Can TTR Assays Track Tafamidis Success in Cardiac Amyloidosis?

October 19, 2021

Assay levels of transthyretin (TTR) seem to reflect the efficacy of drug therapy aimed at TTR amyloid cardiomyopathy (ATTR-CM) and so might be useful for indirectly assessing patient responses to treatment, say researchers, based on an observational study.

Treatment success can be otherwise hard to assess in ATTR-CM, they note, because the once-rare but increasingly diagnosed disorder can progress slowly or at varying rates.

In the new study, serum TTR levels rose by more than a third over several months in patients with ATTR-CM who took tafamidis (Vyndamax, Pfizer) or tafamidis meglumine (Vyndaqel, Pfizer), two forms of the drug recently introduced for the disorder.

Such increases would be expected if tafamidis is working in the body as it should, Rodney H. Falk, MD, Brigham and Women’s Hospital, Boston, Massachusetts, told | Medscape Cardiology.  They and other drugs in development stabilize TTR molecules in the circulation, rendering them less likely to split into amyloid precursors.

Moreover, TTR levels rose in nearly all patients who took tafamidis, "so virtually everybody got an effect of the drug," said Falk, who is lead author on the study, published online October 19 in JACC: CardioOncology. There are no assays for TTR stabilization, but tafamidis appears to prevent or slow amyloid deposition, suggesting TTR levels could serve as "a good surrogate marker" for treatment effectiveness.

If so, TTR may not track with more familiar biomarkers. Overall in the study, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) appeared to rise slightly but nonsignificantly, and levels of troponin T by high-sensitivity assay (hs-TnT) also seemed to go up, although the change fell short of significance (= .057).

The US Food and Drug Administration (FDA) approved both tafamidis and tafamidis meglumine, classified as orphan drugs, in May 2019 for the treatment of ATTR-CM in adults based on the ATTR-ACT trial. The 441-patient randomized trial showed a significant 30% decline in all-cause mortality and 32% drop in risk for cardiovascular hospitalization over 30 months in patients with the disease on tafamidis.

However, such patients in practice may be interested in whether tafamidis or other TTR-stabilizing agents are working without waiting 30 months to find out. For example, tafamidis itself is an extraordinarily costly drug, with a list price of $225,000 per year. Copays for covered patients may be "in excess of $1000 a month," Falk observed.

The TTR assays potentially allow clinicians to tell patients, "if you want to know whether the drug is working biochemically," he said, "in a month we'll be able to tell you whether you got a good response to it."

Other insights that may help patients come from outside the current study. Echocardiographic follow-up of a small group of patients seen before tafamidis was approved, Falk said, showed signs of adverse remodeling. "Most patients deteriorate on no therapy by 12 months."

Potentially, he said, "I could tell an individual patient, we can look at your echo and, in a year, if the changes are minimal, the likelihood is that tafamidis is working to really slow things down, even if biomarkers go up slightly."

The cohort study followed 72 patients with ATTR-CM — 67 with wild-type disease and five with a variant TTR genotype — with a mean age of 79 years, and all but three were men. They were on either tafamidis or tafamidis meglumine at bioequivalent dosages. Overall, their mean serum TTR levels rose 34.5%, from 21.8 mg/dL to 29.3 mg/dL (P < .0001).

Among those with wild-type amyloidosis, TTR levels increased 32.0%, from 21.9 mg/dL to 28.9 mg/dL. Among the those with the variant form, TTR jumped 70.9%, from a mean of 20.6 mg/dL to 35.2 mg/dL, the group reports.

"Astronomical Cost"

"A clinical question is whether we need to test TTR levels for therapeutic monitoring at all or more than once," states an editorial accompanying the report from Falk et al. "From the available data, the stabilizing effect of tafamidis appears almost universal. Barring a low TTR level from a secondary cause, the data suggest that TTR levels would increase in almost all patients," write Ian C. Chang, MD, Eli Muchtar, MD, and Martha Grogan, MD, from the Mayo Clinic, Rochester, Minnesota.

"ATTR-CM is a life-threatening condition with a poor prognosis if untreated; coupled with the astronomical cost of therapy, patients, providers, and insurers are understandably eager to assess response to therapy," they continue.

"However, treatment response in ATTR-CM is challenging for multiple reasons," and "natural history studies, biomarker staging systems, and clinical experience" are limited in determining treatment efficacy in individuals. "Because this disease likely develops over decades, it may take years to detect clinically significant changes in cardiac imaging parameters."

Alternatively, patients and providers alike "will benefit from the virtue of watchful waiting and avoidance of tests that will not change management," the trio writes. TTR levels may one day be used to guide therapy, but until there is a proven test for tafamidis efficacy, "close monitoring for heart failure symptoms, disease progression, and eligibility for organ transplantation remain the mainstays of clinical follow-up."

Falk and colleagues report that all authors were supported in part by the Antonio Elmaleh and Anne Williams Cardiac Amyloidosis Fund, the Appleby Cardiac Amyloidosis Fund, the Sean McDonough Celebrity Golf Classic Fund for Cardiac Amyloidosis, and the Demarest Lloyd Jr. Foundation. Falk has discloses receiving consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; and research funding from GlaxoSmithKline, Eidos, Akcea, and Pfizer. Further disclosures for the other authors are in the report. Muchtar discloses consulting fee paid to his institution from Protego; Grogan discloses fees for clinical trials and/or consulting paid to his institution from Akcea, Alnylam, Eidos, Pfizer, and Prothena; and Chang reports no relevant relationships.

JACC CardioOncol. Published online October 19, 2021. Abstract, Editorial

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