Transcript Slides
Clinical Trials in Pediatric Neurology Aaron S. Zelikovich Objectives • What is a Clinical Trial and why is it important? • What is Spinal Muscular Atrophy? • How does a new drug get approved by the FDA? • Why Neurology is the best field for clinical research. Objectives • What is a Clinical Trial and why is it important? • What is Spinal Muscular Atrophy? • How does a new drug get approved by the FDA? • Why Neurology is the best field for clinical research. “When I first started out in academic medicine, my interest was more on the clinical and teaching sides,” Greenland said. “But I had a mentor in cardiology who told me, ‘what the world will really remember you for is your research findings — because they get disseminated around the world.’ And I thought that was a very profound thought: the idea that you can have an influence way beyond your individual patients with your research findings.” Philip Greenland, MD https://clinicaltrials.gov/ Objectives • What is a Clinical Trial and why is it important? • What is Spinal Muscular Atrophy? • How does a new drug get approved by the FDA? • Why Neurology is the best field for clinical research. History of Spinal Muscular Atrophy • “Originally described in 2 infant brothers by Guido Werdnig in 1891 and in 7 additional cases by Johan Hoffmann from 1893 to 1900” Werdnig-Hoffman’s Disease – Today this is what we classify as Type I SMA • ”Seminal pathology as anterior horn cell degeneration as well as the pertinent clinical features of symmetrical, proximal predominant extremity weakness” • Molecular Discovery History of Spinal Muscular Atrophy • “Originally described in 2 infant brothers by Guido Werdnig in 1891 and in 7 additional cases by Johan Hoffmann from 1893 to 1900” Werdnig-Hoffman’s Disease – Today this is what we classify as Type I SMA • ”Seminal pathology as anterior horn cell degeneration as well as the pertinent clinical features of symmetrical, proximal predominant extremity weakness” • ”How can one gene defect result in such a wide range of clinical severity?” Clinical Manifestations • • • • Type I SMA Type II SMA Never have been able to sit • Able to have sat independently. independently but never Paradoxical Breathing walked. Respiratory Support • Scoliosis 1-3 years lifespan Type III SMA • Able to have walked at one point in life. Now on to the paper… Lumbar Puncture What is it normally used for? ABSTRACT (taken from publication) • “Objective: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). • Methods: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2–14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6–10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory.” Results: A total of 28 participants enrolled in the study (n 5 6 in first 3 dose cohorts; n 5 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dosedependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4–6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p 5 0.016), which was further increased 9–14 months postdose (5.8 points; p 5 0.008) during the extension study. Conclusions: Results from this study support continued development of nusinersen for treatmentof SMA. Conclusions: Results from this study support continued development of nusinersen for treatment of SMA. Phase 3 Trial and my role Sorry, couldn’t put a picture of the families & kids I worked with… Objectives • What is a Clinical Trial and why is it important? • What is Spinal Muscular Atrophy? • How does a new drug get approved by the FDA? • Why Neurology is the best field for clinical research. 21st International Congress of the World Muscle Society 4-8 October 2016 Granada, Spain Nusinersen treatment of infantile-onset spinal muscular atrophy (SMA): study design and initial interim efficacy and safety findings from the phase 3 ENDEAR study Nancy Kuntz 8 October 2016 Kuntz N,1 Farwell W,2 Zhong ZJ,2 Sun P,2 Gheuens S,2 Schneider E,3 and Finkel R4 on behalf of the ENDEAR study group Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA; 2 Biogen, Cambridge, MA, USA; 3 Ionis Pharmaceuticals Inc., Carlsbad, CA, USA; 4 Division of Neurology, Department of Pediatrics, Nemours Children’s Hospital, Orlando, FL, USA 1 Date of presentation: 8 Oct 2016 ENDEAR Interim Efficacy Analysis Resultsa • Significant improvement in the proportion (P<.0001) of nusinersen–treated motor milestone responders versus sham-procedure control - Highly clinically and statistically significant percentage of motor milestone responders • Interim analysis represents 44.89 patientyears of exposure to nusinersen treatment 13 aThe interim efficacy analysis was conducted on 15 June 2016, once ~80 participants had the opportunity to be assessed at Day 183 visit https://www.facebook.com/luriechildrens/videos/1288500951170234/ Objectives • What is a Clinical Trial and why is it important? • What is Spinal Muscular Atrophy? • How does a new drug get approved by the FDA? • Why Neurology is the best field for clinical research. Clinical Trials in Pediatric Neurology Aaron S. Zelikovich