Angela Genge, MD, FRCP(C)

Angela Genge, MD, FRCP(C) 1 When aTTR gets on your nerves: A primer on ATTR neurological involvement for Cardiologists Disclosures•Consulting services for the following companies: Mitsubishi Tenabe Pharma America, Sanofi Genzyme, AL-S Pharma, AB Sciences, Biogen, Novartis, CSL Behring, Anavex, Avexis, Alexion, Wave life sciences, Revalesio, Roche, Cytokinetics, Orion, Akcea, Clene and Bayshore•Participates as CRU medical director, PI or sub-PI on trials sponsored by the following companies: AB Sciences, AL-S Pharma, Acceleron, Amicus, Alnylam, Bioblast, Biogen, BMS, Boston Biomedical, Cytokinetics, Sanofi Genzyme, Grifols, Ionis, Lily, Mallinckrodt, Medimmune, Novartis, Orion, Orphazyme, Pfizer, Ra Pharmaceuticals, Roche, Teva, UCB, The Science of Antisense: Targeting RNA, Not Proteins •Antisense technology prevents the production of proteins involved in disease–This results in a therapeutic improvement to patients–Potential to treat patients with a wide range of serious rare genetic diseases•Typically, DNA is transcribed into messenger RNA (mRNA) and then translated into protein•Antisense technology binds to mRNA causing it to degrade. With no mRNA to translate, there is no protein product 16 Less RNA = Less PROTEINMore RNA = More PROTEIN RNA ANTISENSE DRUG TRANSCRIPTION Gene mRNAProtein(e.g. Transthyretin) Inotersen in investigational and not approved Inotersen (AKCEA-TTRRx)An Antisense Approach to Treat TTR-related Amyloid Diseases •Inotersen binds to TTR messenger RNA (mRNA) reducing the amount of disease causing TTR protein–Binds to TTR mRNA and all known mutations–Results in degradation of TTR mRNA and reduction of TTR protein production by the liver 7 TTR Protein TTR mRNA DNA Inotersen Inotersen, a Generation 2.0+ Antisense Oligonucleotide (ASO) Phase 1 StudyNormal Subjects(Complete) NEURO-TTRPhase 3 Study -International(Complete)Open-Label Extension Study(Ongoing) Expected FDA decision Q4 , 2018 Inotersen in investigational and not approved