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Clinical Trial
. 2015 Sep 4:10:109.
doi: 10.1186/s13023-015-0326-6.

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

Affiliations
Clinical Trial

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

Ole B Suhr et al. Orphanet J Rare Dis. .

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 .

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Figures

Fig. 1
Fig. 1
Dose response and duration of TTR knockdown. Mean (±SEM) percentage of baseline serum concentration–time profile. Q3W: every 3 weeks; Q4W: every 4 weeks; SEM: standard error of the mean; TTR: transthyretin. *Includes first dose data from additional patient prior to protocol amendment. Excludes post-Day 28 data from patient who experienced drug extravasation during second infusion. One patient discontinued before the second dose of patisiran
Fig. 2
Fig. 2
Effect of patisiran on wild-type and mutant TTR in patients with the Val30Met mutation. a All post-dose data. b Patisiran 300 mg/kg groups (error bars represent SEM). Q3W: every 3 weeks; Q4W: every 4 weeks; SEM: standard error of the mean; TTR: transthyretin; wt: wild-type

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