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 .

• Authors: Ole B Suhr, Teresa Coelho, Juan Buades, Jean Pouget, Isabel Conceicao, John Berk, Hartmut Schmidt, Márcia Waddington-Cruz, Josep M Campistol, Brian R Bettencourt, Akshay Vaishnaw, Jared Gollob, David Adams
• Journal: Orphanet journal of rare diseases (Orphanet J Rare Dis) Vol. 10 Pg. 109 (Sep 04 2015) ISSN: 1750-1172 [Electronic] England
• PMID: 26338094 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• patisiran

Topics

• Aged
• Amyloid Neuropathies, Familial (drug therapy)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• RNA, Small Interfering (administration & dosage, therapeutic use)