 18 Changes in clinical trial design First platform trial for ALS starting now ALS has the largest drug pipeline of any neuromuscular disease Over 130 companies currently focusing on ALS Need to accelerate trials for patients with ALS “I lost the privilege of working on the human time clock on January 6, Park, J.J.H., Siden, E., Zoratti, M.J. et al. Systematic review of basket trials, 2018 – the ALS clock is a lot faster” Sandy – Person with ALS umbrella trials, and platform trials: a landscape analysis of master protocols. Trials 20, 572 (2019). 19 20 5
2/13/2020 First five ALS platform trial drugs Primary endpoint: ALSFRS-R Zilucoplan Speech Turning in bed and Complement C5 inhibitor adjusting clothes Salivation Verdiperstat Walking Myeloperoxidase inhibitor Swallowing Climbing Stairs CNM-Au8 Handwriting Gold nanocrystals Dyspnea Cutting food and Pridopidine handling utensils Orthopnea Sigma 1 receptor agonist Dressing and hygiene Respiratory IC14 Insufficiency Immunotherapy targeting CD14 21 22 Stem cell update Effect of NurOwn stem cell therapy on ALSFRS-R NurOwn, phase 2 results promising Cells are modified and put back into the spinal fluid with no adverse events Results suggest there may be small reductions in the rate of disease Phase 3 trial results expected Fall 2020 NurOwn , phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results. Berry JD, Cudkowicz ME, Windebank AJ, Staff NP, Owegi M, Nicholson K, McKenna-Yasek D, Levy YS, Abramov N, Kaspi H, Mehra M, Aricha R, Gothelf Y , Brown RH. Neurology. 2019 Dec 10;93(24):e2294-e2305. 23 24 6
2/13/2020 Caution about certain alternative Right to try and expanded access therapies for ALS Expensive stem cell options in the US and other countries Need pharma approval to provide the drug Excessive supplement use FDA and IRB approval (accelerated for ALS<2 weeks) Detoxification programs Unusual diets Need funding Taking clinical trial medications off label Provides a way to provide people not eligible for clinical trials to obtain drug http://alsuntangled.com/ 25 26 Robotics and Communication trials Ethical and practical considerations Brain control of robotics and communication system Pre-symptomatic genetic testing (BRAVO) study (UCSF) Access to newly approved therapies Brain Gate 2: Feasibility Study of an Intracortical Neural Decisions about which therapies for which patients Interface System for Persons with Tetraplegia (Stanford) Management of ALS patients living longer 27 28 7
2/13/2020 SUMMARY Early referral to an ALS Center is critical in cases of progressive weakness of unclear etiology Genetic testing is key for the new designer gene therapy trials Biomarkers are helping predict prognosis and aid in diagnosis The new platform design for ALS clinical trials allows more patients to receive active drug and ensures rapid testing of multiple drugs Stem cells show promise in slowing ALS disease progression Robotics and enhanced communication options are in trials now 29 8
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