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

Abstract

BackgroundTransthyretin-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).MethodsIn 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).ResultsOf 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).ConclusionsPatisiran 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 numberNCT01617967.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0326-6) contains supplementary material, which is available to authorized users.

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

“…15 In contrast, subcutaneously administered revusiran is targeted to the liver by a simple carbohydrate ligand that enables receptor-mediated uptake by the ASGPR expressed on hepatocytes and does not require any pre-medication. The level of TTR knockdown observed with revusiran administration in this study is comparable with that reported for intravenous patisiran (0.3 mg/kg every 3 weeks 16 ) and greater than that reported for the antisense oligonucleotide (ASO) agent IONIS-TTR RX in healthy volunteers. 17,18 The most common TEAEs for revusiran were mild to moderate ISRs and the signs and symptoms associated with these reactions.…”

Systemic delivery of factor IX messenger RNA for protein replacement therapy

“…Compared with other lipid formulations from industry leaders like DLin-MC3-DMA or MC3 [heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate], LUNAR is five times more efficient. MC3 is the ionizable lipid component of Patisiran, which is currently in clinical trials for treatment of transthyretin-mediated familial amyloid polyneuropathy (FAP) (13,14). Additionally, doses of up to 10 mg/kg did not cause any increase in circulating aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels (markers associated with acute liver toxicity), thus establishing the safety of this technology (Fig.…”

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

“…47 Unfortunately, these delivery approaches result in limited distribution primarily to the liver and are associated with such intense proinflammatory reactions that prophylactic doses of steroids, histamine antagonists, and NSAIDS are required prior to each administration, and despite these pretreatments, serious infusion reactions are reported in 20% or more of treated patients. [48][49][50][51][52][53][54] However, as mentioned briefly above, a more effective solution to the in vivo delivery of siRNA molecules (at least for the delivery of siRNA to hepatocytes) has been has been the conjugation of double-stranded siRNA molecules (and ASOs) to GalNAc moieties resulting in the active uptake of these conjugates into hepatocytes via Asialoglycoprotein receptors. 43 However, to achieve effective stability and distribution of GalNAcconjugated siRNAs, substantial additional chemical modifications must be incorporated, and thus, most GalNAc-conjugated siRNAs in development contain 10 to 14 PS moieties, 11 to 14 2ʹ-methoxy and 10 to 14 2ʹ-fluoro (2ʹ-F)-modified nucleosides.…”

“…However, several siRNA inhibitors are also currently being evaluated in cancer clinical trials, and in all these trials the siRNA molecules have been formulated into various types of nanoparticles including lipid nanoparticles or liposomes. [47][48][49][50][51][52] Most of these remain at early stages of development, and the data are not yet mature enough to determine their clinical potential. However, evidence of siRNA-mediated target inhibition on systemic delivery for a human solid tumor (melanoma) has been demonstrated, first in a clinical trial with CALAA-01, an siRNA-targeting ribonuclease reductase subunit 2 that is complexed with a cyclodextrin polymer coated with polyethylene glycol and decorated with human transferrin protein on the surface of the particle.…”