Abstract | BACKGROUND: TTR aggregation causes hereditary transthyretin (TTR) polyneuropathy (ATTRv-PN) in individuals with destabilised TTR variants. ATTRv-PN can be treated with ligands that bind TTR and prevent aggregation. One such ligand, tafamidis, is widely approved to treat ATTRv-PN. We explore how TTR stabilisation markers relate to clinical efficacy in 210 ATTRv-PN patients taking tafamidis. METHODS: TTR concentration in patient plasma was measured before and after tafamidis treatment using assays for native or combined native + non-native TTR. TTR tetramer dissociation kinetics, which are slowed by tafamidis binding, were also measured. RESULTS: Native TTR levels increased by 56.8% while combined native + non-native TTR levels increased by 3.1% after 24 months of tafamidis treatment, implying that non-native TTR decreased. Accordingly, the fraction of native TTR increased from 0.54 to 0.71 with tafamidis administration. Changes in native and non-native TTR levels were uncorrelated with clinical response to tafamidis. TTR tetramer dissociation generally slowed to an extent consistent with ∼40% of TTR being tafamidis-bound. Male non-responders had a lower extent of binding. CONCLUSIONS: Native and non-native TTR concentration changes cannot be used as surrogate measures for therapeutic efficacy. Also, successful tafamidis therapy requires only moderate TTR stabilisation. Male patients may benefit from higher tafamidis doses.
|
Authors | Cecília Monteiro, Jaleh S Mesgarzadeh, João Anselmo, Joana Fernandes, Marta Novais, Carla Rodrigues, David L Powers, Evan T Powers, Teresa Coelho, Jeffery W Kelly |
Journal | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
(Amyloid)
Vol. 30
Issue 1
Pg. 81-95
(Mar 2023)
ISSN: 1744-2818 [Electronic] England |
PMID | 36178172
(Publication Type: Journal Article)
|
Chemical References |
- tafamidis
- Prealbumin
- Benzoxazoles
|
Topics |
- Humans
- Male
- Amyloid Neuropathies, Familial
(drug therapy, genetics)
- Prealbumin
(genetics, metabolism)
- Polyneuropathies
(drug therapy, genetics)
- Benzoxazoles
(pharmacology, therapeutic use)
|