New Treatments for Cardiac Amyloidosis Emerging, but Timely Diagnosis Remains Essential to Improving Outcomes

This Clinician’s View is written by Marcos Hazday, MD, FACC, Director of the Hypertrophic Cardiomyopathy Program at AdventHealth Orlando.

Transthyretin amyloid cardiomyopathy (ATTR-CM), also called cardiac amyloidosis, is a progressive and serious condition where the transthyretin (TTR) protein misfolds and builds up in the heart muscle and its surrounding tissues, causing them to stiffen and weaken. Left untreated, it can lead to heart failure and other cardiac complications. Once considered rare, ATTR-CM is more common than originally thought due to its underdiagnosis.

At AdventHealth, we established a multidisciplinary Center for Amyloidosis in 2023 to improve identification and timely treatment of patients suffering from this too often missed disease. Since then, we’ve experienced seismic changes in the treatment of ATTR-CM thanks to the completion of landmark research studies that resulted in approval of new therapies with many others still in the pipeline.

Differentiation of Cardiac Amyloidosis Type Critical to Accurate Diagnosis and Correct Treatment
Approximately 50,000 to 150,000 people in the U.S. have systemic amyloidosis. The overwhelming majority of cardiac amyloidosis cases result from misfolded light-chain amyloidosis (AL) and transthyretin protein amyloidosis (ATTR). It is critical to exclude the diagnosis of AL with a serum free light chain assay and immunofixation electrophoresis as this constitutes a hematological emergency. ATTR can be caused by genetic mutations in the TTR protein (hereditary/hATTR-CM) or more commonly, by instability of the TTR protein that can occur with age (wild-type/wtATTR-CM).

Novel Approaches to Treating ATTR-CM – Stabilizers, Silencers and Depleters
The best treatment approach for ATTR-CM depends on the specific type (hereditary vs. wild-type), the extent of heart involvement and the patient’s overall health. Therapeutics focus on either reducing the production of the misfolded TTR protein (stabilizers and silencers) or removing the existing amyloid deposits (depleters). Stabilizers and silencers are now the standard of care while most current research is focused on depleters. I will break down each class below, including the most common therapies in use or under development.

TTR Stabilizers for Cardiomyopathy – Tafimidas, Acoramidis and Diflunisal
The two primary treatments in this category – tafamidis and acoramidis – bind to the TTR tetramer and prevent the formation of amyloid by inhibiting disassociation or by increasing structural stability. Diflunisal, a nonsteroidal anti-inflammatory drug, can also stabilize the TTR tetramer, helping to halt disease progression.

In 2019, the U.S. Food and Drug Administration (FDA) approved tafamidis meglumine (VYNDAQEL®) and tafamidis (VYNDAMAX®) as the first disease-modifying therapy for use in adults with either hereditary or wild-type cardiac ATTR. The drug was found to significantly reduce disease progression and mortality.

Acoramidis (Attruby™) was approved by the FDA in November 2024 after clinical trials demonstrated it to be effective in reducing mortality and hospitalization rates in patients with ATTR-CM. It was also approved for both cardiomyopathy of wild-type and variant (hereditary) transthyretin-mediated amyloidosis.

TTR Silencer for Cardiomyopathy – Vutrisiran
Transthyretin silencers reduce production of TTR in the liver by preventing transcription of its messenger RNA (mRNA) through either small interfering RNA agents, anti-sense oligonucleotides, or gene editing.

In 2018, the FDA approved inotersen (TEGSEDI™) and patisiran (ONPATTRO®) for hereditary nerve-involved ATTR (polyneuropathy amyloidosis/hATTR-PN) in adults after clinical trials demonstrated their effectiveness in reducing neuropathy impairment. However, studies did not demonstrate improvement in cardiomyopathy and as a result, these two drugs were not approved for that use.

Another silencer medication, vutrisiran (AMVUTTRA®), was initially approved by the FDA in 2022 for hATTR-PN in adults. However, that approval has since been expanded to include both heriditary and wild-type TTR cardiomyopathy. Administered by subcutaneous injection, it is an RNA interference (RNAi) therapeutic. The HELIOS-B trial evaluated vutrisiran for ATTR-CM and found it reduced all-cause mortality, cardiovascular events, hospitalizations and urgent heart failure visits while preserving functional capacity and quality of life. Additional patient follow-up through 42 months was published in May 2025 in the Journal of the American College of Cardiology, and the data were consistent with the primary trial results.

Researchers have also been exploring CRISPR-Cas9 gene editing therapies, including one called NTLA-2001. It was designed to edit TTR in hepatocytes, which silences the protein. While Phase I clinical trial data found NTLA-2001 to be effective and a Phase III trial is actively enrolling, the therapy is cost prohibitive for most patients.

TTR Depleters in Development
The therapies in this class aim to remove existing amyloid deposits rather than just slowing their formation. The hope is that this approach could even reverse organ damage. It is an intense area of research right now with many investigative agents using immunotherapy, especially monoclonal antibodies. Here are a few that are currently being explored for ATTR-CM:

• ALXN2220 (formerly NI006) — This is an investigational humanized anti-ATTR antibody that was designed to deplete cardiac amyloid deposits by engaging phagocytic cells. After a Phase I trial found ALXN2220 to be safe and well-tolerated, it is currently being evaluated in an ongoing Phase III clinical trial called DepleTTR-CM (NCT06183931) to further investigate its efficacy in patients with ATTR-CM. 
• NNC6019-0001 (PRX004) — Another humanized monoclonal antibody, it targets misfolded and aggregated forms of TTR and is currently in Phase III trials.
• AT-02 — This therapy is a fusion of IgG1 with a peptide (p5R) with pan-amyloid reactivity and targets amyloid fibrils through electrostatic interactions. It is currently in the preclinical stage.

Need for Earlier Diagnosis and Referral
New, effective treatments continue to emerge, awareness of cardiac amyloidosis has increased, and we have also made significant advances in non-invasive diagnostic tools, including cardiac magnetic resonance imaging (CMR) and technetium pyrophosphate scan. Yet, a huge challenge remains. Delays in diagnosis are still way too common, leading to poor quality of life and outcomes. Often, by the time a patient arrives in our clinic, it is simply too late. I have seen many who are already wheelchair-bound with advanced musculoskeletal problems, and unfortunately, there is little we can do.

Early identification is essential for effective intervention. I continue to encourage physicians to consider cardiac amyloidosis as a possible diagnosis for any congestive heart failure patient with progressive diastolic dysfunction, especially if the patient exhibits any of the most common and significant early warning signs, which include the following:

• Bilateral carpal tunnel syndrome
• Numbness, tingling or pain in the hands or feet
• Spinal stenosis
• Spontaneous rupture of the biceps tendon

Continually Advancing to Improve Patient Outcomes
This is an exciting time to be working in this field. We have gone from one FDA-approved treatment for ATTR-CM just a few years ago to several with many more potential therapies in clinical trials or early stages of development. Our multidisciplinary AdventHealth team remains committed to educating referring physicians and providing evidence-based medicine that will improve outcomes and quality of life for our patients.

To refer a patient for evaluation by the AdventHealth Center for Amyloidosis, contact our Nurse Navigators at Call407-303-1648 or visit our website.