Cambridge Healthtech Instituteの第5回年次会議
Oligonucleotide CMC and Regulatory Strategies
2023年3月13 - 14日、EDT（米国東部標準時）
Main Conference Registration9:15 am
Welcome Remarks by Conference Organizer10:40 am
INNOVATIVE MANUFACTURING STRATEGIES
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.
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.
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.
Grand Opening Dessert Break in the Exhibit Hall with Poster Viewing12:55 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.
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.
Sponsored Presentation (Opportunity Available)2:40 pm
Refreshment Break in the Exhibit Hall with Poster Viewing3:10 pm
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.
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.
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 Viewing5:25 pm
Close of Day6:30 pm
Registration and Morning Coffee7:45 am
OPTIMIZING CMC & ANALYTICAL CHARACTERIZATION
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.
Sponsored Presentation (Opportunity Available)9:35 am
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 Breakout Discussions for a complete listing of topics and descriptions.
Evaluating CMC and Analytical Strategies
- 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 Viewing10:50 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.
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.
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own12:25 pm
Session Break1:00 pm
Oligonucleotide CMC: Control Strategy
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 or synthetic peptides due to that situation and the various types of oligonucleotides. The presentation will describe solutions for a smooth development and control strategy.
FEEDBACK ON REGULATORY SUBMISSIONS
Refreshment Break in the Exhibit Hall. Last Chance for Poster Viewing2:45 pm
Biological Studies with Thiomorpholino Oligonucleotides
Currently underway are more than 20 biological studies focused on the use of thiomorpholino oligonucleotides (TMOs) as a therapeutic drug for the treatment of various genetic diseases. These collaborations are being carried out with cells in culture and several have progressed to studies in mouse models. Without exception, TMOs are more active than any other analogue tested and, in one case, a TMO is active under conditions where the 2'-MOE analogue is toxic to mice in the same treatment group.
Advances in Chemistry Made RNAi Therapeutics Possible
For siRNAs, chemical modifications are necessary to regulate metabolic stability, potency (through effects on the interaction with the Ago2 enzyme and the targeted mRNA strand), and safety (impacted by metabolites and on-target specificity). We have evaluated numerous chemical modifications beyond the standard 2’-O-methyl, 2’-fluoro, and phosphorothioate linkages. These include backbone chiral phosphorothioates, glycol nucleic acids, altriol nucleic acids, gem 2′-deoxy-2′-α-F-2′-β-C-methyl, 5’-morpholino, and amino-oxy click chemistry (AOCC) mediated conjugates. Furthermore, novel spatial architectures like circular siRNAs have also been evaluated. This presentation will summarize how chemistry has made possible the currently exciting world of RNAi therapeutics.
Development of mRNA-Based Vaccines
The safety and efficacy of mRNA-based vaccines was evidenced during the COVID-19 pandemic: less than one year after the publication of the sequence of SARS-CoV-2, mRNA vaccines against COVID-19 were approved. More mRNA vaccines (against infectious diseases and cancer) are in clinical developments and are expected to be approved in the coming years. New mRNA formats (circular, replicating) and formulations (lipoplexes and polyplexes) are also being tested to further improve mRNA vaccines. I will present the past, present and future of mRNA vaccines.
Close of Conference4:50 pm