Tafamidis Linked to Stable Neurologic Function in Mixed-Phenotype Amyloidosis

Patients with transthyretin amyloidosis that affects both the heart and the peripheral nerves showed remarkably little neurologic deterioration after at least a year of treatment with tafamidis, according to a retrospective real-world study published in Cardiology and Therapy. Across 67 patients treated at four specialist centers in the United States, Portugal, Canada and Italy, the median change in key neurologic scores from baseline was zero, and the vast majority of patients did not worsen in their walking-related disability stage. The findings add to a small but growing body of real-world evidence on how this drug performs outside the tightly controlled setting of a clinical trial.

Transthyretin amyloidosis, or ATTR amyloidosis, is a systemic and progressive disease in which amyloid fibrils derived from transthyretin protein deposit in the heart, peripheral nerves and other tissues. Depending on where the deposits accumulate most, patients may present predominantly with ATTR cardiomyopathy, with ATTR polyneuropathy, or with a mixed phenotype that combines both cardiac and neurologic manifestations. The mixed form is not a rarity: an analysis from the Transthyretin Amyloidosis Outcomes Survey found that one-third of patients with variant or wild-type disease in the registry had a mixed phenotype, and roughly 30 percent of those had migrated from a predominantly neurologic or cardiac presentation to a mixed one over one to two years of follow-up. A separate Canadian analysis of 60 patients with variant ATTR cardiomyopathy found that half had abnormalities on both neurologic examination and nerve conduction studies.

Tafamidis is an oral TTR kinetic stabilizer approved at a dose of 61 mg free acid once daily for ATTR cardiomyopathy. In randomized trial data, patients receiving the drug had a statistically significant reduction in mortality at 30 months compared with placebo. An earlier exploratory real-world study of just 10 patients with variant mixed-phenotype disease reported neurologic stabilization after six or more months of treatment, with seven patients maintaining normal muscle strength, nine showing no decline, and walking capacity stable or improved in the majority. An analysis from the THAOS registry also found that treated patients with mixed-phenotype disease had numerically higher survival, fewer cardiovascular-related hospitalizations and fewer deaths than untreated patients. The new study was designed to extend these observations to a larger and more diverse cohort with a longer minimum treatment duration.

The study is registered as NCT06393465. Eligible patients were adults with variant or wild-type mixed-phenotype ATTR amyloidosis, defined as a diagnosis of both ATTR polyneuropathy and ATTR cardiomyopathy, who had been treated with tafamidis 61 mg for at least 12 months and had neurologic assessments both before and after treatment. Patients with any prior organ transplant, those who were non-ambulatory at baseline, and anyone who had received another disease-modifying therapy were excluded.

Of 465 patients screened, 67 met all eligibility criteria. The median age at baseline was 77.0 years, 79.1 percent were male, and 55.2 percent had variant ATTR amyloidosis, with the V50M variant being the most common at 23.9 percent of patients. The median duration of treatment with tafamidis 61 mg was 35.0 months. Neurologic function was assessed with the Neuropathy Impairment Score motor and reflex subscales, the Medical Research Council Scale for Muscle Strength, and the polyneuropathy disability score, which grades walking capacity from stage 0, meaning no impairment, to stage IV, meaning confinement to a wheelchair or bed. At baseline, most patients had minimal motor impairment, with a median NIS motor subscale of 0.5, and 73.4 percent were in polyneuropathy disability stage I.

After at least 12 months of treatment, the primary neurologic endpoints remained stable: the median change from baseline was zero for the NIS motor subscale, the NIS reflex subscale and the MRC muscle strength score. The distribution of polyneuropathy disability stages also did not change significantly, with 67.2 percent of patients in stage I both at baseline and after treatment, and 92.2 percent of patients experiencing no worsening in stage. Longitudinal mixed-effects analyses, which used all available data points to compare the rate of disease progression before and after treatment began, showed a numerical reduction in the monthly rate of change of the NIS motor subscale, from 0.40 before treatment to minus 0.03 afterward, but the authors emphasized that this difference was not statistically significant and that the same pattern was not seen in the NIS reflex scale.

Beyond the nerves, other measures of general clinical status also held steady. The modified body mass index, calculated as body mass index multiplied by serum albumin to compensate for peripheral edema, showed a median change of 6.7 g/L × kg/m2, which was not statistically significant. Among the 20 patients with available data, 90 percent remained within the same Essential Frailty Toolset score range, a frailty measure collected at the Canadian site only. Cardiac measures were generally maintained, with troponin I, troponin T and NT-proBNP levels remaining stable, although interventricular septal thickness increased modestly by a median of 0.1 centimeters and left atrial diameter increased by a median of 0.3 centimeters, changes the authors suggest may reflect ongoing cardiac remodeling in this progressive disease. Most patients with available data, 30 of 31, showed no worsening in National Amyloidosis Centre stage. TTR concentration, measured by immunoturbidimetry, increased significantly, with a median change of 3.0 mg/dL, a result consistent with the pharmacodynamic target engagement of tafamidis.

Subgroup analyses were broadly consistent with the overall findings. Results were similar for patients with variant and wild-type disease, although patients with variant amyloidosis showed a modest increase in interventricular septal thickness and those with wild-type disease showed an increase in NT-proBNP levels. A separate analysis focused on 16 patients with variant disease who had initially received tafamidis 20 mg for polyneuropathy and were later switched to the 61 mg dose for cardiomyopathy. In this subgroup, neurologic measures were again stable, with a median change of zero in both NIS subscales, only one patient worsened in polyneuropathy disability stage, and cardiac measures showed no significant changes. The authors note, however, that interpreting neuropathy in wild-type ATTR amyloidosis is particularly difficult because older patients may have overlapping conditions such as diabetes, lumbar spinal stenosis or vitamin B12 deficiency that independently cause polyneuropathy, and evaluation of alternative causes was not standardized in this study.

The authors are careful about what the study can and cannot show. Because there was no comparator group, the results represent an association rather than evidence of a treatment effect, and the retrospective design may have been subject to unmeasured confounding. Selection bias is a real concern: 90 patients were excluded for not having the required treatment duration and 142 for lacking both pre- and post-treatment assessments, criteria that may have selected for patients who survived, tolerated treatment and remained on therapy long enough to be assessed, potentially biasing the results toward apparent stability. Baseline NIS motor scores were low, indicating minimal motor impairment at treatment initiation and limiting interpretation of subsequent stability, and neurologic data were collected as part of routine clinical practice rather than under a standardized protocol. Mortality data were not consistently captured, analyses were exploratory and not adjusted for multiplicity, and outcomes were not analyzed by sex. The authors conclude that neurologic and overall clinical function were maintained during tafamidis treatment in this population and that the findings support further examination of tafamidis monotherapy in patients presenting with both ATTR cardiomyopathy and ATTR polyneuropathy.

Subject of Research: Neurologic and clinical outcomes during tafamidis treatment in mixed-phenotype transthyretin amyloidosis

Article Title: Neurologic Stability During Tafamidis Treatment in Transthyretin Amyloidosis with a Mixed Phenotype: A Multicenter Real-World Study

Article References: Fine, N. M., Streicher, N. S., Conceição, I., Agostinho, J., Obici, L., Palladini, G., Carlsson, M., Amass, L., & Sheikh, F. H. (2026). Neurologic Stability During Tafamidis Treatment in Transthyretin Amyloidosis with a Mixed Phenotype: A Multicenter Real-World Study. Cardiology and Therapy, 15(S1), 95-113. https://doi.org/10.1007/s40119-026-00479-z

Image Credits: AI Generated

DOI: 10.1007/s40119-026-00479-z

Keywords: transthyretin amyloidosis, tafamidis, ATTR cardiomyopathy, ATTR polyneuropathy, mixed phenotype, neuropathy, real-world study, TTR stabilization, frailty, retrospective cohort, NIS score, cardiac measures