Early protein rise with heart treatment linked to ATTR-CM survival
Analysis ties Vyndamax boost in TTR levels to lower risk of death
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Vyndamax (tafamidis) leads to rapid and sustained increases in blood levels of the transthyretin (TTR) protein in people with transthyretin amyloid cardiomyopathy (ATTR-CM), and larger increases after one month are linked to a lower risk of death over 2.5 years.
That’s according to a new analysis of data from the Phase 3 ATTR-ACT clinical trial (NCT01994889), top-line data from which supported the therapy’s approval for people with ATTR-CM.
“These findings extend previous reports that lower [initial] TTR levels are associated with poorer survival and worsening of [heart] function and demonstrate that increases in TTR following initiation of [Vyndamax] treatment correlate with improved outcomes,” the researchers wrote.
Still, they added, “variability across disease [features] and [TTR stabilizer therapies such as Vyndamax], along with incomplete understanding of underlying mechanisms, limit the reliability of TTR concentration changes as a biomarker.”
The study, “Impact of Tafamidis on Transthyretin Concentration and Its Relation to All-Cause Mortality in Patients with Transthyretin Amyloid Cardiomyopathy: An Analysis from ATTR-ACT,” was published in Cardiology and Therapy.
Stabilizing TTR
ATTR-CM is marked by the formation and accumulation of toxic clumps of misfolded TTR protein in the heart. Over time, these aggregates can lead to heart failure. ATTR-CM can be caused by inherited mutations or develop sporadically with age (wild-type form).
Pfizer’s Vyndamax, taken as a once-daily oral capsule, works by stabilizing TTR’s four-unit structure as it circulates in the blood, preventing the protein from breaking apart and forming toxic clumps. The treatment is approved to reduce hospitalization and death related to cardiovascular disease in adults with ATTR-CM.
Regulatory approvals were based mainly on data from the global ATTR-ACT study, which showed that Vyndamax was superior to a placebo in significantly reducing the risk of all-cause mortality and cardiovascular hospitalizations in ATTR-CM patients.
Previous studies have shown increases in blood TTR levels after Vyndamax treatment. While the underlying mechanisms “remain incompletely understood,” the researchers wrote, the therapy’s ability to prevent further formation of aggregates may allow more TTR protein to circulate.
While some real-world studies have suggested that early TTR increases with Vyndamax are associated with better survival outcomes, this remains to be examined in a placebo-controlled clinical trial.
To fill this knowledge gap, a team of researchers conducted a post hoc analysis (one designed and carried out after a study is completed) of ATTR-ACT data. Their goal was to assess how TTR levels changed with Vyndamax and whether early increases were associated with a lower risk of death.
The analysis involved data from 175 patients given Vyndamax and 175 given the placebo who were alive after one month into the study. About three-quarters of each group had wild-type ATTR-CM.
Blood TTR levels were measured before treatment, after one month, and at six-month intervals until the end of the study, which lasted 30 months (about 2.5 years).
Data showed that before treatment, TTR levels were similar between the two groups. In the Vyndamax group, levels increased by a mean of 7.3 mg/dL after one month, corresponding to a 36.3% rise. This increase was maintained until the end of the study, according to available data from 110 patients. In contrast, patients given the placebo showed a minimal change in blood TTR levels after one month and up to month 30.
Statistical analyses showed that greater early TTR increases with Vyndamax were significantly associated with better survival outcomes after 2.5 years. Specifically, each 1 mg/dL TTR increase at one month was linked to an 11.3% reduction in the odds of death, while each 5 mg/dL increase was associated with 45% lower odds. No such association was detected in the placebo group.
A separate analysis examining time to death in Vyndamax-treated patients and adjusted for initial TTR levels found that each 1 mg/dL increase at one month was significantly associated with a 9.3% lower likelihood of dying, while a 5 mg/dL increase was significantly linked to a 38.5% lower chance of death.
An analysis adjusted for TTR concentrations and disease stage at the study’s start showed similar trends, but these were no longer statistically significant, meaning they could be due to chance. The researchers noted that the relatively small sample may have limited the statistical power of this analysis.
“The relationship between early [TTR level change] and clinical outcomes is likely to differ across TTR amyloid disease manifestations and even among different [TTR] stabilizers,” the researchers wrote, adding that TTR levels are also affected by inflammation and nutritional state. Therefore, they said, blood TTR levels “cannot be reliably interpreted as a biomarker of therapeutic response.”
Further research is needed to determine whether changes in TTR levels provide useful prognostic information beyond established measures of ATTR-CM progression, the team concluded.
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