Learn The BasicsTransthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and progressive disease affecting the heart. It is caused by the dissociation of units of 4 transthyretin (TTR) proteins called tetramers and the formation of insoluble amyloid aggregates, which accumulate in the heart muscle, among other parts of the body, causing damage.
Currently, only one therapy is specifically approved for treating ATTR-CM; in addition, several therapies can be used off-label. Several experimental therapies are being developed and tested in clinical trials for the potential treatment of the disease.
Tafamidis
Tafamidis, marketed under the brand name Vyndamax or Vyndaqel, is the only therapy approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) specifically to treat ATTR-CM.
It works by stabilizing the TTR tetramer, thereby decreasing protein dissociation and the formation of damaging amyloid fibrils.
Tafamidis is taken by mouth. In clinical practice, patients with ATTR polyneuropathy (ATTR-PN) have experienced adverse events such as headache, urinary tract infection, swelling, abdominal pain, flatulence, diarrhea, influenza, pneumonia, acute heart failure, pain, vaginal infection, and abnormal laboratory test results.
Tolcapone
Tolcapone, with the brand name Tasmar, is another TTR stabilizer. It is used to manage Parkinson’s disease and as an off-label treatment for ATTR-CM.
Clinical studies have shown it can be beneficial in patients with ATTR-CM.
However, the therapy can cause severe side effects such as liver toxicity, sleep disturbances, uncontrolled shaking and tremors and gastrointestinal problems.
Diflunisal
Diflunisal, marketed as Dolobid, is a nonsteroidal anti-inflammatory drug that can be used off-label to treat patients with ATTR-CM. Like tafamidis and tolcapone, it works by stabilizing the TTR protein.
Research has shown that diflunisal can reduce troponin, a marker of heart muscle damage, and brain natriuretic peptide (BNP), a biomarker of heart failure.
Off-label tetramer silencers
Another approach to treating ATTR-CM is to silence the TTR tetramer. This is done via so-called small interfering RNAs or single-stranded antisense oligonucleotides, also known as ”molecular patches,” which interfere with the production of TTR protein.
Three tetramer silencers are approved for treating ATTR-PN. They are also used off-label to treat ATTR-CM.
These are: patisiran, sold under the brand name Onpattro; vutrisiran, sold as Amvuttra; and eplontersen, sold under the name Wainua.
All three therapies are currently being tested in clinical trials for treating ATTR-CM.
Experimental therapies
There are also a number of experimental therapies that have not yet been approved for any disease that are being tested in clinical trials for treating ATTR-CM.
These include the TTR stabilizer acoramidis, monoclonal antibodies such as PRX004, and the gene editing therapy NTLA-2001.
Monoclonal antibodies target misfolded TTR proteins to induce their clearance by the immune system. PRX004 is one such antibody currently being tested in a phase 2 clinical trial.
NTLA-2001 is a gene editing therapy that uses a system called CRISPR/Cas9 to knock out the gene that codes for the TTR protein, thereby reducing its concentration in the serum and potentially treating ATTR-CM.
Reviewed by Kyle Habet, M.D., on November 14, 2024.