progress in the treatment of cardiac amyloidosis€¦ · progress in the treatment of cardiac...
TRANSCRIPT
![Page 1: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/1.jpg)
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
![Page 2: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/2.jpg)
Disclosures
• Alnylam Pharmaceuticals – Research Grant (Revusiran)
• Pfizer Pharmaceuticals – Research Grant (Tafamidis)
![Page 3: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/3.jpg)
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
![Page 4: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/4.jpg)
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
![Page 5: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/5.jpg)
Therapeutic Targets for Amyloidosis
![Page 6: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/6.jpg)
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
![Page 7: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/7.jpg)
Ackermann et al; Amyloid 2012, 19, 43-44.
Transthyretin levels for the single-dose cohorts in the ISIS-TTRRx Phase 1 Study.
![Page 8: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/8.jpg)
Effect of Revusiran on Serum TTR
![Page 9: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/9.jpg)
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)
![Page 10: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/10.jpg)
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
![Page 11: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/11.jpg)
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.
![Page 12: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/12.jpg)
Diflunisal
• Cautions: • Renal dysfunction
• Fluid retention and worsening of HF
• Gastrointestinal bleeding
![Page 13: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/13.jpg)
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
![Page 14: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/14.jpg)
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)
![Page 15: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/15.jpg)
Future Trials: AG10 – TTR Stabilizer
Penchala et al. PNAS 2013
![Page 16: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/16.jpg)
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
![Page 17: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/17.jpg)
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
![Page 18: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/18.jpg)
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.
![Page 19: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/19.jpg)
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
![Page 20: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/20.jpg)
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
![Page 21: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/21.jpg)
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
![Page 22: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/22.jpg)
Clinical and Biomarker Progression of TTR Cardiac Amyloidosis
22 Castaño, A., Drachman, B.M., Judge, D. et al. Heart Fail Rev (2015) 20: 163.
![Page 23: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/23.jpg)
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
![Page 24: Progress in the Treatment of Cardiac Amyloidosis€¦ · Progress in the Treatment of Cardiac Amyloidosis Jignesh Patel MD PhD FACC FRCP Director, Cardiac Amyloid Program Medical](https://reader035.vdocuments.net/reader035/viewer/2022062414/5eaab60dcf033e36a0793d34/html5/thumbnails/24.jpg)