Cambridge Healthtech Institute’s 2nd Annual
Oligonucleotide CMC and Regulatory Strategies
Accelerating Product Development and Commercial Success
March 17-18, 2020
CHI is delighted to build on the success of last year’s inaugural Oligonucleotide CMC and Regulatory Strategies to complement our Discovery and Delivery conference. We bring together top scientists and executives from leading biotech and large pharma
to share exclusive insights on CMC, manufacturing, analytical and regulatory advancements. Learn how to optimise your product development processes and speed up time to market.
Final Agenda
Day 1 | Day 2 | Download Brochure
MONDAY, MARCH 16
12:30 - 6:30 pm Short Course and Pre-Conference Registration*
3:00 - 6:00 SC1: Circular RNAs as a New Therapeutic Modality
Instructors:
Samie Jaffrey, MD, PhD, Department of Pharmacology, Weill Medical College, Cornell University
Bojan Losic, PhD, Associate Professor, Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai
6:30 - 9:30 SC2: Examining the Safety and Toxicity of Nucleic Acid Therapeutics
Instructors to be Announced
*Separate registration required. See page 3 for details.
TUESDAY, MARCH 17
7:00 am Registration and Morning Coffee
8:00 Welcome Remarks from Conference Director
Gemma Smith, Senior Conference Director, Cambridge Healthtech Institute
8:10 Chairperson’s Opening Remarks
Dmitry Samarsky, PhD, CTO, Sirnaomics
8:15 Recent Advances with Antisense Technology at Ionis Pharmaceuticals
Brett Monia, PhD, CEO, Ionis Pharmaceuticals
The development of antisense technology as a novel drug discovery platform to treat a broad range of rare and common diseases is now validated. Antisense medicines offer tremendous hope for patients afflicted with serious diseases that cannot be
addressed with traditional drug discovery platforms. With numerous antisense medicines recently receiving market authorization along with a large and diverse pipeline of medicines on the horizon, antisense is poised to revolutionize the practice
of medicine for generations.
8:45 Using ASOs to Upregulate Protein Expression
Edward Kaye, MD, CEO, Stoke Therapeutics
Stoke has developed an RNA platform that efficiently upregulates protein expression. This is accomplished by removing retained non-coding elements at the pre-mRNA level and thereby increasing the amount of full-length mRNA. This increase in full
length mRNA from a normal copy of the gene results in an increase of full-length protein which we are using to address haplo-insufficient diseases.
9:15 FIRESIDE CHAT: The Future Outlook of RNA Targeted Therapeutics
- Recent breakthroughs and advancements in RNA therapeutics and gene editing/expression
- Opportunities of neurological diseases in drug discovery, development and delivery
- Challenges that lie ahead
Moderator: Dmitry Samarsky, PhD, CTO, Sirnaomics
Panelists: Brett Monia, PhD, CEO, Ionis Pharmaceuticals
Edward Kaye, MD, CEO, Stoke Therapeutics
10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Chairperson’s Opening Remarks
Marc LeMaitre, PhD, Consultant, Sirnaomics
10:50 FEATURED PRESENTATION: Reinventing Oligonucleotide Synthesis
Phil Baran, PhD, Professor, Department of Chemistry, Scripps Research
The advent of phosphoramidite-based coupling chemistry and solid-phase organic synthesis democratized oligonucleotide synthesis for the biochemistry community thus paving the way for stunning developments in the field. This talk will present a fundamentally
different approach to constructing oligonucleotides containing P(S)2, chiral P(S)O and P(Me)O, and canonical P(O)2 linkages to create chimeric sequences that would be outside the realm of what can be obtained with current methods.
11:20 FEATURED PRESENTATION: Manufacturing Process and Control Strategy for GalNAc Conjugated siRNAs
Roumen Radinov, PhD, Director Process Chemistry, Alnylam Pharmaceuticals
Several GalNAc conjugated siRNAs are currently at different stages of clinical development for various programs at Alnylam. The presentation will describe the Alnylam manufacturing process for this type of compounds as well as the development of the CMC
control strategy from early stage to NDA. The possibility of using a platform approach to enhance this strategy will also be discussed.
11:50 Learnings from Process Validation of a Full-Scale Oligonucleotide Manufacturing Process
Jesse Faber, Senior Process Engineer III, ASO Process Engineering and Manufacturing, Biogen
In 2016, Biogen began construction of its first ASO manufacturing facility. After the successful manufacture of several clinical oligonucleotides, Biogen has just completed its first process validation of a commercial oligonucleotide in 2019. This presentation
will focus on key learnings from the process validation effort including process characterization, risk assessment, and platform strategies.
12:20 pm Enjoy Lunch on Your Own
2:00 Monte Carlo Simulations of Amidite Starting Material Impurity Incorporations for Drug Substance Specification Justifications
Francis Ring, Assistant Director, Manufacturing and Operations, Ionis Pharmaceuticals
For starting material-related product impurities, Ionis supplemented the product impurity data with Monte Carlo simulations of the corresponding starting material impurity. By building the Monte Carlo simulations from the entire amidite production history,
significantly more historical variability was captured than any individual Ionis product experienced. The methodology for building the starting material impurity and product incorporation models will be discussed along with the Monte Carlo simulation
results.
2:30 Oligonucleotide DP Development and Manufacturing for Orphan Ophthalmic Diseases
Vera Brinks, PhD, Director Pharmaceutics, ProQR Therapeutics
Oligonucleotide drug product (DP) development for (ultra) orphan ophthalmic diseases can be challenging from a formulation, primary packaging and manufacturing point of view. This presentation will elaborate on some of the challenges related to intravitreal
(IVT) administered products, such as endotoxin and sub-visible particle specifications of DP, but also dosing accuracy. Also, terminal sterilization as part of DP manufacturing will be discussed.
3:00 Accelerated Stability Assessment of Oligonucleotides
Mark Madsen, PhD, Associate Director, Analytical Development/Quality Control, Ionis Pharmaceuticals
Development of an accelerated stability assessment program to determine the activation energy required for degradation of antisense oligonucleotides will be presented. The results from these studies enable calculation of drug product stability at
the long-term storage conditions and the rates of formation for individual degradation products. Study design, example data, and potential applications will be discussed.
3:30 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 Oligonucleotides: Bioanalytical and DMPK Perspective Lessons Learned
Mary M. Sherman, PhD, Principal Consultant, Preclinical & Regulatory Consulting
Having worked with several small biotechs, focused on oligonucleotide research, I have seen a pattern emerging regarding their knowledge, their questions, their strategies, and the outcomes. A summary of some of those lessons will be presented during
this presentation.
5:15 Welcome Reception in the Exhibit Hall with Poster Viewing
6:15 Dinner Short Course Registration*
6:30 - 9:30 SC3: Oligonucleotides for Cancer Immunotherapy
Instructors:
Shanthi Ganesh, PhD, Associate Director, Preclinical Oncology, Dicerna Pharmaceuticals, Inc.
Weston Daniel, PhD, Senior Director Program Management, Exicure, Inc.
Sushma Gurumurthy, PhD, Associate Director, Oncology Research, Moderna
*Separate registration required.
Day 1 | Day 2 | Download Brochure
WEDNESDAY, MARCH 18
8:00 am Breakfast Breakout Roundtable Discussions
Enjoy a continental breakfast and join us for a moderated roundtable discussion with interactive problem solving. These sessions bring together attendees from diverse backgrounds to exchange ideas and develop future collaborations around a focused topic,
in an informal environment.
TABLE 1: Considerations When Developing Splice Modulating Therapies
Moderator: Annemieke Aartsma-Rus, PhD, Professor of Translational Genetics, Leiden University Medical Center
- Developing splice modulating therapies for small patient numbers
- Selecting model systems and controls for pre-clinical exon skipping tests
- Deciding when to move from pre-clinical to clinical studies
- Involve patients in therapy development and trial design
TABLE 2: Oligonucleotide Drug Discovery: From the Drawing Board to the Clinic
Moderator: Troels Koch, PhD, CTO, SVP Science & Technology, IneXos Therapeutics
Drug discovery is an exceptionally complex undertaking. What is of paramount importance is that the initial steps in the process are conducted as well-informed
and qualified as possible. We will discuss drug discovery fundamentals and try to identify how an “ideal” program would look like. Discussion points:
• Delivery - target – modality triangulation: Where to begin, any preference?
•
In vitro and
in vivo assays: Toxicity and potency validation – Establish the right controls and secure high degree of translation
• How to make the best selection of target and indication to favor oligonucleotide
therapeutics in relation to competing modalities?
• Advancing
in silico discovery: Going beyond sequence based bioinformatics with structure based quantum mechanical modelling?
TABLE 3: Examining the Safety and Toxicity of Nucleic Acid Therapeutics
Moderator: Steven Kates, PhD, VP, Regulatory Affairs, Dicerna Pharmaceuticals
- What tox studies are needed and when?
- How to assess your impurities (analytical methods)
- Discussing mutagenicity
- Examining ADA assays
TABLE 4: Adoption and Implementation of Innovative Technologies Used in CMC And Manufacturing
Moderator: Roumen Radinov, PhD, Director Process Chemistry, 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 the current synthesis and purification processes
- Novel approaches will need to be designed and developed to support high-volume oligonucleotide drugs in the near future
- Participants are invited to share their insights and experience in the development of alternative synthesis and purification technologies with potential for the cost-effective ton scale manufacture of oligonucleotides
9:15 Chairperson’s Remarks
Paul Manley, President & Principal Consultant, Orvieto Consulting
9:20 Phase Appropriate Analytical Control Strategy for Antisense Oligonucleotides
Hong Jiang, Scientist II, Analytical Development, Biogen
With the commercial success of Antisense oligonucleotides (ASO) drugs, the footprint of this class of new and exciting therapeutics is quickly increasing in the clinical space. It is vitally important to develop a phase appropriate analytical control
strategy to ensure the safety and efficacy of the product while keeping the drug accessible to patients. Challenges and considerations in developing such a phase appropriate strategy will be discussed. Examples of development and implementation of
new technology and methods will be provided.
9:50 Phase Specific Analytical and CMC Control Strategies for Double Stranded Oligonucleotide Therapeutics
Vidhya Gopalakrishnan, PhD, Senior Vice President, Pharmaceutical Development, Quark Pharmaceuticals
10:20 FEATURED PRESENTATION: Regulatory CMC Experience with Alnylam’s First GalNAc Conjugate
Melissa Marschel, Director, Regulatory Affairs CMC, Alnylam Pharmaceuticals
Alnylam will provide an overview of our CMC-related experiences obtaining approval for Givlaari, our first siRNA GalNAc conjugate. We will discuss the overall dossier strategy, key CMC-related challenges and key regulatory questions received.
10:50 Coffee Break in the Exhibit Hall with Poster Viewing
11:35 Practical, Quality and Regulatory CMC Considerations to Manufacture Clinical Trial Materials for Early Phase. What do you really need to do?
Kevin Fettes, PhD, Consultant and Founder, FTS Pharma Consulting
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.
12:05 pm Submitting Your First Investigational New Drug (IND) Application: A Roadmap of Key Activities
Paul Manley, President & Principal Consultant, Orvieto Consulting
An IND application can be daunting for a small company making such a submission for the first time. This presentation will discuss key activities to consider as you plan for this important FDA interaction, including: Pre-IND dialogue, project plans, use
of internal and external resources, creation of your electronic submission and the IND review process.
12:35 Enjoy Lunch on Your Own
1:05 Dessert Break in the Exhibit Hall with Poster Viewing
1:50 FIRESIDE CHAT: How to Successfully Prepare for a Regulatory Submission and Overcome Common Hurdles
Moderator: Paul Manley, President & Principal Consultant, Orvieto Consulting
Panelists:
Melissa Marschel, Director, Regulatory Affairs CMC, Alnylam Pharmaceuticals
Steven Kates, PhD, Vice President, Regulatory Affairs, Dicerna Pharmaceuticals
- Challenges: Manufacturing development history for regulatory filings
- Global dossiers: FDA, EMA, Japan, Brazil and Canada
- Stability data: What was permitted and what was not?
2:20 PANEL DISCUSSION: Opportunities and Challenges with RNAs
Moderator: Ekkehard Leberer, PhD, Senior Director, R&D Alliance Management, Sanofi; Scientific Managing Director, COMPACT Consortium
Panelists:
Patrick Lu, PhD, President & CEO, Sirnaomics
Kerry Benenato, PhD, Senior Director, Discovery Chemistry, Moderna
David Corey, PhD, Professor, Department of Pharmacology, UT Southwestern
3:05 Networking Refreshment Break
3:35 Chairperson’s Remarks
Chairperson to be Announced
3:40 Biological Activity of Thiomorpholino Oligonucleotides
Marvin
Caruthers, PhD, Distinguished Professor, University of Colorado
Thiomorpholino oligonucleotides are analogues containing morpholino- and 2’deoxyribonucleosides joined through thiophosphor internucleotide linkages. These analogues stimulate biological activity in a dual luciferase assay, in exon skipping with
Marfan Syndrome and Duschenne Muscular Dystrophy, and in regulating TUG 1 RNA. Current research includes regulating microRNA maturation, editing transcription termination, exon skipping of additional genetic diseases, and antisense experiments with
RNase H.
4:10 GIVLAARI™: Story of the First-Ever Approved GalNAc-Conjugate RNAi Therapeutic, for Acute Hepatic Porphyria
Amy
Simon, MD, Executive Director, Clinical Research, Alnylam Pharmaceuticals
4:40 Close of Oligonucleotide CMC and Regulatory Strategies
4:40 Dinner Short Course Registration*
5:00 - 8:00 SC4: Gene Editing for Targeted Therapies
Instructors:
Clifford Steer, MD, Professor of Medicine and Genetics, Cell Biology, and Development; Director, Molecular Gastroenterology Program, University of Minnesota Medical School
Branden Moriarity, PhD, Assistant Professor, Department of Pediatrics, University of Minnesota Medical School
Khalid Shah, MS, PhD, Director, Center for Stem Cell Therapies and Imaging, Harvard Medical School; Vice Chair of Research, Brigham and Women’s Hospital
Jonathan Gootenberg, PhD, McGovern Fellow, McGovern Institute for Brain Research, MIT
Omar Abudayyeh, PhD, McGovern Fellow, McGovern Institute for Brain Research, MIT
*Separate registration required.
Day 1 | Day 2 | Download Brochure