Are we creating a new phenotype? Physiological barriers and ethical considerations in the treatment of hereditary transthyretin-amyloidosis

Tabel 1 Basic information and pharmakokinetics

	Tafamidis (Vyndaqel™/Vyndamax™)	Patisiran (Onpattro™)	Vutrisiran^a	Inotersen (Tegsedi™)	Eplontersen^a	TTR
Dosage	20/61 mg	0.3 mg per kg body weight	25 mg	300 mg	45 mg	NA
Application	oral	i.v.	s.c.	s.c.	s.c.	NA
Frequency	1×/d	1×/3 weeks	1×/3 months	1×/week	1×/4 weeks	NA
Effect site	Liver/blood	Liver	Liver	Liver	Liver	NA
Uptake mechanism/receptors	Unspecific	Unspecific	Specific trough GalNaC modification via ASGPR	Unspecific	Specific trough GalNaC modification via ASGPR	NA
Molecule size [D]	308.12	14,304	MD	7600.8	9046.1	55 K, 16 K g/mol
Plasma t_1/2	24 h	0.79 h	4.8 h	3.9 h	1.6 h	48 h
Tissue distribution	Liver and plasma	Liver ≫ lymphatic tissues > kidneys, lungs, heart, adrenals	Liver, kidneys, injection site	Liver, kidney, lymphatic tissues, injection site, bone marrow	Liver, kidney, injection site	Plasma, CSF, eyes, liver, kidney, pancreas
BBB passage	Partial (1.5%)	None	None	None	None	2–10% synthesis in choroid plexus and retina

Synoptic summary on the three approved drugs tafamidis, patisiran, and inotersen, and the two drugs vutrisiran and eplontersen that are currently in phase III trials. Data were provided by the respective pharma companies (Pfizer, Alnylam, and Ionis). If the exact information was not being publicly available at the time when this paper was written (09/2021) or provided upon request, we indicated this with MD (missing data). For comparison, we provide similar information on the TTR protein on the right. ASGPR, asialoglycoprotein receptor receptor; BBB, blood–brain barrier; CSF, cerebrospinal fluid; GalNac, NA, N-Acetylgalactosamine; h, hour(s); i.v., intraveneous; NA, not applicable; s.c., subcutaneous; t_1/2, half-life
^aDrug not (yet) approved in Europe or in the United States of America

ISSN: 2524-3489