Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study.

ABSTRACT: BACKGROUND: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. TRIAL REGISTRATION NUMBER:NCT01617967 .

SUBMITTER: Suhr OB 

PROVIDER: S-EPMC4559363 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature