Cambridge Healthtech Institute's 4th Annual

Oligonucleotide CMC and Regulatory Strategies

Accelerating Product Development and Commercial Success

March 15 - 16, 2022 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.

Tuesday, March 15

7:00 am Short Course Registration (Gallery Foyer)
8:00 am Recommended Pre-Conference Short Course* (Salada)
SC1: Examining the Safety and Toxicity of Nucleic Acid Therapeutics

*All Access Premium Pricing or separate registration required. See short course page for details.

9:15 am Main Conference Registration and Morning Coffee (Gallery Foyer)
10:15 am Organizer's Welcome Remarks



10:25 am

Chairperson's Opening Remarks

Mike Webb, PhD, Independent Consultant, MikeWebbPharma Ltd.; Former Vice President, API Chemistry & Analysis, GSK
Mano Manoharan, PhD, Distinguished Scientist & Senior Vice President, Innovation Chemistry, Alnylam Pharmaceuticals

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

Phil Baran, PhD, Chair & Professor, Department of Chemistry, Scripps Research Institute

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.

Dr. Jill Caswell, Biology Technical Leader, Almac Sciences, Almac Group

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.

12:00 pm Session Break


Marvin Caruthers, PhD, Distinguished Professor, Biochemistry, University of Colorado

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. 

12:40 pm Session Break



1:15 pm

Chairperson's Opening Remarks

Mike Webb, PhD, Independent Consultant, MikeWebbPharma Ltd.; Former Vice President, API Chemistry & Analysis, GSK
1:20 pm

Computational Prediction of RNA Higher Order Structures

Christina Bergonzo, PhD, Research Chemist, National Institutes of Standards and Technology

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.

1:50 pm

Strategies for Identity Testing of Therapeutic Oligonucleotide Drug Substances and Drug Products

Daniel Capaldi, PhD, Vice President, Analytical and Process Development, Ionis Pharmaceuticals

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.          

2:20 pm

Considerations for Terminal Sterilization of Oligonucleotide Drug Products

Nadim Akhtar, PhD, Senior Principal Scientist, New Modalities, AstraZeneca R&D

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.

2:50 pm Refreshment Break in the Exhibit Hall with Poster Viewing (Bohea)



3:30 pm

Chairperson's Opening Remarks

Jonathan Watts, PhD, Associate Professor, RNA Therapeutics Institute, University of Massachusetts Chan Medical School
Nagy Habib, ChM, FRCS, Head of R&D and CMO, MiNA Therapeutics Ltd.

Small activating RNAs (saRNA) are double stranded 21 nucleotide RNA that either target promoters or enhance genes leading to mRNA upregulation. saRNAs can be delivered with liposomes into the systemic circulation or subcutaneously by conjugation with aptamers or GalNAC.  MTL-CEBPA is an investigative drug that resulted from the conjugation of saRNA CEBPA with NOV 340 lipsomes that targets tumour associated macrophages, in order to favorably alter the tumor microenvironment.  MTL-CEBPA has been administered safely in over 100 patients with advanced cancer and improved clinical outcome in a sub-set of patients when co-administered with TKI or check point inhibitor.

Luke Koblan, PhD, Former Graduate Student, Laboratory of David Liu, Department of Chemistry and Chemical Biology, Harvard University and Broad Institute of MIT and Harvard

Base editors hold significant promise to precisely correct the underlying genetic cause of many diseases. Correcting pathogenic mutations in disease-relevant contexts has remained challenging due to low editing efficiencies and limited editor delivery modalities. Systematic improvements to base editor performance and delivery enabled efficient adenine base editor-mediated correction of the predominant mutation underlying Hutchinson-Gilford Progeria Syndrome in a mouse model of this disease, ultimately rescuing major hallmarks of disease pathology.  

Jonathan Watts, PhD, Associate Professor, RNA Therapeutics Institute, University of Massachusetts Chan Medical School

We describe progress toward complete chemical modification of CRISPR guides and their in vivo genome editing activity. We have identified patterns of backbone and sugar modifications that allow robust gene editing activity in mRNA and RNP formats, in vitro and in vivo.  We also describe a broadly accessible modification strategy for DNA donors used as templates for homology-directed repair, which improves the efficiency of HDR up to 8-fold over normal DNA donors.

Paloma H. Giangrande, PhD, Vice President, Platform and Discovery Sciences Biology, Wave Life Sciences

The talk will cover proof-of-concept preclinical in vivo data demonstrating effective and durable editing of human SERPINA1 Z allele mRNA in the liver, resulting in a therapeutically meaningful increase in circulating, functional wild-type AAT protein. These initial in vivo studies utilize Wave’s proprietary transgenic mouse model, which has both the human SERPINA1 Z-allele as well as human ADAR that is expressed comparably to human cells.

5:35 pm Welcome Reception in the Exhibit Hall with Poster Viewing (Bohea)
6:35 pm Close of Day

Wednesday, March 16

7:30 am Registration Open (Gallery Foyer)



8:00 am Breakfast Interactive Discussions

Interactive Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. For in-person events, the facilitator will lead from the front of the room while attendees remain seated to promote social distancing. For virtual attendees, the format will be in a Zoom room. 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 Interactive Discussion page on the conference website for a complete listing of topics and descriptions. 

INTERACTIVE DISCUSSION: CMC & Regulatory Considerations for Oligo Drug Development

Marc Lemaitre, PhD, Oligonucleotide Therapeutics CMC/Strategy Consultant, ML_Consult LLC
Jennifer Franklin, PhD, Executive Director, CMC Regulatory Affairs, Ionis Pharmaceuticals, Inc.
Mike Webb, PhD, Independent Consultant, MikeWebbPharma Ltd.; Former Vice President, API Chemistry & Analysis, GSK
  • Oligonucleotide drug substance specifications 
  • Starting material for oligonucleotides​
  • Identity testing of oligonucleotides and impurity limits
8:45 am Session Break


8:55 am

Chairperson's Opening Remarks

Marc Lemaitre, PhD, Oligonucleotide Therapeutics CMC/Strategy Consultant, ML_Consult LLC
9:00 am

CMC/Regulatory for Oligonucleotide Therapeutic Submission

Marc Lemaitre, PhD, Oligonucleotide Therapeutics CMC/Strategy Consultant, ML_Consult LLC

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.

9:30 am

Challenges in Establishing Commercial Analytical Control Strategy for the Lifecycle of a Therapeutic Oligonucleotide

Mike Webb, PhD, Independent Consultant, MikeWebbPharma Ltd.; Former Vice President, API Chemistry & Analysis, GSK

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.

Joseph Fraone, Business Development Manager, Oligonucleotides, Business Development, Bachem Americas, Inc.

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.

10:15 am Coffee Break in the Exhibit Hall with Poster Viewing (Bohea)
11:10 am

Regulatory Interactions and Intelligence for Development and Late Phase Programs

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

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.

11:40 am

CMC Challenges and Regulatory Strategies for the Development and Approval of RNAi Therapeutics

Sergei Poletaev, Associate Director, Regulatory Affairs CMC, Alnylam Pharmaceuticals

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.

12:10 pm Enjoy Lunch on Your Own
12:50 pm Dessert Break in the Exhibit Hall with Poster Viewing (Bohea)



1:25 pm

Chairperson's Opening Remarks

Isabel Aznarez, PhD, Vice President, Discovery Research, Stoke Therapeutics

A Novel RNA-Based Approach to Treat Genetic Diseases

Isabel Aznarez, PhD, Vice President, Discovery Research, Stoke Therapeutics

Targeted augmentation of nuclear gene output (TANGO) is a novel technology that exploits antisense oligonucleotide (ASO)-mediated modulation of pre-mRNA splicing to increase full length, fully functional protein expression. In haplo insufficiencies; e.g. Dravet syndrome and autosomal dominant optic atrophy, TANGO ASOs increase protein expression by leveraging the wild type allele. TANGO can be employed to target a wide range of gene types, functions and sizes to address genetic diseases amenable to protein upregulation.


RNA Targeting Progress in Severe and Rare Disease

Richard Geary, PhD, Chief Development Officer and Executive Vice President, Antisense Drug Development, Ionis Pharmaceuticals, Inc.

More than ten RNA targeted products have been approved and launched in the rare and severe disease space.  Both increase and decrease in protein target production have been utilized with RNA engaging oligonucleotides.  Pipeline progress will be summarized along with the challenges and opportunities that have become apparent as the research continues.

2:30 pm Refreshment Break in the Exhibit Hall & Last Chance for Poster Viewing (Bohea)

Intratumoral Delivery of a CpG-A TLR9 Agonist Using a Virus-Like Particle Can Overcome Resistance to PD-1 Blockade in Patients with Advanced Melanoma

Arthur M. Krieg, Founder & CSO, Checkmate Pharmaceuticals

Innate immune activation is an appealing approach to overcoming resistance to PD-1 blockade in patients with advanced cancer, and yet positive results in murine tumor models have usually not translated into human clinical data. CpG-A TLR9 agonists have unique immune effects that are enhanced by delivery using an immunogenic virus-like particle, leading to enhanced systemic anti-tumor effects in preclinical models and in humans.


Engineering Antibody Oligonucleotide Conjugates (AOCs): Taking Receptor-Mediated Uptake One Step Further

Arthur Levin, PhD, CSO, Avidity Biosciences

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. 


Harnessing Endogenous Retroviral-Like Proteins for RNA Delivery

Michael Segel, PhD, Postdoctoral Fellow, Laboratory of Dr. Feng Zhang, Broad Institute of MIT and Harvard

Retroelement derived proteins are scattered throughout the human genome. One such protein, the retroviral-like Gag protein PEG10, can be harnessed to facilitate efficient intercellular delivery of cargo RNAs in mammalian cells.

4:40 pm Close of Conference

Present a Poster

2024 Conference Programs

Oligo Discovery & Delivery