Tafamidis, an oral non-NSAID and highly specific stabilizer of the TTR protein, delays neurologic progression in early-stage transthyretin familial
amyloid polyneuropathy (ATTR-FAP), according to
research published online ahead of print April 10
ATTR-FAP is a progressive condition caused by mutations in the TTR gene that destabilize the TTR protein,
thereby facilitating misfolding and aggregation. The
neuropathy may be accompanied by cardiac, gastrointestinal, renal, or ocular symptoms, and death occurs at
an average of 10 years after symptom onset.
A pivotal phase III trial compared tafamidis with
placebo over 18 months in 128 patients with early-stage ATTR-FAP. Researchers observed a trend toward a smaller increase in Neuropathy Impairment
Score for Lower Limbs (NIS-LL) with tafamidis, compared with placebo, but the result was not statistically significant. Baseline NIS-LL values were higher
among controls than among actively treated patients,
however, and many participants dropped out of the
study for liver transplantation.
In a post hoc analysis, the investigators took these
factors into account and reanalyzed change from baseline in NIS-LL in the trial. They also analyzed change in
NIS-LL plus three small-fiber nerve tests (NIS-LL+Σ3)
and NIS-LL plus seven nerve tests (NIS-LL+Σ7) without
baseline measurements as covariates.
The analysis indicated a significant benefit of tafamidis, compared with placebo, at Months 12 and 18. The
baseline-adjusted mean increase in NIS-LL from baseline to Month 12 was 1. 5 points in the tafamidis group
versus 4. 5 points in the placebo group. By Month 18,
the mean change from baseline was 2. 9 points in the
tafamidis group versus 5. 6 points in the placebo group.
When the researchers applied sensitivity analysis
based on multiple imputation for missing data by treatment group, the mean estimates of the increase in NIS-LL total score from baseline to Month 18 were significantly lower for tafamidis, compared with placebo. A
more conservative model based on multiple imputation
showed a benefit of tafamidis, but results did not reach
The researchers also found a statistically significant benefit of tafamidis, compared with placebo, on NIS-LL+Σ3 at
Months 12 and 18. Significant differences favoring tafamidis also were observed on NIS-LL+Σ7 at Months 12 and
18. Four of the study’s five authors are employees of Pfizer,
which owns tafamidis and sponsored the study. NR
Keohane D, Schwartz J, Gundapaneni B, et al. Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial. Amyloid. 2017
Apr 10 [Epub ahead of print].
Tafamidis Delays Progression
of Rare Polyneuropathy
The drug appears to slow the deterioration of lower limb function and nerve fiber function.