Tafamidis stabilizes transthyretin in cohort with transthyretin amyloid cardiomyopathy
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According to a non-trial, published in JACC: CardioOncology, in unselected patients, serum transthyretin change after tafamidis initiation for transthyretin amyloid cardiomyopathy may serve as a surrogate measure of drug efficacy.
“Transthyretin (TTR)-derived amyloid (ATTR) cardiomyopathy is an increasingly recognized disease characterized by infiltration of the myocardium with either variant or wild-type amyloid derived from transthyretin,” Rodney H. Falk, MD, director of the cardiac amyloidosis program and a cardiovascular medicine specialist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, and colleagues wrote. “One method of treatment is to use small molecules that stabilize TTR, thereby lessening breakdown into amyloidogenic monomers. To date, three main stabilizing drugs have been used in the treatment of either ATTR cardiomyopathy or neuropathy; diflunisal, tafamidis, and acoramidis (AG10). Of these, only the first two are clinically available, and AG10 is still undergoing evaluation in a pivotal trial.”
Therefore, researchers conducted a study among patients with transthyretin amyloid cardiomyopathy to evaluate the effect of tafamidis (Vyndamax and Vyndaqel; FoldRx/Pfizer) on serum transthyretin and compare data with prior research.
Utilizing records at Brigham and Women’s Hospital, researchers identified 72 patients (mean age, 80 years; three women) with transthyretin amyloid cardiomyopathy who were prescribed tafamidis, since its FDA approval. Transthyretin was measured at baseline and 3 to 12 months follow-up.
Among these patients, 67 patients had wild-type transthyretin amyloid cardiomyopathy and five had variant transthyretin.
Tafamidis and change in serum transthyretin
According to researchers, tafamidis increased serum transthyretin by 34.5%, from 21.8 mg/dL to 29.3 mg/dL.
Moreover, among the five patients with variant transthyretin, the researchers observed an increase of 70.9%, compared with a 32% among those with wild-type transthyretin.
“This is virtually identical to the 33% increase seen in a study of AG10, even though those 32 patients were slightly younger and, by virtue of being in a clinical trial, were more highly selected,” the researchers wrote, citing Judge and colleagues, in the Journal of the American College f Cardiology. In that study, treatment AG10 was well tolerated and achieved target plasma and stabilization of transthyretin.
In other findings, N-terminal pro-B-type natriuretic peptide increased during a mean follow-up of 21 weeks, but the increase was not statistically significant.
Falk and colleagues also noted a small increase in high-sensitivity troponin T during the same period, that met borderline significance (P = .057).
“Whether the difference between the effect on TTR levels of tafamidis at clinically approved doses and AG10 at the higher dose is real and, if so, whether the slightly more potent effect of AG10 is of clinical significance cannot be determined by the current findings,” the researchers wrote. “However, our results suggest that there may not be much difference in clinical efficacy if it is predictable by change in TTR levels. This is emphasized by the finding in the ATTR-ACT trial that both 20 mg and 80 mg of tafamidis meglumine had identical benefits over placebo during the 30 months of the study despite prior data showing lesser stabilization with the lower dose.”
Measuring efficacy of an expensive medication
In a related editorial, Ian C. Chang, MD, of the department of cardiovascular medicine at Mayo Clinic Rochester, and colleagues discussed the implications of this research on such an expensive cardiac medication.
“With a list price of $225,000 per year, tafamidis treatment results in a significant financial burden for many patients, even with insurance coverage,” the editorial authors wrote. “Therefore, with an expensive treatment that has relatively few side effects in this slowly progressive disease, patients and providers commonly wonder whether tafamidis is working and naturally seek measures of efficacy.
“Falk et al report the observation that serum TTR levels increased with tafamidis use and speculate that TTR levels may provide insight into TTR stability and drug efficacy,” the editorial authors wrote. “There is an ongoing need for more data from both clinical trials and post approval use to help inform clinical decision making as it pertains to the use of serum TTR levels in monitoring the treatment of patients with ATTR cardiac amyloidosis.”
References:
- Chang IC, et al. JACC CardioOncol. 2021;doi:10.1016/j.jaccao.2021.09.007.
- Judge DP, et al. J Am Coll Cardiol. 2021;doi:10.1016/j.jacc.2019.03.012.
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