This talk will cover chemical modifications and structure-activity relationships; delivery mechanisms and clinical advances and going beyond liver using oligonucleotide therapeutics.

This talk will discuss the development of new tools to synthesize and potentially manufacture small (cyclic dinucleotides, CDNs) and large oligonucleotides using the naturally occurring oxidation state of phosphorus: P(V). A suite of commercially available reagents, developed in collaboration with BMS, will be described and showcase how they can be used to generate exotic CDNs, chimeric oligonucleotides, and other P-based nucleoside analogs such as di- and tri-phosphates.

Biocatalysis has transformed chemical synthesis of small molecule APIs. Enzymes are now seeing applications beyond small molecule and are being exploited in the application of oligonucleotide synthesis. This presentation will showcase how enzymes can be used in both single and double stranded oligonucleotide synthesis. It will highlight Almac’s ‘3-2-3-2’ hybrid biocatalytic approach for oligonucleotide synthesis that alleviates the pressures on existing solid phase capacities and utilizes more convergent synthesis.

Thiomorpholino oligonucleotides (TMOs) and their DNA chimeras are new analogues containing morpholino- and 2’-deoxyribonucleosides joined through thiophosphoramidate internucleotide linkages. The TMO and TMO/DNA chimeras were observed to have higher melting temperatures when compared to natural DNA/DNA and DNA/RNA duplexes and are active with RNase H1. These analogues are efficiently taken up by cells and stimulate biological activity in primary cells as well as various established cells lines. Current research underway in over 20 collaborations are focused primarily on rare and fatal genetic diseases. The lecture will focus on results from Duschenne Muscular Dystrophy, Niemann-Pick type C1 and regulating the maturation of TUG 1 and TERT RNA. 

Computational modeling can be used to screen covalent modifications to RNA structure quickly and at low cost, relating to the intended function of the drug product through thermodynamic measurements. Previous work has shown that dsRNA modeled in silico quantitatively agrees with solution state experimental data. Combining high quality all-atom models with the predicted behavior of oligonucleotide modifications, we propose a set of primary sequence-based rules which direct oligonucleotide product stability.

A risk-based approach for routine identity testing of therapeutic oligonucleotide drug substances and drug products will be presented. Risk analysis of solid phase oligonucleotide synthesis indicates that intact mass measurement is a powerful technique for confirming synthesis of the intended oligonucleotide. Further risk assessment suggests that addition of a second, sequence-sensitive identity test, which relies on comparison of some property of the sample to a reference standard of proven identity, results in a sufficient test of identity for most oligonucleotide drug substance and products. Alternative strategies for drug product identity testing will be described. The analysis creates a common way to communicate risk and should result in a harmonized approach to identity testing that avoids the unnecessary analytical burden associated with routine de novo sequencing without compromising quality or patient safety.          

A primary function of the parenteral drug product manufacturing process is to ensure sterility of the final product. Although terminal sterilization process has always been the preferred choice of the regulators, the recent EMA guidance demands a substantial effort to enable terminal sterilization and a robust data package to justify an aseptic sterile filtration process. This guidance also applies to synthetic oligonucleotides which due to their size, structural complexity, and relative lack of governing regulations pose many development challenges. This presentation will discuss specific considerations and challenges associated with terminal sterilization of oligonucleotides.

CMC (Chemistry, Manufacturing and Control) for oligonucleotides synthesized by solid phase synthesis and purified by chromatography is an unusual regulatory situation compared to small molecules and synthetic peptides due to the relative short experience and the various types of oligonucleotides. Some of the usual ICH guidelines for drug substances and drug products do not fully apply. This talk will provide some suggestions on what can be done based on my experience.

The talk will discuss how the analytical control strategy for an oligonucleotide drug substance and product needs to address the challenges of oligonucleotides, satisfying regulatory requirements and supporting QC for a fast-moving supply chain. We will discuss the regulatory strategies required to deal with issues of control of starting materials and drug substance identity, diastereomeric control (of phosphorothioates), assays, impurity profiling, and reducing testing with no value to the patient.

Bachem known as the leading CMO for pharmaceutical grade peptides is expanding its technology platform to offer chemical manufacturing services for nucleic acid based APIs. We would like to take the opportunity to present Bachem’s capabilities as the first CMO servicing the global TIDES market.

Current regulatory intelligence for early development and late-phase filings will be discussed, including common health authority requests and recent regulatory guidance, and approaches for their phase appropriate implementation.  Use of agency interactions for guiding development activities will also be discussed and examples provided.

The development and approval of several RNAi therapeutics denote a significant milestone in the field of oligonucleotide-based drug development. This talk explores the CMC challenges and regulatory strategies for the development and approval of RNAi therapeutics including the delivery challenges of siRNAs and the applicability of available guidance on regulatory control strategies for oligonucleotides.