What are the attributes of amyloid (a protein)?

From the Guidelines

ATTR amyloidosis should be treated with tafamidis (Vyndaqel, 80mg daily) as the primary treatment for wild-type ATTR (wtATTR), and supportive care is essential for all patients, including heart failure management with diuretics, pain control, and nutritional support. The disease mechanism involves either mutated TTR (in hereditary cases) or normal TTR (in wild-type) becoming unstable and forming amyloid fibrils that deposit in tissues, causing progressive organ dysfunction 1. For hereditary ATTR (hATTR), liver transplantation has been the traditional approach to remove the source of mutant TTR, and newer medications include RNA-targeting therapies such as patisiran (Onpattro, 0.3mg/kg IV every 3 weeks) and inotersen (Tegsedi, 284mg subcutaneous weekly) that reduce TTR production by silencing the gene 1.

Key Considerations

• Early diagnosis is crucial as these treatments are most effective before significant organ damage occurs
• Clinical recognition and diagnosis of cardiac amyloidosis at an early stage of the disease is critical, affording an affected patient the widest array of treatment options that have a favorable impact on survival and/or prevent potentially irreversible loss of physical function and quality of life 1
• The nomenclature for systemic amyloidosis includes an “A” for amyloid followed by an abbreviation of the protein that misfolds, and the vast majority of encountered cases of amyloid CM will be caused by misfolding of 1 of 2 proteins: 1) monoclonal immunoglobulin light chain produced in bone-marrow plasma cell disorders; and 2) transthyretin (abbreviated TTR) 1

Diagnostic Approach

• Imaging techniques and monoclonal light chain testing now allow for accurate noninvasive diagnosis of ATTR-CM in the proper clinical context without the need for confirmatory endomyocardial biopsies 1
• If biopsy of surrogate site is negative, Congo red staining, identification, and assessment of the plasma cell monoclonal protein burden should be performed 1
• Mass spectrometry-based analysis (LC-MS/MS) of the biopsy is the gold standard for tissue diagnosis, with a reported sensitivity of 88% and specificity of 96% 1

From the Research

Overview of ATTR Amyloid

• ATTR amyloidosis is a progressive, life-threatening disease characterized by the aggregation and deposition of amyloidogenic misfolded transthyretin (TTR) in the myocardium 2
• The gradual accumulation of insoluble TTR amyloid fibrils can result in restrictive cardiomyopathy and heart failure 2
• Approximately 50,000 to 150,000 people in the US have heart failure due to ATTR amyloidosis, with a median survival of approximately 5 years without treatment 3

Treatment Options

• Tafamidis, a TTR stabilizer, has been approved for use in the treatment of adults with ATTR-CM in several countries 2, 4, 3, 5, 6
• Tafamidis stabilizes both wild-type and mutant TTR, inhibiting the formation of TTR amyloid fibrils 2
• Other treatment options include diflunisal, patisiran, and inotersen, although these are not always FDA-approved for ATTR amyloidosis treatment 4, 6
• Novel therapies using RNA interference, such as vutrisiran and AKCEA-TTR-LRx, are also being investigated 6
• Monoclonal antibodies, such as PRX004 and NI301A, are being tested for their ability to target misfolded ATTR 5

Clinical Considerations

• Treatment selection is based on subtype and presence of cardiac or neurological manifestations 6
• Side effects, monitoring, and administration are important considerations when selecting a treatment 6
• The small ATTR-CM patient population raises several challenges for clinical development 4
• Despite these challenges, several drug candidates are in the clinical development pipeline, offering hope for improved treatment options 4, 5