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

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

OPENING PLENARY

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

Monia_BrettBrett 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 

Kaye_EdwardEdward 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

Dmitry-SamarskyModerator: Dmitry Samarsky, PhD, CTO, Sirnaomics


Monia_BrettPanelists: Brett Monia, PhD, CEO, Ionis Pharmaceuticals


Kaye_EdwardEdward Kaye, MD, CEO, Stoke Therapeutics


10:00 Coffee Break in the Exhibit Hall with Poster Viewing

INNOVATIVE CMC AND MANUFACTURING STRATEGIES

10:45 Chairperson’s Opening Remarks

Marc LeMaitre, PhD, Consultant, Sirnaomics


10:50 FEATURED PRESENTATION: Reinventing Oligonucleotide Synthesis

Baran_PhilPhil 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

Radinov_RoumenRoumen 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

Faber_JesseJesse 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 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:50 Session Break

2:00 Monte Carlo Simulations of Amidite Starting Material Impurity Incorporations for Drug Substance Specification Justifications

Ring_FrancisFrancis 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 Talk Title to be Announced

Speaker to be Announced

3:00 Sponsored Presentation (Opportunity Available)

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 CMC Case Study from ProQR Therapeutics

Brinks_VeraVera Brinks, PhD, Director Pharmaceutics, ProQR Therapeutics


SAFETY AND TOXICITY OF OLIGONUCLEOTIDES

4:45 Oligonucleotides: Bioanalytical and DMPK Perspective Lessons Learned

Sherman_MaryMary 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.

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: Adoption and Implementation of Innovative Technologies Used in Discovery and Delivery

Marvin Caruthers, PhD, Distinguished Professor, University of Colorado


TABLE 2: 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 3: 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 4: 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 5: 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


TABLE 6: CMC Regulatory Hurdles in Rare Disease

Moderator: Kimberly Tyndall, Principle, CMC Tyndall Consultant

  • How to successfully proceed
  • Never a marketed product N=1
  • Overcoming CMC hurdles
  • Why

 

OPTIMIZING ANALYTICAL APPROACHES

9:15 Chairperson’s Remarks

Paul Manley, President & Principal Consultant, Orvieto Consulting

9:20 Phase Appropriate Analytical Control Strategy for Antisense Oligonucleotides

Jiang_HongHong 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 Industry Case Study from Quark Pharmaceuticals

Gopalakrishnan_Vidhya_Vidhya Gopalakrishnan, PhD, Senior Vice President, Pharmaceutical Development, Quark Pharmaceuticals


CRITICAL FEEDBACK ON REGULATORY SUBMISSIONS

10:20 FEATURED PRESENTATION: Regulatory CMC Experience with Alnylam’s First GalNAc Conjugate

Marschel_MelissaMelissa 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?

Fettes_KevinKevin 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 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Dessert Break in the Exhibit Hall with Poster Viewing

1:50 Rare Disease: CMC Regulatory Pathway

Tyndall_KimKimberly Tyndall, Principal, CMC Tyndall Consultant

This talk will focus on CMC regulatory hurdles and pathways encountered when filing oligonucleotide drug substance and drug product. We will explore both hurdles that may be faced in the US as well as across the globe. How these can be overcome and how to streamline the process so as to ensure quality.

2:20 PANEL DISCUSSION: How to Successfully Prepare for a Regulatory Submission and Overcome Common Hurdles

Moderator: Kimberly Tyndall, Principal, CMC Tyndall Consultant

Panelists: Steven Kates, PhD, Vice President, Regulatory Affairs, Dicerna Pharmaceuticals

Melissa Marschel, Director, Regulatory Affairs CMC, Alnylam Pharmaceuticals 

Paul Manley, President & Principal Consultant, Orvieto Consulting

Mary M. Sherman, PhD, Principal Consultant, Preclinical & Regulatory Consulting

  • Challenges: Manufacturing development history for regulatory filings
  • Global dossiers: FDA, EMA, Japan, Brazil and Canada
  • Stability data: What was permitted and what was not?

3:05 Networking Refreshment Break

CLOSING PLENARY

3:35 Chairperson’s Remarks

Chairperson to be Announced

3:40 Biological Activity of Thiomorpholino Oligonucleotides

CaruthersMarvin 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

Simon_AmyAmy 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.

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