VO659 is an antisense oligonucleotide currently being developed to treat patients with polyglutamine diseases including HD, SCA1, and SCA3. This presentation will focus on the work performed within the CMC department at VICO Therapeutics to prepare for the first-in-human clinical trial, and will summarize our lessons learned from the interactions with various European regulatory agencies on the submission of the Investigational Medicinal Product Dossier for VO659.

Investigating the origins of n-1 impurities during solid-phase synthesis is crucial for enhancing therapeutic oligonucleotide quality. In producing 2’-O-[2-(methylamino)-2-oxoethyl] modified phosphorothioate antisense oligonucleotide (NMA PS ASO), we identified n-NMA 5-methylcytosine (n-NMA MeC) as a key impurity caused by deletions of any of five MeC residues. Employing desulfurization for chromatographic separation and direct fragmentation for MS2-based quantitation, we differentiated five isomeric impurities. Incorporating targeted capping steps reduced n-1 levels to <1%.

Avidity Biosciences is developing Antibody Oligonucleotide Conjugates (AOCs), combining monoclonal antibodies with oligonucleotide therapies to treat rare genetic diseases, such as Myotonic Dystrophy Type 1 and Duchenne Muscular Dystrophy. This talk will review siRNA and PMO modalities, focusing on differences in analytical methods for the oligos and their conjugates. Key challenges include analytical methods for AOCs with high drug-to-antibody ratios (DAR) and peak identification through CE-SDS.

CMC has an opportunity to reimagine its innovation to improve drug development. It’s a complex multidisciplinary function critical to the successful development of any drug. Its purpose is to develop processes and methods for producing safe and effective medicines. In the shadows of clinical development, it drives important advances to accelerate drug development, devise new forms of drug delivery that make conditions “druggable,” optimize development cost, and increase patient adherence.

The EMA have recently published draft CMC guidelines for oligonucleotides. We will discuss the implications of these guidelines for the control strategy of therapeutic oligonucleotides from early development to registration. With the guidelines in mind, we will discuss the evolution of a control strategy for impurities in double-stranded oligonucleotides with typical 2' chemical modifications and a limited number of phosphorothioate linkages.

Mass spectrometry proves useful for quality assurance of therapeutic mRNA due to its unique ability to measure base modifications, capping, stability, and impurities. NIST is developing measurement capabilities and oligonucleotide-based reference materials to support measurements of critical quality attributes (CQAs) for therapeutic drug products. A new NIST Test Material (RG 10202 FLuc mRNA) serves as a system suitability standard, a primary quantitative standard, or QC/QA material for comparability assays.

Nucleic acid therapeutics (NATs) have revolutionized the potential to treat many debilitating diseases and life-threatening infections by targeting their genetic fingerprints in vivo. This presentation will provide a comprehensive review of safety challenges and risk mitigation strategies for NATs, including antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles, adeno-associated virus vectors, and CRISPR. 

QurAlis is developing precision therapies, targeting genetic drivers in sub-forms of ALS. Two of QurAlis's programs are in early-phase clinical trials. One of these programs is a splice modulator ASO delivered by intrathecal injection. The talk will focus on how to successfully work with your CMO to meet your timelines and regulatory expectations.

Purification is probably the most time-consuming and critical step in the manufacture of oligos/modified oligos. The topic covers purification method selection criteria and strategies in minimizing the risk in the purification steps which are specifically applicable to clinical products manufacture.