Cambridge Healthtech Institute’s 6th Annual

Oligonucleotide CMC & Regulatory Strategies

Enhancing Analytical and Manufacturing Methods and Accelerating Time to Market

March 13-14, 2024



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

Tuesday, March 12

Registration Open12:00 pm

Recommended Short Course*5:30 pm

SC1: Safety & Toxicity of Nucleic Acids

*Separate registration required. See short course page for details.

Wednesday, March 13

Registration and Morning Coffee7:00 am

Organizer's Welcome Remarks8:30 am

OPTIMIZING CMC & ANALYTICAL CHARACTERIZATION

8:40 am

Chairperson's Opening Remarks

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

8:45 am

Experimental Strategies and Applications of Accelerated Stability Assessment Program (ASAP) Studies of Oligonucleotide Therapeutics

Carolyn Mazzitelli, PhD, Director, Analytical Development & Quality Control, Ionis Pharmaceuticals

An overview of experimental strategies and applications of Accelerated Stability Assessment Program (ASAP) studies of oligonucleotide drug substances and drug products will be presented. Practical considerations related to experimental design and execution specific to oligonucleotides will be presented, along with examples of how ASAP studies may be utilized throughout the development lifecycle of oligonucleotide therapeutics. This includes studies aimed at demonstration of material comparability and to augment platform stability data.

9:15 am

Analytical Challenges for Antibody Oligonucleotide Conjugates 

Matthew McQueen, Associate Director, Analytical Development, Avidity Biosciences

Avidity Biosciences is a clinical stage company developing a new type of modality, Antibody Oligonucleotide Conjugates (AOCs). These therapeutics consist of a monoclonal antibody as well as an oligonucleotide,and are therefore hybrids of a biologic and a small molecule. In this talk, we will discuss workflows to overcome the challenges associated with analytical method development and characterization of these novel hybrid therapeutics.

9:45 am

CMC Considerations for siRNA Drug Substance Manufacturing

Jeske Smink, PhD, Head of Drug Substance, Manufacturing, Silence Therapeutics

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 as well as to reduce costs.

10:15 am Measurement and Control of Oxidation Strength in Iodine/Pyridine Oxidation Reagents used in Oligonucleotide Manufacture

Bruce Flint, Associate Principal Scientist, Analytical Development, Nitto Avecia

Synthesis of oligonucleotides with mixed phosphorothioate (P=S) and phosphodiester (P=O) linkages are prone to formation of impurities in which one or more P=S linkage is replaced by a P=O linkage, aka “PO impurity”.  One cause for PO impurity formation is insufficient “aging” of oxidizing reagent prior to use in manufacture.  A control strategy is introduced via measurement of oxidation strength, setting specifications, and exploring options for reducing the aging time. 

Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:45 am

11:35 am

Strategies for the Characterization of Stereopure Platform Chemistry

Sridhar Vaddeboina, PhD, Senior Vice President, CMC Operations, Wave Life Sciences

Traditional phosphorothioate (PS) oligonucleotide synthesis methods generate stereorandom mixtures comprising up to several hundred thousand molecules, each with distinct stereochemistry. Wave Life Sciences is pioneering the development and manufacture of oligonucleotides with control over the backbone chirality. We will outline the various analytical tools we have deployed to characterize the platform processes that generate stereopure oligonucleotides, and unambiguously determine the structural composition, identity, and stability of stereopure oligonucleotides.

12:05 pm

Demonstrating Comparability with Changes in Oligonucleotide Manufacturing

Nadim Akhtar, PhD, Senior Principal Scientist, New Modalities, AstraZeneca

Effective change management is an essential part of drug product lifecycle. Typical changes include pre- and post-approval changes to drug substance and drug product manufacturing processes and analytical procedures and supply of raw materials to address regulatory, safety, quality, and supply risks. This presentation will share a phase-appropriate, risk-based approach to understand the risk on critical quality attributes and demonstration of comparability.

12:35 pmPlease attend a sponsored lunch in either Seaport A (Oligonucleotide Discovery and Delivery) or Seaport BC (mRNA Design & Delivery)
1:55 pm

Chairperson's Remarks

Robert Dream, PhD, Managing Director, HDR Co. LLC

2:00 pm

Toxicity and Immunogenicity Considerations for Oligonucleotide-Related Impurities: The Impact on Control Strategy Development

Brian Pack, PhD, Executive Director, Eli Lilly and Company

With limited regulatory guidance on the acceptable levels of impurities in oligonucleotides, ambiguity regarding specifications and comparability assessment expectations exists. While impurities are anticipated to exhibit the same safety profile as the parent oligonucleotide, they likely offer no inherent benefit and are expected to be controlled. This work outlines an approach to bridge process capability and oligonucleotide impurity safety from a toxicology and immunogenicity perspective to support specifications and comparability.

2:30 pm

Challenges in Establishing Assay, Purity, and Impurity Levels for Double-Stranded Oligonucleotides

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

Double stranded oligonucleotides with multiple 2’substituents, and several phosphorothioate linkages lead to significant numbers of related impurities. Denaturing UPLC methods to separate single strands and their impurities yields complex and often poorly resolved peaks. Non-denaturing methods are often not specific for duplexed impurities. Despite these challenges, sponsors are required to produce a control strategy that identifies and quantifies impurities. In this presentation we will discuss the challenges, strategies to overcome them.

Refreshment Break in the Exhibit Hall with Poster Viewing3:00 pm

PLENARY KEYNOTE SESSION

3:40 pmOrganizer's Welcome Remarks
3:45 pm

Plenary Chairperson's Remarks

Jim Weterings, PhD, Vice President Research, RNA Therapeutics & Delivery, Sirnaomics

3:50 pm

Biomimetic Chemistry of RNA Therapeutics

Mano Manoharan, PhD, Distinguished Scientist & Senior Vice President, Innovation Chemistry, Alnylam Pharmaceuticals

Achieving success in RNA therapeutics depends on proper understanding of mechanisms of nature. In stages of discovery, delivery, and development of RNA-based therapeutics we follow and mimic many natural processes. We will illustrate this concept by taking several key steps of molecular mechanisms involved and examples of medicines which are either approved or in clinical development.

4:20 pm

Applications for mRNA Therapeutics: Immunological Issues and Considerations

Arthur Krieg, MD, Adjunct Professor, University of Massachusetts, Chan School of Medicine

From an immunological perspective, there are 3 distinct categories of mRNA therapeutics, including: 1. Protein expression mRNAs (including e.g., enzyme replacement, antibody expression, gene editing with encoded programmable nuclease), wherein any immune activation is highly undesirable; 2. Infectious disease mRNA vaccines such as COVID (immune activation desirable to induce neutralizing antibodies); and 3. Cancer mRNA vaccines (immune activation desirable to induce CD8+ T cells able to kill tumors). Achieving these distinct immune effects requires intentional design of the mRNA and delivery system, which will be reviewed.

Welcome Reception in the Exhibit Hall with Poster Viewing4:50 pm

Close of Day5:50 pm

Thursday, March 14

Registration and Morning Coffee8:00 am

PLENARY KEYNOTE SESSION

8:30 amOrganizer's Welcome Remarks
8:35 am

Plenary Chairperson's Remarks

Paloma Giangrande, PhD, CTO, Eleven Therapeutics

8:40 am

Realizing the Promise of in vivo CRISPR Therapeutics

Sean Burns, PhD, VP Disease Biology, Intellia Therapeutics Inc.

NTLA-2001 is an investigational CRISPR-based therapy being evaluated in a Phase 1, two-part, open-label study in adults with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) or with cardiomyopathy (ATTR-CM). NTLA-2002 is being developed for hereditary angioedema (HAE), designed to knock out the KLKB1 gene in the liver with the potential to permanently reduce total plasma kallikrein protein and activity, a key mediator of the disease. NTLA-2002 is being evaluated in a Phase 1/2 study in adults with Type I or Type II HAE. Preclinical and clinical data for both programs will be presented.  

9:10 am

Harnessing RNA Metabolism for Precision RNA Therapeutics

Jeffery M. Coller, PhD, Bloomberg Distinguished Professor of RNA Biology and Therapeutics, Johns Hopkins University

We have created a therapeutic technique that enhances mRNA translation. This technology has numerous clinical applications and works by binding to mRNA and improving translation. The approach offers key benefits: it is disease-modifying, restoring normal protein levels; it is mutation agnostic; it can be tailored to precisely control expression, reducing the risk of overexpression; and lastly, it is applicable across indications and highly versatile.

Coffee Break in the Exhibit Hall with Poster Viewing9:40 am

REGULATORY INTELLIGENCE

10:30 am

Chairperson's Remarks

Jennifer Franklin, PhD, Executive Director, CMC Regulatory Affairs, Ionis Pharmaceuticals, Inc.

10:35 am KEYNOTE PRESENTATION:

Regulatory CMC Intelligence for Oligonucleotide Programs

Jennifer Franklin, PhD, Executive Director, CMC Regulatory Affairs, Ionis Pharmaceuticals, Inc.

Current regulatory interactions and intelligence for oligonucleotide programs in all phases of development will be discussed, including common health authority requests and recent regulatory experience and guidance. 

11:05 am

Practical, Quality, and Regulatory Considerations to Manufacture Clinical Trial Materials for First-in-Human Trials—What Do You Really Need to Do?

Kevin Fettes, PhD, Founder & Principal, FTS Pharma Consulting LLC

The complexity of oligonucleotide drug candidates being selected for clinical development has increased in recent years. These oligonucleotides often have significant chemical modifications requiring novel starting materials as well as technical innovations in process development, analytical chemistry, manufacturing and controls. This places extraordinary demands on both sponsor companies and contract manufacturing organizations to meet regulatory expectations under aggressive timelines.

11:35 amEnjoy Lunch on Your Own
1:00 pm

Leveraging ICH for Control of Oligonucleotide Impurities

Lori Troup, Director, Analytical Development, Dicerna Pharmaceuticals

For complex drug substances such as oligonucleotides, it is helpful, and sometimes even necessary, to introduce impurity controls throughout the process and not just on the final specification. This presentation will explore opportunities to leverage ICH guidelines to create a comprehensive control strategy, including examples of successes and failures, in a variety of areas, such as starting materials, elemental impurities, and the use of orthogonal HPLC methods.

1:30 pm

Key Pharmacology and Toxicology Elements of the FDA's Assessment Aid

Emily Noonan Place, PhD, Senior Consultant, Aclairo Pharmaceutical Development

This talk will focus on the FDA Assessment Aid, a voluntary submission to facilitate FDA assessment of NDA/BLA applications in the Office of Oncologic Drugs. The talk will go over important considerations to include in the pharmacology and toxicology section of the application.

2:00 pm PANEL DISCUSSION:

Oligonucleotides: From Preclinical to Product Launch

PANEL MODERATOR:

Robert Dream, PhD, Managing Director, HDR Co. LLC

According to the FDA site, there are 10 approved Oligonucleotides Drug Products on the market. 27 Oligonucleotides products ranging from Preclinical to Phase III Clinical under development. ICH recently published a concept paper that is addressing the need to establish a Guideline on the Development and Manufacture of Synthetic Oligonucleotides. From an analytical and regulatory perspective, oligonucleotides are interesting since they present a link between products derived from biotechnology and small molecular chemical compounds.This panel discussion will address the following topics required for oligonucleotides in order to deliver these modalities to patients: ​

  • Manufacturing strategies
  • Operation obstacles
  • Regulatory limitations
  • Facility requirements
PANELISTS:

Jennifer Franklin, PhD, Executive Director, CMC Regulatory Affairs, Ionis Pharmaceuticals, Inc.

Brian Pack, PhD, Executive Director, Eli Lilly and Company

Roumen Radinov, PhD, Vice President, Process Sciences, Alnylam Pharmaceuticals

INTERACTIVE BREAKOUT DISCUSSIONS

2:30 pmInteractive Breakout Discussions

Interactive Breakout Discussions are informal, moderated, small-group discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator(s) who keeps the discussion on track and the group engaged.  To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the Breakout Discussion page for a complete listing of topics and descriptions.

IN-PERSON ONLY BREAKOUT DISCUSSION:

Analytical Challenges in Controlling Purity in Double-Stranded Oligonucleotide Drug Substances and Drug Products

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

  • Identifying and controlling impurities in complex UPLC separations
  • Orthogonal methods and detection
  • The application and use of assays and purity determination of drug substances
  • Non-denaturing methods and purity
IN-PERSON ONLY BREAKOUT DISCUSSION:

In Your Experience, to What Extent is RNA a Multi-Product Platform Technology?

Zoltán Kis, PhD, Associate Professor, Chemical and Biological Engineering, The University of Sheffield

  • Do you see substantial differences in yield when using different template DNA sequences?
  • Do you see substantial differences in dsRNA when using different template DNA sequences?
  • Do you have purification processes that work as a platform, for different RNA sequences?
  • Does your formulation/encapsulation process work as a platform, for different RNA sequences?
  • Are there any best practices that you are willing to share?​

Refreshment Break in the Exhibit Hall with Last Chance for Poster Viewing3:10 pm

IMPLEMENTING SUCCESSFUL MANUFACTURING STRATEGIES

3:45 pm

Adoption of Innovative Technologies in Oligonucleotide Manufacturing: Improving the Efficiency of the siRNA Manufacturing Process

Roumen Radinov, PhD, Vice President, Process Sciences, Alnylam Pharmaceuticals

The solid-phase oligonucleotide synthesis based on sequential coupling of phosphoramidite monomers is a well-established industrial manufacturing process, currently performed routinely on kilo-scale mainly due to limitations of synthesis and purification processes. Novel approaches towards more efficient, scalable, and sustainable large-scale manufacture will be discussed supporting future commercialization of the expanding range of high-volume siRNA therapeutics.

4:15 pm

End-to-End Manufacturing: Challenges and Opportunities in Implementation

Robert Dream, PhD, Managing Director, HDR Co. LLC

End-to-End (aka, from-seed-to-unit-dose) manufacturing represents the next generation of biopharmaceutical manufacturing processes for both large and small molecules. It is recognized by regulatory authorities as a key emerging technology. The US FDA has approved various small molecule products and recently issued draft guidance for industry on continuous manufacturing.  The International Council for Harmonization issued (ICH) Q13 and is adopted by the European Medicines Agency (EMA) to support the technology and give guidance as well. Companies can add flexibility and maximize the value of process analytics ICH Q14 [6] to enhance E-2-E manufacturing.

4:45 pm

Toward the Development of Standardized mRNA CQAs for Therapeutic Applications

Steven Wolk, PhD, Vice President, Analytical Chemistry, Boulder Site Head, Editas Medicine

With the recent explosion in the field of mRNA-based therapeutics, there is growing need for the standardization of mRNA and LNP critical quality attributes (CQAs) that can guide the development of assays needed for characterization, QC release, and stability studies. Several initial efforts toward providing this guidance have been made by industry SMEs, creating an initial standard that can be continuously improved through cooperation with the agencies, academia, and industry.

Close of Conference5:15 pm






Call For Papers