2023 ARCHIVES

Cambridge Healthtech Institute’s 5th Annual

Oligonucleotide CMC and Regulatory Strategies

Accelerating Product Development and Commercial Success

March 13 - 14, 2023 ALL TIMES EDT

Cambridge Healthtech Institute's conference on Oligonucleotide CMC and Regulatory Strategies brings together top scientists and executives from leading biotech and pharma companies to share insights on new developments in analytical characterization, CMC, manufacturing and regulatory issues. The conference will provide an opportunity to discuss and collaborate on how to optimize product development processes and speed up time to market.

Monday, March 13

Main Conference Registration (Gallery Foyer)9:15 am

Welcome Remarks by Conference Organizer10:40 am

10:50 am

Chairperson's Opening Remarks

Lubomir Nechev, PhD, Senior Vice President, CMC Development, Alnylam Pharmaceuticals

10:55 am

FEATURED PRESENTATION: Developing Manufacturing and Quality Control Strategy for siRNA Therapeutics

The last few years showed a significant increase in the number of approved oligonucleotide products, not only in the liver-targeting rare disease area but also in CNS and prevalent diseases. This increased the interest in the process of systematic development of CMC strategies in the field. The talk will focus on successful manufacturing and quality control strategies for synthetic siRNA therapeutics, utilizing different delivery solutions.

11:25 am

CMC Considerations for siRNA Drug Substance Manufacturing – Improving Processes and Learnings from Outsourcing

The quality attributes of siRNA drug substances are affected by used raw materials including customized starting materials such as linkers and conjugates, as well as by the manufacturing process, process parameters, and potential degradation products of the compounds. It is important to increase the understanding of processes and products to allow for improvements of processes and product quality. One of the prerequisites for this is to have good analytics in place. Outsourcing these processes allows the use of different equipment settings and parameters and learning from the experience of the different CMOs.

11:55 am

Adoption and Implementation of Innovative Technologies – Reducing OPEX and Improving Efficiency in Manufacturing

Driving manufacturing process improvement is one of the most effective ways to increase quality, operational efficiency, and ROI (return on investment). Improving the processes that contribute to the final product is an easy way to create scalable and sustainable change. The right improvements can reduce defects, decrease production time, and boost client satisfaction. Organizations experiencing rapid growth, finding new and innovative approaches will ensure that the enterprise operates at full capacity during busy periods. Those that simply want to improve their approach will benefit from adopting modern lean and innovative thinking methods. Every business could take advantage of new ideas, technologies, and best in practice/class in a way that fits with their existing model. Methodologies that can drive manufacturing process improvement, boosting the productivity of the operation, and insuring business outlooks.

12:25 pm

LUNCHEON PRESENTATION:Control and Mitigation of Endotoxin Contamination in Single Stranded Oligonucleotides

Nitto Denki Image Chad Ratterman, Process Development, Process Development, Nitto Avecia

As the list of oligonucleotide therapeutics targeting CNS diseases grows, control of bacterial endotoxincontamination within the API has become critical.Endotoxin can be found on almost every surface andinmanyraw materialswithin the laboratory environment and cannot be eliminated via standard sterilizationmethods. Therefore, control of endotoxin contamination within the API is largely a matter of avoidingintroduction,which requires precautions begin early and continue throughout the manufacturing process.However, unforeseen complications can allow for contamination to occur despite the most rigid ofprecautions. Nitto Avecia has developed a processforresolvingendotoxin contamination withinlyophilized API allowing for rescue of non-conforming batches. This talk will focus on effective controlstrategiesfor endotoxin contamination andoutline a simpleand robust chromatographicpost-hocmitigationprocedure.

Grand Opening Dessert Break in the Exhibit Hall with Poster Viewing (Bohea)12:55 pm

1:35 pm

Chairperson's Remarks

Lubomir Nechev, PhD, Senior Vice President, CMC Development, Alnylam Pharmaceuticals

1:40 pm

Regulatory CMC Interactions and Intelligence for Development and Late-Phase ASO Programs

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. The impact of recent regulations on development activities will be discussed and examples provided.

2:10 pm

Phosphoramidite Standards to Support Quality of Oligonucleotide Biotherapeutics

Currently, there are no standards available for Phosphoramidites, which augments the necessity of developing Phosphoramidite standards.USP have explored new opportunities for development of standards for Phosphoramidites raw materials, including both DNA amidites RS and RNA amidites RS. This talk will focus on the development of DNA amidites RS, which will be available to customers soon. Each of the DNA amidites RS has been evaluated through collaborative studies with multiple international labs involved. The reference standard materials were analyzed for identification and purity using HPLC, MS and NMR techniques. Water content and residual solvent level were also determined for quality control. All the DNA amidites RS have shown NLT 98% purity within the specification limits. The results collected during collaborative study support the suitability of use as reference standards for DNA amidites, the raw materials of oligonucleotide-related products.

2:40 pm

Novel Approaches to Oligonucleotide Synthesis Using Enzymes

Darren Gray, Biology Technical Leader, Sciences, Almac Group

Biocatalysis has transformed chemical synthesis of small molecule APIs in recent years by shortening routes, lowering waste and reducing costs. Enzymes are now seeing applications beyond small molecule and are being exploited in oligonucleotide synthesis. This presentation will showcase how enzymes can be used in both single and double stranded oligonucleotide synthesis.

Refreshment Break in the Exhibit Hall with Poster Viewing (Bohea)3:10 pm

3:50 pm

Plenary Chairperson's Remarks

Dmitry Samarsky, PhD, CTO, Sirnaomics

3:55 pm PLENARY PRESENTATION:

Nucleic Acid Delivery Systems for RNA Therapy and Genome Editing

Here we describe our work developing nanoformulations for RNA therapy and genome editing. Libraries of degradable polymers and lipid-like materials have been synthesized, formulated, and screened for their ability to deliver RNA payloads inside cells. These nanoformulations facilitate in vivo delivery to a range of tissues and can enable targeted gene suppression with siRNA, gene expression with mRNA, or even permanent genetic editing using the CRISPR/Cas9 system.

4:25 pm PLENARY PRESENTATION:

Advances in CRISPR Genome Editing for Therapeutics Application

At Intellia, we are building a full-spectrum genome editing company. We are deploying the industry’s broadest and deepest toolbox, including novel editing and delivery solutions, to harness the immense power of CRISPR-based technologies for in vivo and ex vivo therapeutic applications, each with the potential to revolutionize the future of medicine. In this presentation, we will share the advances in the therapeutic application of CRISPR/Cas9 for genome editing.

4:55 pm PLENARY PRESENTATION:

Recent Developments in Oligo Conjugates

The promise of oligonucleotide therapeutics is to use Watson-Crick-Franklin base-pairing rules to design drugs directly and rationally based on genomic information. Until recently, that promise has remained elusive because of cell barriers to oligonucleotide uptake. Receptor-mediated uptake through bioconjugation oligonucleotides has changed that. Avidity’s AOC technology uses monoclonal antibodies to cell surface proteins that are internalized in order to facilitate the functional delivery of oligonucleotide therapeutics into a broad range of cell and tissue types.

Welcome Reception in the Exhibit Hall with Poster Viewing (Bohea)5:25 pm

Close of Day6:30 pm

Tuesday, March 14

Registration and Morning Coffee (Gallery Foyer)7:45 am

8:30 am

Chairperson's Remarks

Rachel Johns, Senior Director, Formulations, Avidity Biosciences LLC

8:35 am

FEATURED PRESENTATION: Strategies for Optimizing Performance of the Ionis Platform Method for Determination of Assay, Purity, and Impurity Profile of Oligonucleotide Therapeutics Using IP‑HPLC‑UV‑MS

Ionis Pharmaceuticals developed an analytical method for the determination of assay, purity, and impurities of ASOs using IP‑HPLC‑UV‑MS. The method permits identification and quantitation of oligonucleotide impurities and has excellent analytical selectivity. Leveraging over 15 years of experience gained through application of the method for compounds in all phases of development at global testing sites, recommended best practices to ensure successful analysis, and strategies to minimize downtime will be presented.

9:05 am

Identifying the Best Analytical Methods for Characterizing Impurities

Sharing novel methods developed to characterise challenging impurities and method simplification for QC methods.

9:35 am

Therapeutic Potential of an RNA Editing Platform Using Editing Oligonucleotides (EONs)

Gerard Platenburg, CSO and Co-Founder, ProQR Therapeutics

Axiomer, an RNA editing technology, uses Editing Oligonucleotides (EONs) to target specific RNA for A-to-I editing by recruiting endogenous Adenosine Deaminase Acting on RNA (ADAR). This presentation will highlight the therapeutic possibilities of this platform that are not limited to disease causing mutations and can potentially address high unmet medical needs by editing wild-type RNA to engineer proteins or modify their function as well as creating de novo mutations.

10:05 amBreakout Discussions

Breakout discussions provide an opportunity to discuss a focused topic with peers from around the world in an open, collegial setting. Select from the list of topics available and join the moderated discussion to share ideas, gain insights, establish collaborations, or commiserate about persistent challenges. Please visit https://www.optcongress.com/interactive-discussions for a complete listing of topics and descriptions.

IN-PERSON BREAKOUT DISCUSSION:

Evaluating CMC and Analytical Strategies

Mike Webb, PhD, Founder and CEO, Mike Webb Pharma; Former Vice President, API Chemistry & Analysis, GSK

Do we need an ICH guideline for the development of oligonucleotides?
How should we address diastereogmer control in phosphorothioated oligonucleotides?
Avoiding lyophilisation and providing drug substance in solution, a better approach to compounding?
A single industry specification and methods for amadite impurities

Coffee Break in the Exhibit Hall with Poster Viewing (Bohea)10:50 am

11:30 am

Focusing on the Key Control Challenges for Therapeutic Oligonucleotide Drug Substances

There are a number of challenges in developing a control strategy for therapeutic oligonucleotides. In this presentation we will discuss these challenges. Ensuring identity is confirmed with the correct sequence, that reproducible quantitation of impurities is maintained across batches, providing reliable batch purity for drug product compounding and demonstrating consistent diastereomeric ratios across batches of phosphorothiolated oligonucleotides will be discussed as some of the current hot topics.

12:00 pm

Advanced CMC Strategies for Novel Modalities

Avidity Biosciences is a clinical phase company developing a new type of modality, Antibody Oligonucleotide Conjugates (AOCs). This therapeutic consists of a monoclonal antibody, as well as an oligonucleotide and, is therefore a hybrid of a biologic and a small molecule. In this talk, we will discuss the challenges and pathways associated with the Chemistry, Manufacture, and Control of these novel hybrid therapeutics.