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

Disclosures

• Alnylam Pharmaceuticals – Research Grant (Revusiran)

• Pfizer Pharmaceuticals – Research Grant (Tafamidis)

Major Amyloid Types and Causative Proteins

Amyloid Types Constituent Protein Subunits

Light chain (AL) [Primary] Immunoglobulin Light Chains

Wildtype Transthyretin (ATTRwt) [“Senile”]

Transthyretin - Wildtype

Hereditary Transthyretin (ATTRm) [FAC/FAP*]

Transthyretin with Mutation

Hereditary Apolipoprotein (AApoA1) Apolipoprotein A1 mutations

Hereditary Fibrinogen (AFib) Fibrinogen mutations

Isolated Atrial Amyloid (IAA) Atrial Natriuretic Peptide

Secondary Amyloidosis (AA) Amyloid Protein A

11/16/2017 3

*FAC = Familial Amyloid Cardiomyopathy FAP = Familial Amyloid Polyneuropathy

Geographic Distribution and Age

11/16/2017 4 Sravan C. Penchala et al. PNAS 2013;110:9992-9997

AL Cardiac Amyloidosis 2000-2500 cases/year in US

Therapeutic Targets for Amyloidosis

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

Ackermann et al; Amyloid 2012, 19, 43-44.

Transthyretin levels for the single-dose cohorts in the ISIS-TTRRx Phase 1 Study.

Effect of Revusiran on Serum TTR

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)

TTR Stabilization

Drug Mechanism

Diflunisal NSAID: Binds and stabilizes common familial variants against acid-mediated fibril formation

Epigallocatechin-gallate (EGCG) “Green Tea”

Inhibits fibril formation by directly binding to native unfolded peptides

Tafamidis Binds to thyroid-binding sites of the TTR tetramer, inhibiting dissociation into monomers. Blocks rate-limiting step in the TTR amyloidogenesis cascade

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 patients1

• 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 months2

11/16/2017 11

1 Berk et al. JAMA 2013 310:2658–67 2 Sekijima Y et al. XIVth International Symposium on Amyloidosis; OP70 Indianapolis, USA, 2014:89–90.

Diflunisal

• Cautions: • Renal dysfunction

• Fluid retention and worsening of HF

• Gastrointestinal bleeding

Tafamidis in TTR Cardiac Amyloid – Phase 2 Study

Maurer M et al. Circ HF 2015, (8); 3; 519-26

• 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)

NT-ProBNP

Trop I

Trop T

6MWT

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)

Future Trials: AG10 – TTR Stabilizer

Penchala et al. PNAS 2013

Green tea halts progression of cardiac transthyretin amyloidosis: an observational report.

Kristen AV et al. Clin Res Cardiol. 2012 Oct;101(10):805-13. Epub 2012 May 15.

N=19 Green Tea for 12 months

Fibril Degradation

Drug Mechanism

Doxycycline-TUDCA Removes already deposited amyloid

Monoclonal anti-SAP Antibodies 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

Phase I/II Study of NEOD001 in Patients With Light Chain (AL) Amyloidosis and Persistent Organ Dysfunction

Gertz MA et al. J Clin Oncol. 2016 Apr 1;34(10):1097-103.

NEOD001 Clinical Trials for Cardiac AL Amyloidosis

VITAL Study

• Primary Outcome Measures: Time to composite of all-cause mortality or cardiac hospitalization

• Planned therapy with protoeosome inhibitor

• Closed to recruitment

PRONTO Study

• Primary Outcome Measures: Cardiac best response as measured by NT-proBNP [ At 12 months ]

• Prior AL directed therapy with at least partial response

• Closed to recruitment

Survival post OHT for ATTR amyloidosis patients

ATTR amyloidosis (N=16)

SRTR restrictive cardiomyopathy (N=206)

1.0

0.75

0.50

0.25

0

Surv

ival

Time (years) 2 0 4 6

p=0.08

Semigran, M, Patel J et al. iCCAT Registry

Survival post OHT for AL amyloidosis patients

SRTR restrictive cardiomyopathy

(N=206)

AL amyloidosis (N=56)

Time (years)

Surv

ival

1.0

0.50

0.25

0

0.75

0 2 4 6

p=0.90

Semigran, M, Patel J et al. iCCAT Registry

Clinical and Biomarker Progression of TTR Cardiac Amyloidosis

22 Castaño, A., Drachman, B.M., Judge, D. et al. Heart Fail Rev (2015) 20: 163.

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