ATTR-CM Treatment: TTR Stabilizers vs. Gene Silencers

If you’ve been diagnosed with transthyretin cardiac amyloidosis (ATTR-CM), you may be debating between two treatments: transthyretin (TTR) stabilizers and gene silencers. Both drug families are relatively new and have dramatically improved the prognosis for people with this heart disease, but one may be a better choice for you depending on your ATTR-CM type and severity, as well as your personal preferences.

• acoramidis (Attruby)
• tafamidis (Vyndaquel, Vyndamax)

How They Work

Medications like acoramidis and tafamidis attach to the thyroxine-binding sites of TTR proteins, helping them maintain their normal four-part shape and preventing them from breaking apart and forming amyloid fibrils, says Dr. Vallakati.

The Results

By slowing or preventing the accumulation of TTR proteins, TTR stabilizers reduce the risk of a heart health crisis and early death.

These findings align with Vallakati’s practical experience: “We see that people need fewer hospital visits for worsening heart failure after a year [on these medications],” he says. Patients also notice improvements in their quality of life. They feel better and can do more physical activity around this same time, says Vallakati.

Side Effects and Considerations

TTR stabilizers have potential side effects, though they’re generally mild.

TTR stabilizers are generally well tolerated, which makes them a practical option for many older patients, says Andrew Scott Rudin, MD, a board-certified cardiologist with Natural Heart Doctor, a holistic heart health clinic in Scottsdale, Arizona.

However, TTR stabilizers may be less effective in patients with more advanced or rapidly progressing disease. “In those cases, slowing new amyloid formation may not be enough to meaningfully change symptoms or outcomes,” says Dr. Rudin.

Other gene silencers are approved to treat ATTR-related neuropathy but not for the heart condition itself. While some are being studied in ATTR-CM patients, it’s too early to know whether they’re effective for this heart disease, says Vallakati. Unapproved gene silencers include the following:

• eplontersen (Wainua)

  [14]

• inotersen (Tegsedi)

  [15]

• patisiran

  [16]

These medications are also administered via injection.

How They Work

Vutrisiran is an RNA interference agent. The medication uses tiny, double-stranded bits of RNA called small interfering RNA (siRNA), which are delivered to liver cells. “Inside the liver cells, siRNA finds and chops up the TTR mRNA, stopping it from being used to make the protein,” says Vallakati.

The Results

Vutrisiran can reduce the risk of hospitalization and early death.

Vallakati's clinic has primarily prescribed vutrisiran for ATTR-CM since it was approved, though it can take time for patients to notice changes.

Side Effects and Considerations

• Joint pain
• Pain in the arms and legs
• Shortness of breath

• Bruising
• Itching
• Pain
• Redness
• Warmth

“Gene silencers may not be the right choice for patients with very mild ATTR-CM or those who are stable on other therapies, since these treatments are more intensive and often require ongoing monitoring,” says Rudin.

“TTR stabilizers and gene silencers haven’t been directly compared in big studies, so we can’t say for sure which one works better,” says Vallakati. “The choice usually depends on what the patient prefers: taking a daily pill or getting an injection every few months.”

The appropriate treatment for you may also depend on the type and severity of your ATTR-CM.

You may also have the option of combining a TTR stabilizer with a genetic silencer. “However, insurance often doesn’t approve both together because there’s no strong evidence that using two medicines is better than one,” says Vallakati.

• The TTR stabilizers acoramidis and tafamidis are daily oral medications that prevent TTR proteins from misfolding and clumping into the heart-stiffening deposits that characterize ATTR-CM.
• Administered via injection every three months, the gene silencer vutrisiran works by slowing the production of TTR proteins in the liver, thereby reducing the amount of harmful amyloid that can build up in the body.
• Clinical trials for both drug classes have demonstrated significant benefits, including improved survival rates, fewer heart-related hospitalizations, and better quality of life.
• Your cardiologist’s recommendation may depend on your preferences, or it may depend on your disease type and severity, with TTR stabilizers typically used at an earlier stage and gene silencers often preferred for more progressive or hereditary cases.