Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial

Abstract

Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP).

Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population.

Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups.

Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment.

Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.

Figure 1. The TTR amyloidogenesis cascade is blocked by tafamidis-mediated kinetic stabilization of tetrameric TTR

Tafamidis, depicted as the black space-filling structure with a red carboxyl group, binds to tetrameric TTR (far left), slowing TTR tetramer dissociation, which is the rate-limiting step for TTR amyloid fibril formation. Thus, the TTR-tafamidis complex is locked in a functional, nonamyloidogenic state, rendering the neurodegenerative amyloidogenesis cascade inaccessible. TTR = transthyretin.

Figure 2. Coprimary endpoints in the ITT population and secondary analysis in the EE population

(A) Percentage of patients in each treatment group classified as NIS-LL responders at month 18 based on an increase of <2 points in NIS-LL overall score in both the ITT (primary analysis) and EE (prespecified secondary analysis) populations. EE = efficacy-evaluable; ITT = intent-to-treat; NIS-LL = Neuropathy Impairment Score–Lower Limbs. (B) LS Mean (±SE) change from baseline at month 18 in the TQOL score from the Norfolk QOL-DN in the same populations. LS Mean = least-squares mean; QOL-DN = Quality of Life–Diabetic Neuropathy Questionnaire; TQOL = Norfolk Quality of Life–Diabetic Neuropathy total score.

Figure 3. Secondary endpoints in the ITT population

This figure shows the LS Mean (±SE) changes from baseline at months 6, 12, and 18 for the NIS-LL (A), small- (Σ3 NTSF nds) and large- (Σ7 NTs nds) nerve fiber function (B and C, respectively), mBMI (D), and TQOL (E). Analyses were performed using observed cases. ITT = intent-to-treat; LS Mean = least-squares mean; mBMI = modified body mass index; NIS-LL = Neuropathy Impairment Score–Lower Limbs; TQOL = Norfolk Quality of Life–Diabetic Neuropathy total score; Σ7 NTs nds = summated 7 nerve tests normal deviates; Σ3 NTSF nds = summated 3 nerve tests small-fiber normal deviates.