Amyloidosis
William R. Mikesell, PharmD
Objectives:
• Describe the pathophysiology of amyloidosis
• Summarize differences between AL
amyloidosis and ATTR amyloidosis
• Understand treatment mechanisms and their
respective place in therapy
• Recognize treatment differences between
patients with HFrEF and patients with HFrEF
complications due to amyloidosis
• Interpret a patient case and provide a
treatment option
1
Definition: Amyloidosis
Amyloidosis are proteins with an abnormal shape
• They stick together
• Causing them to setting in tissues
The accumulation of the pathologic
Amyloids in a variety of tissues
damaging them
Amyloidosis can be characterized by
• Systemic
• Primary - amyloidosis = main problem
• Secondary - Another disease
• Localized (one organ)
1
Systemic Amyloidosis
When these deposits sit in the heart:
• Stiffens the heart walls
• Restrictive Cardiomyopathy
• Ventricles can no longer fill with as much blood
• This can lead to congestive heart failure over time
• Amyloids can also interfere with the electrical
conduction of the heart
• Causing arrhythmias
• Leading to heart failure
1
Localized Amyloidosis
Familial Amyloid Cardiomyopathy
• Mutant Transthyretin protein misfolds
• Rest in the heart causing restrictive
cardiomyopathy
Senile Cardiac Amyloidosis
• Normal amyloids gradually deposit in the heart
2
AL Amyloidosis
Pathophysiology:
• Bone marrow is responsible for making plasma cells
developing a specific part of the protein called light chains
• In AL amyloidosis, amyloid fibrils are made from abnormal
light chains produced by plasma cells.
• Also known as primary or light chain amyloidosis
Treatment:
• Daratumumab is the first and only FDA approved therapy
3
Daratumumab (Darzalex)
Mechanism of Action:
• Human immunoglobulin monoclonal antibody targeting CD38 which is uniformly
expressed on clonal plasma cells
Dosing:
• Cycles 1 + 2: (each cycle = 4 weeks)
• 16 mg/kg once weekly for 8 doses
• Cycles 2 - 6: (each cycle = 4 weeks)
• 16 mg/kg once every 2 weeks for 8 doses
• Cycle 7 and beyond:
• 16 mg/kg once every 4 weeks for up to 24 months
Administration:
• Premedicate with a corticosteroid, APAP, and antihistamine 1-3 hours before IV
infusion.
• Need a low protein-binding polyethersulfone filter (0.22 or 0.2 micrometer)
Adverse Effects:
• GI: constipation, decreased appetite, N/V/D
• Hematologic: anemia, lymphocytopenia, thrombocytopenia, neutropenia
• Neuro/skeletal: fatigue, headache, arthralgia, back pain
• Respiratory: cough, dyspnea, URTI
• Misc: Injection site reaction
Pricing:
• 100 mg/5 mL and 400 mg/20 mL = $160.56
4
Daratumumab (Darzalex)
Complete Hematologic Response:
• (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval
[CI], 2.1 to 4.1; P<0.001).
Survival free from major organ deterioration or hematologic
progression:
• Favored the daratumumab group (hazard ratio for major organ
deterioration, hematologic progression, or death, 0.58; 95% CI,
0.36 to 0.93; P=0.02).
At 6 months, more cardiac and renal responses occurred in the
daratumumab group than in the control group (41.5% vs. 22.2% and
53.0% vs. 23.9%, respectively).
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Treatment of Heart Failure AL
Cornerstone of therapy
• Diuretics - Relieves congestion
• Loop Diuretics
• Mineralocorticoid receptor antagonist
Orthostatic hypotension is commonly
encountered due to autonomic dysfunction
• Midodrine - maintain blood pressure
RAAS antagonist and Beta-Blockers are poorly
tolerated
2
ATTR Amyloidosis
Pathophysiology
•Transthyretin (TTR) is a protein normally present in everyone
that carries other proteins in the blood (Vitamin A, thyroid
hormone).
• TTR is made up of 4 components.
• In ATTR the tetramer becomes unstable and breaks down
into single parts (monomers).
• Monomers will deposit into other organs
2
ATTR Subgroups
Wild-Type (ATTR-wt)
• Commonly seen in men over the age of 70
• Aging=related protein misfolding and ATTR deposition
• Cause is not known but is not considered hereditary
• Characterized by a greater left ventricular wall thickness, a
more substantial reduction in ejection fraction, and a higher
degree of longitudinal strain
Variant (ATTR-v)
• Primary cause is familial amyloid cardiomyopathy
• Age of onset 30 - 80 years of age
• The most common mutation in the United States is the ATTR
V122I variant
2
ATTR Amyloidosis
ATTR pharmacological treatment includes both
TTR silencers and stabilizers
2
Treatment
ATTR-wt
• Tafamidis
• Diflunisal
ATTR-v
• Cardiomyopathy
• Tafamidis
• Diflunisal
• Cardiomyopathy + Neuropathy
• Eplontersen (Wainua)
• Vutrisiran (Amvuttra)
• Tafamidis
• Diflunisal
• Neuropathy
• Vutrisiran (Amvuttra)
• Eplontersen (Wainua)
• Diflunisal
3
Tafamidis (Vyndamax, Vyndaqel)
Mechanism of Action
• TTR stabilizer that selectively binds to TTR at the thyroxine binding
site and stabilized the tetramer of the TTR transport protein,
slowing dispersing into monomers which is the rate-limiting step in
the amyloidogenic process.
Tafamidis meglumine
• Dose: 20 mg to equal 80 mg dose
• 4 capsules by mouth once daily
• Administration: Swallow capsules whole, do not crush or open
• ADE: diarrhea, UTI, vaginal infections, GI
• $225,000 per year
• $208.72 per tab (x4)
Tafamidis free salt
• Dose: 61 mg by mouth once daily
• Administration: Swallow capsules whole, do not crush or open
• ADE: Unknown
• Cost: $225,000 per year
• $834.85 per tab
5
Tafamidis
33% reduction in overall mortality
• NNT = 7 patients to prevent one
death over 2.5 years
32% reduction rate of
hospitalization with tafamidis
compared to placebo
• NNT = 4 patients to prevent 1
hospitalization per year
5
Tafamidis
3
Eplontersen (Wainua)
Mechanism of Action:
• Ligand-conjugated antisense oligonucleotide
which decreases the amount of TTR protein
that is made, which slows disease progression
and improves neuropathy and the patient's
quality of life.
Dose:
• 45 mg SubQ once monthly
Adverse Effects:
• Vitamin A deficiency, atrioventricular block,
vomiting, proteinuria, injection site reaction
Price:
• $463,500 per year
• $38,625 per injection
3
Vutrisiran (Amvuttra)
Mechanism of Action:
• Double-stranded small interfering ribonucleic
acid (siRNA)-N-acetylgalactosamine conjugate
that causes degradation of mutant and
wild-type TTR messenger RNA
Dosing:
• 25 mg SubQ every 3 months
Adverse Effects:
• Arthralgia, limb pain, atrioventricular block,
vitamin A deficiency, antibody development,
injection site reactions
Price:
• $143,221.20 per injection
2
Treatment of Heart Failure: ATTR
Cornerstone of therapy
• Diuretics
• Loop diuretics
• Mineralocorticoid receptor antagonist
RAAS antagonist are better tolerated
ATTR amyloidosis usually have isolated heart
involvement
• Suitable candidates for heart transplants
Patient Case:
Louis Gara is a 75 year old male who comes into the
HF clinic for a follow up on his medications. He states
his BP was really low when he started the metoprolol
succinate 25 mg. He also complains of pain, tingling
and numbness in his hands and feet.
PMH: HFrEF, HLD, PAD, COPD.
Current medications: atorvastatin 40 mg, enalapril 2.5 mg, empagliflozin
10 mg, furosemide 40 mg, metoprolol succinate 25 mg, spironolactone
25 mg, Anoro 62.5 mcg/25 mcg, albuterol 90 mcg.
Labs: HR: 132 BPM BP: 83/48 mmHg TTR Mutation: Positive
ProBNP: 453 LVEF: 25 - 30% SCr: 0.8
What should we do for Louis?
References
1. Desai R, Xiao Y, Gillespie S. Amyloidosis | osmosis. Osmosis.
https://www.osmosis.org/learn/amyloidosis. Published 2023. Accessed
January 16, 2024.
2. Shams P, Ahmed I. Cardiac Amyloidosis. [Updated 2023 Jul 30]. In:
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
Available from: https://www.ncbi.nlm.nih.gov/books/NBK580521/
3. Multiple Drug Entries. Lexi-Drugs. Lexi-Comp Online. Lexicomp, Inc. Hudson,
OH. Available at: http://online.lexi.com/crlonline. Accessed January 17th,
2024
4. Teng C, Li P, Bae JY, Pan S, Dixon RAF, Liu Q. Diagnosis and treatment of
transthyretin-related amyloidosis cardiomyopathy. Clin Cardiol. 2020
Nov;43(11):1223-1231. doi: 10.1002/clc.23434. Epub 2020 Jul 29. PMID:
32725834; PMCID: PMC7661658.
5. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for
Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med.
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