FDA Funds Collaborative Project to Develop New Approaches to Assess the Quality of Oligonucleotide Therapies

Dr. Jace Jones (UM School of Pharmacy), jointly with co-PIs Dr. Steven Fletcher (UM School of Pharmacy), Dr. Michael Cummings (University of Maryland, College Park) and Dr. Robert G Brinson (NIST-IBBR), was recently awarded a grant from the FDA Center for Drug Evaluation and Research to develop and evaluate new analytical approaches to assess the quality of oligonucleotide therapeutics.

The proposal seeks to develop a synergistic analytical characterization scheme for an emerging drug product class, known as antisense oligonucleotide therapeutics (ASO). ASOs target important rare diseases that do not have other treatment options. This therapeutic class is manufactured through synthetic methods, and the sugar-phosphate backbone is altered from being linked through phosphorus and oxygen to a backbone that is linked through phosphorus and sulfur, known as a phosphorothioate linkages. Such changes are made to improve the pharmacokinetics of ASO drugs, but introduce a chiral center or a ‘handedness’ at the position of the altered structure. Current manufacturing methods lead to a diastereomeric distribution, meaning a mixture of both left- and right-handed conformations, and this specific distribution of an ASO is an important quality attribute (QA) that can impact the overall effectiveness of the drug product. 

The researchers will use multiple batches of the approved drug TEGSEDI (inotersen) as their model ASO therapeutic. Inotersen is prescribed to treat damage to peripheral nerves that arises from a condition known as hereditary transthyretin-mediated amyloidosis. They plan to combine liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy methods to fully characterize the diastereomeric distribution. They will then apply multivariate and machine learning techniques to predict the overall diastereomeric distribution of test samples. Successful completion of this research will provide tools to the pharmaceutical industry and regulators that will help ensure batch-to-batch quality and comparability for this class of drug products.