Pan-Amyloid Radiotracer Excels at Early Cardiac Amyloidosis Detection

PHOENIX — An investigational pan-amyloid binding tracer proved its mettle in detecting and quantifying cardiac amyloidosis, particularly among early, low-burden cases, in a phase III study.

In the REVEAL study, the positron emission tomography (PET) and CT tracer ¹²⁴I-evuzamitide achieved a sensitivity of 93.5%, specificity of 86.0%, negative predictive value of 94.1%, and positive predictive value of 84.7% in identifying cardiac amyloidosis in people suspected of having the condition.

It performed similarly well at detecting light-chain (AL) amyloidosis and transthyretin amyloidosis (ATTR), reported Mathew Maurer, MD, of Columbia University Irving Medical Center in New York City, at the Heart Failure Society of America (HFSA) annual meeting.

Evuzamitide PET outperformed bone scintigraphy in identifying early ATTR (93% vs 68%, P=0.016). The tracer flagged early, low-burden ATTR more often than did bone scintigraphy, including patients with a NT-proBNP under 350 ng/L (89% vs 74%) and under 600 ng/L (92% vs 75%) as well as those with left ventricular wall thickness less than 12 mm (100% vs 78%) and less than 13 mm (95% vs 79%).

Having a single test that detects both AL and ATTR across the full spectrum of disease without the need for biopsy is especially important in early disease so that people can be diagnosed earlier and receive timely disease-modifying therapies available on the market, according to Maurer.

“We’ve made tremendous advances on the therapeutic side,” Maurer added. In the current era, patients have their pick of the transthyretin (TTR) stabilizers tafamidis (Vyndamax, Vyndaqel) and acoramidis (Attruby) and the gene silencer vutrisiran (Amvuttra). Though eplontersen (Wainua) was recently shown to offer no cardiovascular outcome benefit in the CARDIO-TTRansform trial, other drug candidates are in the pipeline, including the TTR depleter cliramitug.

However, the diagnosis of cardiac amyloidosis has relied on radionuclide imaging using bone-avid tracers, which produce many false negatives due to their lower sensitivity for early disease. Even if systemic amyloidosis is strongly suspected due to carpal tunnel syndrome or other orthopedic manifestations, the only diagnostic option for these false negative cases is biopsy.

“A really tricky population that we all see very often in clinic is those early patients who have a high suspicion for ATTR [or cardiac amyloidosis] and we just can’t find the test or proof that they have it, and we know that these patients need to be treated early in order to get the best [outcomes],” said session discussant Jan Griffin, MD, of Beth Israel Deaconess Medical Center in Boston.

In REVEAL, ¹²⁴I-evuzamitide PET also showed promise as a metric for amyloid load that can be tracked over time, perhaps as a way to track whether a treatment is working.

“What the patient is asking you about in the office is most important,” Maurer told the audience. “They’ve been asking for a long time ‘How much [amyloid] am I going to have? Where is it? And can you tell me if it’s getting better or worse?’ This presents an opportunity to really answer the questions the patients have.”

The investigators found that quantitative uptake of the tracer was in line with ATTR burden across NT-proBNP, troponin, global longitudinal strain, and left ventricular (LV) wall thickness. In patients who were PET-positive but negative on bone scintigraphy, cardiac uptake of ¹²⁴I-evuzamitide was threefold lower than those with advanced disease, Maurer reported.

Based on the data, Bayer said it plans to submit ¹²⁴I-evuzamitide for regulatory approval.

REVEAL was a prospective single-arm study conducted at 18 U.S. centers. It included 170 people with suspected cardiac amyloidosis who underwent PET/CT with 1 mCi of ¹²⁴I-evuzamitide and were given oral potassium iodide for 3 days to block the effects of iodine on the thyroid.

The cohort had a median age of 72 years, and 75.3% were men. Over 75% were in New York Heart Association class I/II. Baseline NT-proBNP was 471 ng/L, LV wall thickness 13 mm, and LV ejection fraction 57%.

Three blinded PET/CT readers interpreted the study scans. Another three amyloidosis experts, blinded to the scans, were asked to interpret the other clinical records to determine diagnosis of cardiac amyloidosis. Ultimately, out of the 170 screened, there were 54 individuals found to have ATTR, while 21 had AL amyloidosis.

These scans detected ATTR across all bone-scintigraphy grades, even several cases that had been equivocal or negative on bone scintigraphy (Perugini grade 0-1). No patient detected by bone scintigraphy was missed by ¹²⁴I-evuzamitide PET.

In a post hoc analysis, 44% of subjects with PET-detected ATTR had early disease (NT-proBNP <350 ng/L or LV wall thickness <12 mm).

The scans showed what the researchers called an acceptable safety profile based on safety visits on days 5 and 30.

Maurer acknowledged the limitations of a 60-day follow-up in REVEAL, the relatively few patients with AL, and having the clinical diagnostic reference standard constrained by available clinical data.

It remains to be seen how ¹²⁴I-evuzamitide scans would play out in the real world.

During the HFSA session, Brett Sperry, MD, of Saint Luke’s Mid America Heart Institute in Kansas City, Missouri, stressed educating clinicians about having cardiac amyloidosis on their radar.

“If you’re not thinking about it, then you’re not going to diagnose it, right? It has to be on your differential diagnosis, and we try to give people the red flags. Main one is demographics,” he said. “If you see an older man who is coming to you for clearance for carpal tunnel surgery, that’s like all the red flags are going off, you should work on getting this patient diagnosed.”