For Pfizer, Some Challengers in ATTR-CM Treatment

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare heart condition that often goes undiagnosed and can be fatal without treatment. The disease stems from a defect in the transthyretin (TTR) protein that causes it to become misfolded and dissociate into single molecules. The molecules then form amyloid fibrils that accumulate in the heart muscle.

TTR, which was previously called prealbumin, is made in the liver and normally circulates in the body carrying retinol and the thyroid hormone thyroxine. The accumulation of misshapen TTR in the heart causes stiffening of the myocardial walls, leading to thickening and enlargement of the heart. As a result, the left ventricle is unable to relax well enough to fill with blood. Arrhythmias, especially atrial fibrillation, are a common manifestation of ATTR-CM. Eventually, patients develop congestive heart failure.

ATTR-CM is grouped into two types, hereditary and wild type. Hereditary ATTR-CM results from a mutation in the gene that codes for the TTR protein. This type of ATTR-CM typically occurs in people in their 50s or 60s. Wild-type ATTR-CM is the more common form of the condition and happens as a result of aging. This version of the disease typically affects adults in their 70s and 80s.

Diagnosing ATTR-CM can be challenging, as the symptoms mimic those of other conditions, such as other types of cardiomyopathy and progressive heart failure. However, for patients with ATTR-CM, an average survival rate of two to six years after diagnosis means early diagnosis and treatment are critical.

There is a huge range in the estimates of the prevalence of ATTR-CM, partly because of the way the disease is coded. Research presented at the 2024 American College of Cardiology’s annual scientific meeting showed the 12-month prevalence in 2020 to be 17.4 per million using a stringent estimate, but
173 per million using a broad one.

‘Most expensive cardiac medication’

Currently, there are three drugs approved to treat ATTR-CM. Two are made by Pfizer and contain the same active ingredient, tafamidis. The third was developed by biopharmaceutical company BridgeBio Pharma and was recently approved by the FDA.

Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) are transthyretin stabilizers approved by the FDA in May 2019. Both products are oral capsules, but Vyndaqel requires four 20-milligram (mg) capsules to obtain one dose, while Vyndamax delivers one dose in one 61-mg capsule.

Vyndaqel and Vyndamax work by attaching to the thyroxine binding sites of TTR, thereby stabilizing the protein form and slowing its dissociation. These drugs can slow disease progression, but they do not reverse it. Hence, starting treatment early is imperative. With a price tag of $225,000 per patient per year, Vyndaqel and Vyndamax have been dubbed “the most expensive cardiac medication in history.”

BridgeBio’s Attruby (acoramidis), a newcomer TTR stabilizer, was approved by the FDA in November 2024 to treat ATTR-CM in adults. In the phase 3 ATTRibute-CM study, Attruby achieved 90% stabilization of the TTR protein while preserving its native function of thyroxine and retinol carrier. The approval was based on trial results showing a significant reduction in death and cardiovascular-related hospitalization and improvement in quality of life for patients taking Attruby versus placebo.

Attruby’s approval ends Pfizer’s total market share in ATTR-CM and might bring down treatment prices. BridgeBio has pledged to provide Attruby free for life for U.S. patients who participated in the ATTRibute-CM trial.

A few companies aim to further increase the competition with a pipeline of products designed to stop the production of the mutated TTR protein or clear TTR amyloid deposits responsible for the morbidity associated with the disease. Two candidates are in the late stages of development; one is in a phase 2 clinical trial.

Amvuttra (vutrisiran)

Amvuttra (vutrisiran) is a transthyretin-directed RNA interference therapeutic agent approved by the FDA as a treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTR-PN) in adults. With this type of ATTR, amyloid deposits build up in peripheral nerve cells. Amvuttra works by preventing the liver from producing both wild-type and mutant TTR messenger RNA (mRNA). Consequently, TTR blood levels decrease before amyloid
fibrils can form.

Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, has completed the phase 3 HELIOS-B trial evaluating the use of Amvuttra in adults with hereditary or wild-type ATTR-CM. The researchers randomly assigned 655 participants to receive either 25 mg of Amvuttra subcutaneously once every three months for up to 36 months or a placebo. About 40% of patients were receiving Vyndamax at baseline (overall population), and the rest received only Amvuttra or placebo (monotherapy group).

The study met the primary end point, reducing the risk of all-cause mortality and recurrent cardiovascular events by 28% in the overall population and by 33% in the monotherapy group. Amvuttra also significantly reduced death by all causes through 42 months in both groups versus placebo. Patients taking Amvuttra also had significant improvements in quality of life and measures of disease progression, such as the 6-minute walk test and the New York Heart Association heart failure symptom classification.

Based on these sterling results, Alnylam filed for priority review of Amvuttra for the treatment of ATTR-CM. A decision from the FDA is expected on March 23, 2025.

Wainua (eplontersen)

Wainua (eplontersen), marketed by British company AstraZeneca and
California-based Ionis Pharmaceuticals is an antisense RNA silencing treatment that binds to the TTR mRNA to inhibit the production of both mutant and wild-type TTR. The binding results in lower circulating TTR levels, which prevents its accumulation in nerve cells and organ tissues. The drug was approved by the FDA in 2023 to treat ATTR-PN in adults and was granted fast-track designation for the treatment of ATTR-CM in February 2024.

AstraZeneca and Ionis are now conducting a large phase 3 study called CARDIO-TTRansform evaluating the use of Wainua to treat ATTR-CM. The study is fully enrolled with 1,400 adults with ATTR-CM randomly assigned to receive either subcutaneous injections of Wainua once every four weeks or placebo for up to 120 weeks. The primary end point is the composite outcome of cardiovascular mortality and recurrent cardiovascular events at up to 35 months. Secondary end points include the change from baseline in the 6-minute
walk test and cardiovascular and all-cause mortality at 35 weeks. The study’s estimated primary completion date is April 2026.

Coramitug

Coramitug is an investigational monoclonal antibody designed to deplete TTR amyloid deposits and prevent new amyloid accumulation in nerve cells and organ tissues. In July 2021, Danish pharmaceutical company Novo Nordisk obtained coramitug along with a broad ATTR amyloidosis pipeline from Prothena Biosciences in a $1.2 billion agreement.

The investigational agent, then called PRX004, was well tolerated in a phase 1 dose-escalation study. Novo Nordisk plans to focus on developing coramitug for the potential treatment of ATTR-CM. The candidate is currently in a phase 2 trial of patients with wild-type or hereditary ATTR-CM. Results are expected in 2025.