Sudden clearing of ATTR amyloidosis with cardiomyopathy seen in UK

Spontaneous disease reversal in 3 men may lead to new treatments

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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ATTR amyloidosis with cardiomyopathy (ATTR-CM), noting damage to the heart, is usually considered to be an irreversible condition. But in a first known reporting, the disease spontaneously resolved for three men in the U.K.

Accompanying ATTR-CM’s resolution was the presence in the bloodstream of antibodies targeted against the insoluble transthyretin protein (amyloid) deposits that cause the disease.

Researchers believe these antibodies could be leveraged to develop new treatments for ATTR-CM and other diseases marked by transthyretin buildup, including familial amyloid polyneuropathy (FAP).

“We have seen for the first time that the heart can get better with this disease,” Marianna Fontana, MD, PhD, a professor at University College London (UCL) and the report’s first author, said in a university press release. “That has not been known until now and it raises the bar for what might be possible with new treatments.”

The findings were published as a letter to the editor, titled “Antibody-Associated Reversal of ATTR Amyloidosis–Related Cardiomyopathy,” in The New England Journal of Medicine.

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Transthyretin amyloidosis, also called ATTR amyloidosis, refers to any disease marked by the buildup of amyloid deposits made of the transthyretin protein in the body’s cells. FAP is a hereditary form of ATTR that mainly affects nerve cells.

ATTR-CM can be hereditary or occur spontaneously, and it is marked by transthyretin accumulation in the heart. Patients experience cardiomyopathy — where the heart muscle has a hard time pumping blood — that can ultimately result in heart failure.

The disease is progressive and considered irreversible, with about half of all patients dying within four years of diagnosis. Currently available treatments aim to ease symptoms of heart failure but cannot target the disease’s underlying cause.

Scientists in the U.K. now reported three cases of ATTR-CM that spontaneously reversed. The three men, ages 68, 76, and 82, had reported improvements in their cardiac symptoms without the introduction of any new or potential disease-modifying treatments.

True reversal of ATTR-CM was confirmed for all three patients through a series of blood and imaging tests. Cardiovascular magnetic resonance (CMR) scans confirmed that transthyretin buildup in the heart had almost completely cleared, and that heart structure and function were nearly normal.

These findings prompted researchers to examine records from an additional 1,663 AATR-CM patients followed at the National Amyloidosis Center in London. No reports of a similar spontaneous recovery were evident for these other patients.

Decades ago, identifying that the condition had reversed would not have been easy. But newer imaging techniques like CMR help doctors to diagnose and monitor the disease more precisely, according to the scientists.

A heart muscle biopsy in one of the three men revealed an atypical inflammatory response around the transthyretin deposits. By comparison, this immune response was not seen in any of 286 biopsies taken from people with normally progressing ATTR-CM.

The scientists then identified that all three patients with reversed disease had antibodies that actively targeted transthyretin amyloid deposits in both mouse and human tissue, as well as in lab-made amyloid. Again, such antibodies were not seen in 350 other patients whose disease progressed as expected.

“The cause and clinical significance of the anti-ATTR amyloid antibodies are intriguing and presently unclear,” the scientists wrote.

“Whether these antibodies caused the patients’ recovery is not conclusively proven,” said Julian Gillmore, MD, PhD, a professor at UCL and head of the UCL Centre for Amyloidosis at the Royal Free Hospital in London. “However, our data indicates that this is highly likely.”

The team suggested these antibodies could be leveraged to develop new ways of treating ATTR-CM and other forms of transthyretin amyloidosis, like FAP. The scientists are investigating this possibility in preliminary studies.

“The clinical recovery of these patients establishes the unanticipated potential for reversibility of ATTR-CM and raises expectations for its treatment,” they wrote.

Such a therapy might be used in combination with currently investigative treatments designed to suppress transthyretin production.

A possible combination could involve NTLA-2001, a potential gene-editing therapy from Intellia Therapeutics and Regeneron Pharmaceuticals that aims to disrupt the activity of the TTR gene that’s responsible for producing transthyretin, the scientists noted. The one-time therapy particularly targets cells in the liver where this protein is mainly produced.

NTLA-2001 is headed for Phase 3 trials in both ATTR-CM and FAP patients, based on promising early data from a Phase 1 trial (NCT04601051), which Gillmore helped to lead. The Phase 3 studies could begin to open this year.

If ultimately used together, an antibody-based therapy and a treatment like NTLA-2001 would work both to clear amyloid buildup and to prevent more from being produced.

“This work not only represents a major breakthrough in our understanding of cardiac amyloidosis, but crucially opens up new possibilities for more effective treatment options,” said Jon Spiers, chief executive of the Royal Free Charity, which provided funding for the recent study.