Progress in the Treatment of Cardiac Amyloidosis

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1 Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical Director, Heart Transplant Program Clinical Professor Cedars-Sinai Heart Institute, Los Angeles, CA

2 Disclosures Alnylam Pharmaceuticals Research Grant (Revusiran) Pfizer Pharmaceuticals Research Grant (Tafamidis)

3 Major Amyloid Types and Causative Proteins Amyloid Types Light chain (AL) [Primary] Wildtype Transthyretin (ATTRwt) [ Senile ] Hereditary Transthyretin (ATTRm) [FAC/FAP*] Hereditary Apolipoprotein (AApoA1) Hereditary Fibrinogen (AFib) Isolated Atrial Amyloid (IAA) Secondary Amyloidosis (AA) Constituent Protein Subunits Immunoglobulin Light Chains Transthyretin - Wildtype Transthyretin with Mutation Apolipoprotein A1 mutations Fibrinogen mutations Atrial Natriuretic Peptide Amyloid Protein A *FAC = Familial Amyloid Cardiomyopathy FAP = Familial Amyloid Polyneuropathy 11/16/2017 3

4 Geographic Distribution and Age AL Cardiac Amyloidosis cases/year in US 11/16/2017 Sravan C. Penchala et al. PNAS 2013;110:

5 Therapeutic Targets for Amyloidosis

6 Suppression of TTR Drug Class Mechanism Antisense Oligonucleotides (ASO) Suppresses hepatic TTR mrna and serum TTR levels Small Interfering RNA (sirna) sirna bound to RNA-induced silencing complex (RISC) mediates cleavage of target mrna

7 Transthyretin levels for the single-dose cohorts in the ISIS-TTR Rx Phase 1 Study. Ackermann et al; Amyloid 2012, 19,

8 Effect of Revusiran on Serum TTR

9 ENDEAVOUR Study - Revusiran Study halted by Data Monitoring Committee: Deaths 17 revusiran 2 placebo (2:1 randomization) Majority due to HF Worsening neuropathy reported in Phase 2 follow up Development of Revusiran Discontinued (GalNAC conjugation) Patisiran (IV) studies ongoing for Familial Amyloid Polyneuropathy (FAP) (Lipid nanoparticle)

10 TTR Stabilization Drug Diflunisal Epigallocatechin-gallate (EGCG) Green Tea Tafamidis Mechanism NSAID: Binds and stabilizes common familial variants against acid-mediated fibril formation Inhibits fibril formation by directly binding to native unfolded peptides Binds to thyroid-binding sites of the TTR tetramer, inhibiting dissociation into monomers. Blocks rate-limiting step in the TTR amyloidogenesis cascade

11 Diflunisal Non-steroidal Anti-inflammatory (NSAID) Non-selective stabilizer of TTR tetramer Randomized, placebo-controlled study in FAP showed significant reduction in rate of neurological deterioration and improvement in quality of life in diflunisal treated patients 1 Japanese observational study in FAP reported sustained effects of diflunisal on both neurological and cardiac function, observing no deterioration in cardiac wall thickness or EF at 24 months 2 11/16/ Berk et al. JAMA : Sekijima Y et al. XIVth International Symposium on Amyloidosis; OP70 Indianapolis, USA, 2014:89 90.

12 Diflunisal Cautions: Renal dysfunction Fluid retention and worsening of HF Gastrointestinal bleeding

13 Tafamidis in TTR Cardiac Amyloid Phase 2 Study NT-ProBNP 6MWT Trop I Trop T Tafamidis treatment maintained TTR stabilization (98%) and was well tolerated. The absence of significant changes in most biochemical and echocardiographic parameters 20/28 preserved NYHA Class 15/31 further clinical events (CHF, AF, syncope) Maurer M et al. Circ HF 2015, (8); 3;

14 Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy (ATTR-ACT) Phase 3 Primary Outcome Measures (30 months): All-cause mortality and frequency of cardiovascular-related hospitalization Enrollment: 400 Estimated Primary Completion Date: February 20, 2018 (Final data collection date for primary outcome measure)

15 Future Trials: AG10 TTR Stabilizer Penchala et al. PNAS 2013

16 Green tea halts progression of cardiac transthyretin amyloidosis: an observational report. N=19 Green Tea for 12 months Kristen AV et al. Clin Res Cardiol Oct;101(10): Epub 2012 May 15.

17 Fibril Degradation Drug Doxycycline-TUDCA Monoclonal anti-sap Antibodies Mechanism Removes already deposited amyloid Ab against a normal non-fibrillary glycoprotein SAP promotes a giant cell reaction that removes visceral amyloid deposits TUDCA Taursodeoxycholic Acid SAP Serum Amyloid P

18 Phase I/II Study of NEOD001 in Patients With Light Chain (AL) Amyloidosis and Persistent Organ Dysfunction Gertz MA et al. J Clin Oncol Apr 1;34(10):

19 NEOD001 Clinical Trials for Cardiac AL Amyloidosis PRONTO Study Primary Outcome Measures: Cardiac best response as measured by NTproBNP [ At 12 months ] Prior AL directed therapy with at least partial response Closed to recruitment VITAL Study Primary Outcome Measures: Time to composite of all-cause mortality or cardiac hospitalization Planned therapy with protoeosome inhibitor Closed to recruitment

20 Survival Survival post OHT for ATTR amyloidosis patients SRTR restrictive cardiomyopathy (N=206) 0.50 ATTR amyloidosis (N=16) 0.25 p= Time (years) Semigran, M, Patel J et al. iccat Registry

21 Survival Survival post OHT for AL amyloidosis patients SRTR restrictive cardiomyopathy (N=206) 0.50 AL amyloidosis (N=56) 0.25 p= Time (years) Semigran, M, Patel J et al. iccat Registry

22 Clinical and Biomarker Progression of TTR Cardiac Amyloidosis Castaño, A., Drachman, B.M., Judge, D. et al. Heart Fail Rev (2015) 20:

23 Summary The development of drugs for the treatment of amyloidosis has focused on specific targets Despite a variety of agents with potential therapeutic efficacy, progress in the cardiac arena has been slow. There is optimism for effective therapies in the future given the multitude of targets and therapies in the pipeline Development is restricted by costs in view of the limited market for a spectrum of orphan diseases Efficacy of treatment may depend upon early diagnosis

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