Main Conference Day 2Wednesday, 12 November 2025 - Europe/Amsterdam

2’-N-methylacetamide (NMA) nucleotides are a novel type of monomer for splice modulating Antisense Oligonucleotides (ASOs). Recently, a sequence consisting of 18 NMA nucleotides was developed and manufactured at scales up to 163 mmol. Despite the seemingly inert nature of the 2’ NMA functionality, it is prone to engaging in side reactions that result in the formation of late-eluting impurities (LEI), which are challenging to control without negatively impacting coupling completion. Ultimately, LEI were mitigated by judicious choice of the amidite to activator ratio used in coupling. Targeted capping steps were introduced in select elongation cycles that were prone to generating deletion impurities, thereby reducing the incidence of deletion impurities with minimal introduction of capping related impurities. Additionally, it was necessary to develop a new cleavage and deprotection protocol to control the rate of NMA related cleavage products, as well as impurities related to the addition of methylamine to the ASO. Described herein is a summary of development efforts and the first on-scale manufacture of a 2’-NMA functionalized ASO.

At Wave Life Sciences, stereopure oligonucleotides containing chimeric phosphorothioate (PS), phosphoryl guanidine (PN) and phosphodiester (PO) backbones are rationally designed to optimize pharmacology and efficacy. Our methods enable synthesis of stereopure oligonucleotides with PS and PN linkages, therefore the configuration of each linkage must be confirmed as part of identity testing. We will describe approaches to confirm stereochemical identity of the oligonucleotide with an emphasis on confirming configuration using chromatography and enzymatic digestion in addition to the standard techniques of Mass ID and MS/MS sequencing.

RBD4059 is a first-in-class GalNAc-siRNA targeting coagulation Factor XI (FXI), designed to reduce thrombosis risk with fewer bleeding complications. In a Phase 1 study, it showed dose-dependent, sustained FXI knockdown with a favorable safety profile in healthy volunteers. The drug’s long duration and selective action support its potential as a next-generation anticoagulant. Phase 2a trials are underway.

The presentation will address the clinical characteristics of customized therapies with a focus on epilepsy. Possible clinical considerations regarding efficacy, side effects, and dealing with parents' fears and wishes will be discussed.