ArticlePDF Available

Early intervention with tafamidis provides long-term benefit in delaying neurological progression in patients with transthyretin familial amyloid polyneuropathy

Authors:
POSTER PRESENTATION Open Access
Early intervention with tafamidis provides long-term
benefitindelayingneurologicalprogressionin
patients with transthyretin familial amyloid
polyneuropathy
Marcia Waddington-Cruz
1*
, Leslie Amass
2
, Denis Keohane
3
, Jeffrey Schwartz
4
, Balarama Gundapaneni
5
, Hui Hua Li
2
From First European Congress on Hereditary ATTR amyloidosis
Paris, France. 2-3 November 2015
Background
Tafamidis is a transthyretin (TTR) stabilizer approved to
delay neurological progression associated with stage 1
TTR familial amyloid polyneuropathy (FAP). A placebo-
controlled, randomized 18-month registration trial
allowed for continued evaluation of patients receiving
tafamidis (20 mg oral once-daily) through an ongoing
open label extension study. The effectiveness of tafami-
dis for delaying long-term neurological progression rela-
tive to baseline levels of neuropathy impairment at the
start of treatment has not been reported previously.
Methods
This analysis describes the trajectory of the disease progres-
sion over 5.5 years or more for 71 patients with the V30M
mutation and stage 1 TTR-FAP who received tafamidis
either at the start of the registration trial or after the switch
from placebo following 18 months of study participation.
All V30M patients treated with tafamidis in the original
trial or its extension and for whom follow-up data were
available were included. The impact of tafamidis on neuro-
logical progression over time was evaluated using the Neu-
ropathy Impairment Scale for lower limbs (NIS-LL).
Baseline NIS-LL at active treatment start was defined as the
last measurement before the first active dose of tafamidis.
Results
Patients (30 male, 41 female) were primarily Caucasian
(91.5%) with a mean (standard deviation [SD]) age of dis-
ease onset of 35.7 (11.31) years. Very low baseline disease
severity, defined as NIS-LL 10 at treatment start (baseline
mean NIS-LL [SD] = 4.1 [3.1]), was associated with a
minimal level of disease progression over time. Mean
change in NIS-LL from baseline (SD) over 5.5 years of
treatment was: 0.6 (3.2) at 1 year, 1.3 (3.7) at 2 years, 2.3
(6.0) at 3 years, 1.7 (4.8) at 4 years and 5.3 (10.1) at 5.5
years. Additional categorization of patients according to
baseline NIS-LL of 0-5 and 5-10 revealed a similar pattern
of reduced disease trajectory. For 3 patients, there was evi-
dence after 3-5 years of treatment of an increase in the
NIS-LL score to 30 or more.
Conclusion
Early intervention with tafamidis provides long-term bene-
fit in delaying neurological progression associated with
TTR-FAP. These data underscore the need to intervene as
early as possible with symptomatic TTR-FAP patients.
Note
First presented at the Peripheral Nerve Society Con-
gress, Montreal, Canada, June 2015.
Authorsdetails
1
Hospital Universitario Clementino, Neuromuscular Diseases Unit, 21941-913,
Rio de Janeiro, Brazil.
2
Pfizer, Pfizer, PA 19426, Collegeville, USA.
3
Pfizer, Pfizer,
NY 10017, New York, USA.
4
Pfizer, Pfizer, CT 06340, Groton, USA.
5
InVentiv
Health, Statistics, MA 01803, Burlington, USA.
Published: 2 November 2015
doi:10.1186/1750-1172-10-S1-P12
Cite this article as: Waddington-Cruz et al.: Early intervention with
tafamidis provides long-term benefit in delaying neurological progression in
patients with transthyretin familial amyloid polyneuropathy. Orphanet Journal
of Rare Diseases 2015 10(Suppl 1):P12.
1
Hospital Universitario Clementino, Neuromuscular Diseases Unit, 21941-913,
Rio de Janeiro, Brazil
Full list of author information is available at the end of the article
Waddington-Cruz et al.Orphanet Journal of Rare Diseases 2015, 10(Suppl 1):P12
http://www.ojrd.com/content/10/S1/P12
© 2015 Waddington-Cruz et al. This is an Open Ac cess article distribute d under the terms of the Creative Commons Attribution
License (http ://creativecommons.org/licenses/by/4.0) , which permits unrestricted use, distribution, and reproduction in any mediu m,
provided the or iginal work is properly cited. The Creative Commons Public Domain Dedicatio n waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Article
Background: Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors. Objectives: To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs). Search methods: On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites. Selection criteria: We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial. Data collection and analysis: We followed standard Cochrane methodology. Main results: The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP. Authors' conclusions: Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed.
ResearchGate has not been able to resolve any references for this publication.