An estimated 100,000 Americans have sickle cell disease, the vast majority of them of African or Caribbean origin. But more than 1.5 million Black men in the US are genetically predisposed to a much lesser-known illness: transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).

John L. Berk, MD (Photo courtesy Boston University School of Medicine)

That’s the warning from John L. Berk, MD, a professor at the Boston University School of Medicine in Massachusetts, where he directs Clinical Trials for Familial Amyloidosis and the Localized Amyloid Clinic.

Dr. Berk recently gave an online presentation about the current treatment landscape on behalf of the Amyloid Research Consortium, a Boston-based charity that advocates on behalf of patients with all types of amyloidosis, including hereditary transthyretin-mediated amyloidosis (hATTR).

This family of diseases is particularly complex, given their vastly different symptoms, treatment, and prognosis. What they all have in common, though, is the production of misfolding proteins that form amyloid fibrils, eventually causing health problems and damaging organs. In some cases, it can be life-threatening.

A Growing Awareness

While amyloidosis, in all its forms, is currently classified by the National Institutes of Health (NIH) as a rare disease, this classification may change, according to the Clarkston, Michigan-based Amyloidosis Foundation.

“Many experts suspect that some of the amyloidosis diseases are not that rare, just rarely diagnosed. As funding increases for research, our understanding of amyloid diseases will lead us in new directions,” the foundation says on its website. “A major challenge is the current lack of early diagnosis for a patient with amyloidosis. Awareness of all the amyloidosis diseases by the medical community and by the general public is essential in order to turn this around.”

Dr. Berk has been involved with the Amyloid Clinic for 25 years, the past 18 of which have been focused on therapeutics for transthyretin (TTR) genetic mutations. The TTR protein, made mostly in the liver, gets its name—transthyretin— because it carries the thyroxine hormone and retinol (vitamin A) around the body.

Hereditary ATTR amyloidosis (hATTR) occurs when an inherited mutation results in an abnormal TTR protein promoting misfolding. But harmful deposits generally don’t cause problems until adulthood; in some cases, carriers of the mutation may never show symptoms of the disease.

Further complicating the picture, hereditary amyloidosis diseases are classified by the misfolding protein as either ATTR and non-TTR. At present, 136 genetic variations are known in ATTR, and at least 60 in non-TTR diseases, according to the Amyloidosis Foundation. Median life expectancy for untreated patients with ATTR-CM is 2 to 3.5 years.

“Pharmaceuticals dichotomize TTR amyloid into cardiomyopathy and polyneuropathy,” Dr. Berk said. “The reality is that the vast majority of people have complete systemic involvement.”

Experts think between 7500 and 10,000 people in the US have polyneuropathy, with the worldwide estimate at 50,000—though Dr. Berk believes the actual number is higher.

“Cardiomyopathy is a different kettle of fish, particularly the wild-type form of TTR amyloid,” he said, referring to ATTRwt—a subtype of disease that develops with age and is acquired rather than inherited. “Rare disease in the US is defined as having less than 200,000 people afflicted. If you do some calculations, there probably are more like 400,000 to 500,000 men age 80 or older walking around with amyloid cardiomyopathy. It’s effectively an unrecognized pandemic.”

An Underlying Cause of Heart Failure

Some 1.6 million African Americans, roughly 4% of the country’s total Black population, carry the V122I mutation that causes wild-type ATTR. Yet it’s not clear how many of them actually manifest clinical disease. Dr. Berk puts the amount at under 50%, and probably closer to 25%.

“We believe that ATTRwt is massively underdiagnosed and is often the underlying cause of heart failure,” says the Amyloidosis Research Consortium, which was founded in 2015 and reported 2021 revenues of $1.7 million.

Yet enrolling Black patients in clinical trials is difficult.

“There’s a long history, certainly in the United States, of mistreatment of African-American patients. That legacy carries over to today, in terms of the distrust that many African-Americans have toward the research process,” Dr. Berk said. “We work very hard to try and interest and involve people of color in clinical trials to properly reflect what occurs in the real world.”

“A significant proportion of people of color have associated diseases that make it more difficult to identify those that have infiltrative cardiomyopathy versus hypertensive disease,” he said. “Cardiologists have been trained to seek and treat hypertensive disease, but many people in the investigative area of TTR are trying to encourage them to think a little more expansively and test the African American heart failure patients in particular for hereditary amyloid cardiomyopathy.”

TTR Gene Silencers in Development

In December 2021, Pfizer announced that treatment with tafamidis meglumine (Vyndaqel®)/tafamidis (Vyndamax®) provided a clinically significant survival benefit at 5 years for patients with ATTR-CM. The 2 formulations of tafamidis are the only medicines approved by the US Food and Drug Administration (FDA) for the treatment of wild-type and hereditary ATTR-CM.

The company said that its pivotal ATTR-ACT study of tafamidis, along with a long-term extension with tafamidis meglumine after 30 months, showed a 39% drop in all-cause mortality in patients with wild-type ATTR-CM versus those on placebo, and a 43% drop in mortality for patients with hereditary ATTR-CM.

“Tafamidis has been shown to have some inhibitory effect in the course of polyneuropathy. The FDA encouraged Pfizer to undertake a cardiomyopathy trial, which proved to be a real landmark event, resulting in the first FDA‑approved agent for ATTR cardiomyopathy,” Dr. Berk said. “But even in the treated population, there is still progressive disease. Consequently, unmet need remains. That is really the challenge for TTR gene silencers, which are in development.”

He added: “We’re on the verge of seeing the potential impact of gene editing. Obviously, there’s a huge amount of excitement about that.”