This activity was funded by Alnylam Pharmaceuticals. The medical content was developed independently by M3 and Professor Violaine Planté-Bordeneuve.

Highlights from

Amyloidosis Conferences



Tafamidis treatment in ATTRv-PN: clinical and real-world evidence

Hereditary transthyretin-mediated (hATTR) amyloidosis, a rare progressive disease, is the result of mutations in the transthyretin (TTR) protein that destabilise the protein’s tetrameric structure, facilitating dissociation into monomers that misfold and aggregate into amyloid fibrils.1,2 These fibrils are deposited throughout a patient’s body, giving rise to a multisystemic disease. hATTR is traditionally described, according to the predominant clinical manifestation, as hATTR with polyneuropathy (ATTRv-PN) or hATTR with cardiomyopathy (ATTRv-CM).3 More than 80 TTR mutations have been described, of which the Val30Met (V30M) mutation is the most frequently reported worldwide.4

ATTR amyloidosis can be managed with therapies for the relief of symptoms, such as loop diuretics to reduce filling pressure in ATTR-CM, and with therapies that target the underlying pathophysiology, such as gene silencers and TTR stabilisers.

Tafamidis, which is now approved in the EU for stage 1 symptomatic ATTRv-PN and for wild-type or variant ATTR-CM, works by slowing the dissociation of the TTR tetramer into monomers - the rate-limiting step in the amyloidogenic process - by binding to TTR at the thyroxine-binding sites.

At this year's World Congress of Neurology, Dr Fabio Barroso discussed the clinical and real-world evidence that supports the long-term safety and efficacy of tafamidis in ATTRv-PN.

Pivotal 18-month study1

The safety and efficacy of tafamidis was first assessed in 2012 in a randomised, double-blind, placebo-controlled study in 128 patients with early-stage V30M ATTRv-PN. "This study provided the first evidence in efficacy evaluable patients that tafamidis was effective in delaying the progression of neurological impairment in ATTRv-PN," explained Dr Barroso. At 18 months, analysis of the coprimary endpoints showed (ITT population, N=125):

  • more patients receiving tafamidis versus placebo were NIS-LL responders (<2-point increase in NIS-LL overall score; 45.3% vs 29.5%; p=0.068)
  • patients receiving tafamidis had a smaller LS mean change in TQOL from baseline (increase = worsening TQOL) than patients receiving placebo (2.0 vs 7.2; p=0.116)

Long-term extension study5

More recently, the long-term safety and efficacy of tafamidis has been investigated in a 36-month open-label study, that recruited patients who had completed the original pivotal study and 12-month extension, and patients without a V30M mutation who had completed a 12-month study with tafamidis:

  • 37 patients with a V30M mutation had received placebo for 18 months before switching to tafamidis
  • 38 patients with a V30M mutation received tafamidis continuously from Day 1
  • 18 patients without a V30M mutation received tafamidis continuously from Day 1

"A post hoc analysis of this population showed that the earlier the treatment the better, in terms of preservation of neurological function", Dr Barroso shared with the audience, showing that patients who were treated with tafamidis from the beginning of their treatment showed less deterioration in neurological function than patients who initially received placebo instead of tafamidis.

The safety data revealed that tafamidis was generally well tolerated over a period of up to 6 years. The rate of adverse events (AEs) was similar in patients who continuously received tafamidis and patients who switched from placebo to tafamidis. Some AEs were more common in patients without a V30M mutation but, Dr Barroso noted, "this was attributed to higher age of these patients and more severe disease when they started treatment."

Real-world evidence6

Dr Barroso ended his talk by sharing real-world evidence for tafamidis, from a multi-institutional, hospital-based study of patients with V30M ATTRv-PN. This study compared 1,771 untreated patients, 957 patients who received a liver transplant and 432 patients treated with tafamidis. Dr Barroso showed that 10-year survival was greater in patients treated with tafamidis (96%) versus patients who received a liver transplant (72%-73%) with an HR of 0.37 (95% CI:0.14-1.00; p=0.05),* concluding that "this shows clearly that there is this additional benefit in survival when using this treatment."

*Data from patients with early-onset disease (younger than 50 years of age).6

CI: confidence interval; HR: hazard ratio; ITT: intention-to-treat; LS: least squares; NIS-LL: neuropathic impairment score-lower limbs; TQOL: total quality of life

Based on: Barroso F. Targeted treatment for ATTR amyloidosis: clinical and real-world evidence. Presented at the World Congress of Neurology, 3-7 October 2021


  1. Coelho T, Maia L F et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012;79(8):785-792
  2. Lamb Y N, Deeks E D. Tafamidis: a review in transthyretin amyloidosis with polyneuropathy. Drugs 2019;79(8):863-874
  3. Hawkins P N, Ando Y et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med 2015;47(8):625-638
  4. Gertz M A, Benson M D et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 2015;66(21):2451-2466
  5. Barroso F A, Judge D P et al. Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years. Amyloid 2017;24(3):194-204
  6. Coelho T, Ines M et al. Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy. Neurology 2018;91(21):e1999-e2009

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