Recent breakthroughs in ATTR-CM treatment
Recent years have seen rapid advancements in treating transthyretin (ATTR) amyloidosis, a rare but progressive disease caused by misfolded transthyretin (TTR) proteins. These misfolded proteins accumulate in the body as amyloid fibrils, leading to organ damage, especially in the heart (cardiomyopathy, or ATTR-CM). Until recently, therapeutic options were limited. However, two significant drug approvals for ATTR-CM by the U.S. Food and Drug Administration (FDA) have transformed the treatment landscape: Attruby (acoramidis) in November 2024 and Amvuttra (vutrisiran) in March 2025.
Acoramidis (Attruby): A TTR stabilizer
Acoramidis is an oral medication approved for adults with wild-type or hereditary ATTR-CM. It belongs to a class of drugs known as TTR stabilizers. By binding to the TTR protein, it prevents the tetramer structure from breaking apart, thereby reducing the misfolding that leads to amyloid fibril formation.
The FDA approval for Attruby was based on positive results from the Phase III ATTRibute-CM trial. This study showed that acoramidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations over a 30-month period compared to a placebo. Common side effects reported were mild, including diarrhea and upper abdominal pain.
Vutrisiran (Amvuttra): A TTR gene silencer
Vutrisiran, a subcutaneous injection, was granted an expanded FDA approval in March 2025 for ATTR-CM. It represents a different therapeutic approach as an RNA interference (RNAi) therapeutic, a form of gene silencing. Instead of stabilizing the protein, vutrisiran stops the production of the TTR protein in the liver entirely by degrading the messenger RNA (mRNA) that serves as the blueprint for its creation.
Its approval was based on data from the HELIOS-B trial, which demonstrated a significant reduction in cardiovascular mortality and hospitalizations in ATTR-CM patients. Originally approved in 2022 for hereditary ATTR-polyneuropathy (ATTR-PN), its expanded indication is a major milestone for patients with heart involvement.
Understanding different therapeutic mechanisms
Treatments for ATTR amyloidosis can be broadly categorized based on their mechanism of action. The recent approvals highlight two distinct strategies:
- TTR Stabilizers: These drugs, including tafamidis (Vyndamax, Vyndaqel) and the new acoramidis (Attruby), work downstream by binding to the TTR protein to prevent its misfolding. They are designed to slow down the formation of new amyloid deposits.
- TTR Silencers (RNAi Therapeutics): Therapies like vutrisiran (Amvuttra) and eplontersen (Wainua) operate upstream by targeting the genetic instructions (mRNA) in the liver to block the production of the TTR protein itself. This reduces the amount of misfolded protein circulating in the body.
Comparison of recent ATTR-CM drug approvals
| Feature | Attruby (acoramidis) | Amvuttra (vutrisiran) |
|---|---|---|
| Mechanism | TTR Stabilizer | TTR Gene Silencer (RNAi) |
| Administration | Oral, twice daily | Subcutaneous injection, quarterly |
| Indication | Wild-type and hereditary ATTR-CM | Wild-type and hereditary ATTR-CM |
| Key Trial | ATTRibute-CM | HELIOS-B |
| Key Benefit | Reduced all-cause mortality and cardiovascular hospitalizations | Reduced cardiovascular mortality, hospitalizations, and urgent heart failure visits |
| Administration Location | Self-administered | Administered in a clinic/hospital |
Advancements in AL amyloidosis treatment
While ATTR amyloidosis has seen major advances, light chain (AL) amyloidosis, driven by abnormal plasma cells, also has new standards of care. The regimen of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) has become the only FDA-approved first-line treatment for AL amyloidosis. This combination therapy has been shown to achieve high rates of hematologic response, indicating a strong reduction in the production of the misfolded light chain protein.
The future of amyloidosis treatment
Beyond current approvals, the next generation of amyloidosis treatments is already in development, exploring even more precise and potentially curative approaches:
- TTR Depleters: This class of therapies, including investigational monoclonal antibodies like ALXN2220, is designed to actively remove existing amyloid deposits from organs, potentially reversing organ damage rather than just slowing disease progression. Phase III trials for ALXN2220 in ATTR-CM are currently underway.
- CRISPR-Cas9 Gene Editing: Therapies such as NTLA-2001 use gene-editing technology to silence the TTR gene in the liver, offering the possibility of a single-dose, permanent treatment. A Phase III trial for NTLA-2001 in ATTR-CM began in late 2024.
- Anti-Fibril Immunotherapies for AL Amyloidosis: Researchers are investigating new monoclonal antibodies designed to target and clear the amyloid fibrils in AL amyloidosis. While recent Phase III trials for birtamimab and anselamimab unfortunately failed to meet their primary endpoints, they have provided valuable insights for future research.
- CAR-T Cell Therapy: In the relapsed/refractory setting for AL amyloidosis, novel anti-plasma cell therapies like CAR-T cells are showing promise in clinical investigations.
Conclusion
The treatment landscape for amyloidosis has evolved dramatically, moving beyond supportive care and general chemotherapy toward highly targeted therapies. The recent FDA approvals for acoramidis and vutrisiran for ATTR-CM, along with the established Dara-CyBorD regimen for AL amyloidosis, represent major milestones. As new TTR depleters and cutting-edge gene-editing technologies advance through clinical trials, the future holds even greater promise for transforming amyloidosis from a fatal diagnosis into a manageable condition for many patients. For the latest information on these and other therapies, patients can refer to the Amyloidosis Research Consortium.
