Delving into the Latest Updates on Renadirsen with Synapse

Overview

Basic Info

Drug Type

ASO

Synonyms

ENA oligonucleotides, duchenne muscular dystrophy therapeutics - Daiichi Sankyo/Orphan Disease Treatment Institute

+ [1]

Target

dystrophin

Action

modulators

Mechanism

DMD gene modulators

Therapeutic Areas

Nervous System DiseasesCongenital DisordersSkin and Musculoskeletal Diseases+ [1]

Active Indication

Muscular Dystrophy, Duchenne

Inactive Indication-

Originator Organization

Daiichi Sankyo Co., Ltd.

Active Organization

Daiichi Sankyo Co., Ltd.

Inactive Organization

Orphan Disease Treatment Institute Co., Ltd.

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

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Sequence Code 32858997

Source: *****

Author: Ito, Kentaro ; Koizumi, Makoto ; Asano, Daigo ; Kakuta, Masayo ; Masuda, Takeshi ; Matsuo, Masafumi ; Goda, Ryoya ; Kanda, Akira ; Takagi, Nana ; Onishi, Yoshiyuki ; Takakusa, Hideo ; Nagase, Hiroyuki ; Onoda, Toshio ; Nakamura, Akifumi ; Takeshima, Yasuhiro ; Takaishi, Kiyosumi ; Watanabe, Nobuaki

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients’ DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2′-O,4′-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2′-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2′OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.

Nucleosides, Nucleotides & Nucleic Acids

Tissue distribution of renadirsen sodium, a dystrophin exon-skipping antisense oligonucleotide, in heart and diaphragm after subcutaneous administration to cynomolgus monkeys

Article

Author: Fusegawa, Keiichi ; Yamamura, Naotoshi ; Takeshima, Yasuhiro ; Shibaya, Yukari ; Watanabe, Kyoko ; Yamanaka, Ryo ; Matsuo, Masafumi ; Asano, Daigo ; Koizumi, Makoto ; Kanda, Akira ; Takaishi, Kiyosumi ; Takakusa, Hideo ; Nagase, Hiroyuki

The pharmacokinetics and tissue distribution of renadirsen sodium, a dystrophin exon-skipping phosphorothioate-modified antisense oligonucleotide with 2'-O,4'-C-ethylene-bridged nucleic acid (ENA), after subcutaneous or intravenous administration to cynomolgus monkeys were investigated. The plasma concentration of renadirsen after subcutaneous administration at 1, 3, and 10 mg/kg increased with the dose. The absolute bioavailability at 3 mg/kg after subcutaneous administration was calculated as 88.6%, and the time to reach maximum plasma concentration of renadirsen was within 4 h, indicating the efficient and rapid absorption following subcutaneous administration. The exposure of muscle tissues to renadirsen was found to increase with repeated dosing at 6 mg/kg, and higher exposure was observed in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen achieved more exon 45-skipped dystrophin mRNA in the diaphragm and heart than in the quadriceps femoris and anterior tibialis muscles. Renadirsen also showed a cumulative skipping effect in a repeated-dose study. The findings on exon 45-skipped dystrophin mRNA in these muscle tissues were consistent with the concentration of renadirsen in these tissues. Because it is not feasible to directly evaluate drug concentration and exon skipping in the heart and diaphragm in humans, the pharmacokinetics and pharmacodynamics of renadirsen in these tissues in monkeys are crucial for the design and interpretation of clinical settings.

100 Deals associated with Renadirsen

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Muscular Dystrophy, Duchenne	Preclinical	Japan	Orphan Disease Treatment Institute Co., Ltd.	01 Oct 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02667483 (CTgov)	Phase 1/2	Muscular Dystrophy, Duchenne	8	DS-5141b (All: DS-5141b 2.0 mg/kg)	oqzdokhkyv(zldifxxahx) = pubqmkiiix mjkzcmuntt (wxyozncpld, ymusebekry - atsgabiwwj) View more	-	07 Mar 2024
				DS-5141b (All: DS-5141b 6.0 mg/kg)	oqzdokhkyv(zldifxxahx) = pctkxssltb mjkzcmuntt (wxyozncpld, jtfozobvyl - foktocxujw) View more
ASH2023	Phase 1/2	-	51	ASTX727 + VEN + IVO	(ucgvjpxrjg) = ogkgadpxbt blprdnqsfo (ixtcsdokxg ) View more	-	11 Dec 2023
				ASTX727 + VEN + ENA	(ucgvjpxrjg) = aoikdpeytd blprdnqsfo (ixtcsdokxg ) View more