Better Amyloidosis Treatments Expand Options and Cures

The new understanding of molecular events that drive the various forms of amyloidosis has led to the expansion of therapeutic options to prevent end-stage disease or even offer a cure, which has added pressure for prompt diagnoses.

Amyloidosis is typically thought of as a rare disease, but the variety of subtypes that involve the heart — one of the organs most commonly involved — challenge this characterization, according to Mathew S. Maurer, MD, professor of cardiology and director of the Cardiac Amyloidosis Program at Vagelos College of Physicians and Surgeons, Columbia University, New York City.

“When a cardiologist says to me, ‘I have never seen a case of amyloidosis,’ I respond that you may never have diagnosed a case, but you’ve seen one,” Maurer said.

Because treatments that meaningfully slow or halt the progression of some subtypes of amyloidosis have been available for more than 5 years, a missed diagnosis has become a serious issue. And an emerging generation of new therapeutic approaches appear to lower precursor proteins indefinitely, including gene therapies, which, so far, have been shown to suppress disease after a single dose.

Early Diagnosis Essential

“Disease awareness is critical,” said Maurer, who participated in a symposium on amyloidosis at the American Heart Association (AHA) Scientific Sessions in Chicago. The busy cardiologist must now add amyloidosis to a long list of conditions for which a “high index of suspicion” must be maintained, but it might save lives, he said.

“If you are not thinking about it, you are never going to diagnose it,” he added. Even if the promise of the newer therapies with the potential to permanently suppress or “cure” amyloidosis is not yet common, the urgency of making a prompt diagnosis is not just coming, “it is already here,” he said.

Of the two subtypes that cause the most cardiomyopathy, transthyretin amyloidosis (ATTR) is more common one, but the other subtype, immunoglobulin light chain amyloidosis, can also be lethal. The responses seen with drugs that suppress the known protein precursors for each of these subtypes have generated excitement.

For light chain amyloidosis, “we have seen this when patients achieve a deep hematological response to plasma-cell-directed therapies,” said Sarah Cuddy, MD, assistant professor of medicine at Brigham and Women’s Hospital, Harvard Medical School, Boston.

Light chain amyloidosis is caused by plasma cells in the bone marrow that produce more light chain proteins than heavy chain proteins, which ultimately leads to the deposition of amyloid fibrils in the heart muscle and elsewhere. Cuddy explained during the AHA symposium.

The goal of the most commonly used treatments for this type of amyloidosis — such as the combination of daratumumab, an anti-CD38 monoclonal antibody that targets plasma cells, plus cyclophosphamide, bortezomib, and dexamethasone (CyBordD) — is to suppress the production of proteins that underlie the pathogenic process and substantially slow, halt, or even reverse the infiltrative process.

Pathology of Amyloidosis Is Targetable

“A small but significant proportion of patients” do not respond to the standard of care of daratumumab plus CyBordD, Cuddy said. So “there is a lot of excitement about the potential of BCMA [B-cell maturation antigen]-targeting therapies in this cohort.” 

Because BCMA is expressed by plasma cells, BCMA-targeted therapies — there are several candidates — promise to substantially deplete the source of light chain–causing proteins. A research protocol with the bispecific T-cell engager elranatamab, which induces T cells to eliminate plasma cells, is moving forward after showing promise in the experimental setting, she reported.

In ATTR, the precursor protein TTR drives amyloid deposits in the heart and elsewhere. Although treatments for the various amyloidosis subtypes differ, the expected benefit from the suppression of this protein is the same. Emerging gene therapies are nearly eliminating TTR production, which could lead to a radical change in the prognosis of patients with ATTR.

Pursuing Causative Proteins Changes Outcomes

“The phase 1 results presented at the AHA in ATTR-cardiomyopathy [CM] were very exciting, showing a 90% mean reduction in TTR at 12 months,” Cuddy said.

That phase 1 trial — presented as a late breaker at the AHA 2024 meeting and published simultaneously in The New England Journal of Medicine — was conducted with nexiguran ziclumeeran (nex-z). Nex-z is a CRISPR-Cas9-created inhibitor of TTR that uses a nanoparticle delivery system to reach hepatocytes, where most TTR is produced, and is designed to alter messenger RNA function after a single dose.

“The effect of nex-z on clinical outcomes is now being evaluated in the phase 3 MAGNITUDE trial,” reported Marianna Fontana, MD, PhD, from the National Amyloidosis Centre at Royal Free Hospital in London, England.

It is perhaps premature to speculate on the ability of this gene therapy to “cure” ATTR-CM, but a sustained 90% mean reduction in TTR is a substantial breakthrough in the immediate control of this form of amyloidosis, given the critical role of elevated levels of TTR in driving progression.

A strategy of suppressing TTR to improve outcomes in patients with ATTR is not new. Patisiran, an RNA interference (RNAi) therapeutic that targets TTR, was first approved for a form of amyloidosis in 2018. And recently, vutrisiran was shown to be associated with a 28% reduction in risk for death or recurrent cardiovascular events relative to placebo in patients with ATTR-CM (P =.01) in the phase 3 HELIOS-B trial.

However, these drugs require repeated dosing for sustained TTR suppression. The excitement over gene-edited therapies like nex-z is because of their potential to change the course of the disease after a single dose.

Experimental Therapies Effective After One Dose

Nex-z is not the only drug in clinical trials to do so. At the AHA, a set of phase 1 data on the RNAi nucresiran was presented, which, like nex-z, showed a 90% reduction from baseline in TTR 12 months after a single dose.

Maurer described five major lessons learned from the past 10 years of progress in amyloidosis. The first is the critical importance of early diagnosis. Although some of the most promising therapies might offer some degree of benefit even in patients with advanced disease, existing therapies work best when the disease is caught early.

Cuddy made the same point.

“If we detect and diagnose cardiac amyloidosis in the early stages of disease, patients do very well with known therapies,” she said. “However, in more advanced cardiac disease, there is such a burden of amyloid within the heart that slowing or stopping disease progression is not sufficient.”

There are numerous red flags that should arouse the suspicion of amyloidosis, including nonspecific abnormalities on imaging or on an ECG and elevated biomarkers of heart dysfunction, such as troponin or N-terminal pro-B-type natriuretic peptide.

Although biopsies or other invasive tests are typically needed to confirm a diagnosis of light chain amyloidosis, biopsy is no longer required in most cases to establish a diagnosis of ATTR-CM. This was the second of Maurer’s five major lessons. Approximately 85% of cases can be made on the basis of symptoms, imaging, and serologic testing alone, he explained.

There were three other lessons: Cardiac amyloidosis is more common than many clinicians recognize; there are effective therapies available now, with the promise of more to come; and the cost of these therapies is too high to be sustainable, particularly if amyloidosis is diagnosed more frequently.

Find Amyloidosis With Active Ascertainment

To change the course of amyloidosis and lower both morbidity and mortality, “we simply need to find cases earlier,” said Maurer. At this stage, he called for “active ascertainment,” meaning pursuing red flags when encountered rather than screening in the absence signs that have raised suspicion. The hope is that this approach will lead to earlier treatment and better outcomes.

“Will it save lives? I don’t think we know. If we diagnose amyloidosis early in its course, then we can expect to see an ever-greater mortality benefit from the most effective therapies, but we need the data,” he said.

The diagnosis of light chain amyloidosis still requires a biopsy, he added. Even though bone scans can be used to diagnose symptomatic ATTR-CM, serologic tests must be performed to identify the pathologic variant, including inherited forms that would prompt family genetic counseling.

“A bone scan alone is no longer acceptable,” said Maurer, citing the 2022 heart failure guidelines from the AHA, the American College of Cardiology, and the Heart Failure Society of America.

Along with the promise of better therapies, several studies have shown the promise of more efficient and potentially more accurate diagnostic tests for amyloidosis. There are, for example, numerous groups using artificial intelligence (AI) to try to analyze the red flags for amyloidosis on ECGs or echocardiography.

AI Might Soon Help With Diagnosis

A meta-analysis of five such ECG studies produced an overall area under the curve of 0.89, suggesting that AI-aided ECG “may provide a useful tool for the early detection an intervention in this disease,” said Laibah Arshad Khan, MD, from King Edward Medical University in Lahore, Pakistan, who presented the work of a multinational collaboration at the AHA scientific sessions.

In fact, although the area under the curve was greater for ATTR-CM than for light chain amyloidosis (0.90 vs 0.80), both were sufficiently high to be considered in a diagnostic algorithm, the meta-analysis showed.

This could circumvent delays in the diagnosis of amyloidosis, some of which, in addition to lack of awareness, are caused by the belief that such diagnoses are best made at a tertiary center with expertise in amyloidosis, Maurer explained.

A diagnosis based on red flags and well-documented steps in the diagnostic workup “is not rocket science,” he said. However, if awareness is effectively raised, it is unlikely that centers with dedicated amyloidosis programs would be able to handle the volume of cases referred, he pointed out.

The potential new therapeutic options to block or even reverse the progression of amyloidosis, along with early diagnosis, means that there might soon be a marked decrease in fatal outcomes, according to several experts who addressed the topic at the AHA scientific sessions.

With cumulative potential advances in diagnosis and treatment, amyloidosis “is certainly a very hot field at the moment,” Cuddy said.

Maurer reported financial relationships with Akcea, Alexion, Alnylam, Attralus, AstraZeneca, Intellia, Ionis, Novo Nordisk, Pfizer, and Prothena. Cuddy reported financial relationships with AstraZeneca, BridgeBio, Ionis, Novo Nordisk, and Pfizer. Fontana reported financial relationships with Alexion, Alnylam, AstraZeneca, Attralus, Caelum, Intellia, Ionis, Janssen, Lexeo, Novo Nordisk, Pfizer, and Prothena. Khan and Hall reported no potential conflicts of interest.