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
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