Suhr, Ole BCoelho, TeresaBonilla, AlfonsoPouget, JeanConceicao, IsabelBerk, JohnSchmidt, HartmutWaddington-Cruz, MarciaCampistol, Josep MBettencourt, Brian RVaishnaw, AkshayGollob, JaredAdams, David2024-07-042024-07-042015-09-04Suhr Ole B, Coelho T, Buades-Reine'S J, Pouget J, Conceicao I, Berk J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015 Sep 04;10:109.1750-1172http://hdl.handle.net/20.500.13003/10700http://hdl.handle.net/20.500.12105/20141Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development.enghttp://creativecommons.org/licenses/by/4.0/PatisiranRNA interferenceTransthyretin-mediated familial amyloidotic polyneuropathyPolyneuropathyHereditary diseaseGenetic mutationPhase IIClinical trialRNA, Small InterferingAgedMaleDose-Response Relationship, DrugFemaleHumansMiddle AgedAmyloid Neuropathies, Familialresearch articleAttribution 4.0 International263380941010910.1186/s13023-015-0326-6Orphanet Journal of Rare Diseasesopen accessNeuropatías Amiloides FamiliaresRelación Dosis-Respuesta a DrogaHumanosPersona de Mediana EdadAncianoFemeninoARN Interferente PequeñoMasculino2-s2.0-84940759062360525400002L605848775