Cambridge Healthtech Institute’s Inaugural

Oligonucleotide CMC and Regulatory Strategies

Accelerating Product Development and Commercial Success

March 26-27, 2019

To complement our Discovery and Delivery conference, CHI is delighted to announce the launch of Oligonucleotide CMC and Regulatory Strategies as part of OPT Congress 2019. 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

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MONDAY, MARCH 25

6:00 pm Dinner Short Course*

6:30-9:30 SC1: Examining the Safety and Toxicity of Nucleic Acid Therapeutics - Detailed Agenda

Nucleic acid drugs continue to deliver on their promise to become a third therapeutic modality, besides small molecules and biologics. Several antisense oligonucleotide drugs have been on the market for some time, while the first RNAi approval was granted last year (2018). In addition, numerous mRNA and CRISPR therapeutic programs have entered clinical stages. Despite the common “nucleic acid” component, the mechanisms of action and of non-specific effects differ for each of these drug types.

Topics to be discussed include:

• Different types of nucleic acid-based drugs
• Mechanisms of actions and non-specific effects
• Current approaches to address non-specific and potentially toxic effects

Aimed at both novice and advanced nucleic drug developers, the course will:

• Introduce and explain the differences between various types of nucleic acids drugs
• Summarize our current understanding of the origins of non-specific and potentially toxic effects
• Provide certain directions as to how to minimize the potential toxic effects of nucleic acids drugs

Instructors:

Muthiah (Mano) Manoharan, PhD, Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals

Dmitry Samarsky, PhD, CTO, Sirnaomics

Richard S. Geary, PhD, Senior Vice President (SVP), Development, Ionis Pharmaceuticals

Thomas Madden, PhD, President & CEO, Acuitas Therapeutics

Additional Instructors to be Announced

*Separate registration required.

TUESDAY, MARCH 26

7:00 am Registration and Morning Coffee

OPENING PLENARY SESSION

8:00 Welcome Remarks

Gemma Smith, Senior Conference Director, Cambridge Healthtech Institute

8:10 Chairperson’s Opening Remarks

Arthur Levin, PhD, Executive Vice President, Research and Development, Avidity Biosciences

8:15 RNA Targeting with Antisense Oligonucleotides: Present and Future

Richard S. Geary, PhD, Senior Vice President, Development, Ionis Pharmaceuticals

The number and chemical breadth of antisense oligonucleotide (ASO) medicines has rapidly grown in both clinical development and in market approvals. As the technology matures and innovations in delivery and increased safety margins are discovered, the ASOs currently in development are well balanced between rare and broad diseases. Some of the unique aspects associated with single strand ASO chemistry, distribution, cell uptake, clinical pharmacology and safety will be discussed as applied to clinical development examples and overall research progress.

8:35 RNAi Therapeutics Delivered: Approval of the First RNAi Therapeutic and Beyond

Muthiah (Mano) Manoharan, PhD, Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals

8:55 RNAi Medicines in Hematology and Rare Diseases: The Silence Experience

David Horn Solomon, PhD, CEO, Silence Therapeutics

SLN124, a GalNAc-conjugated siRNA targeting hepatic TMPRSS6, reduces serum and tissue iron levels in a rodent model for hereditary hemochromatosis type 1, both as monotherapy and in combination with an oral iron chelator. SLN124 also demonstrates therapeutically relevant, dose-dependent and long-lasting effects on iron stores, erythropoiesis and anemia in an animal model for beta-thalassemia. The first-in-human study is planned to commence in 2019 in beta-thalassemia and myelodysplastic syndrome patients.

9:15 PANEL DISCUSSION: Bridging the Gap Between Discovery, Development and Compliance

Moderator: Arthur Levin, PhD, Executive Vice President, Research and Development, Avidity Biosciences

Panelists:

Richard Geary, PhD, Senior Vice President, Development, Ionis Pharmaceuticals

Dmitry Samarsky, PhD, CTO, Sirnaomics

Lubo Nechev, PhD, Vice President, Process and Analytical Sciences, Alnylam Pharmaceuticals

10:00 Networking Coffee Break

INNOVATIVE CMC AND MANUFACTURING STRATEGIES

10:45 Chairperson’s Remarks

Marc Lemaitre, PhD, COO, Sirnaomics and ML Consult

10:50 FEATURED PRESENTATION: Developing the CMC Strategy for ONPATTRO™ (patisiran)

Lubo Nechev, PhD, Vice President Process and Analytical Sciences, Alnylam Pharmaceuticals

ONPATTRO (patisiran), the first RNA interference (RNAi) therapeutic approved in the United States and the European Union is targeting transthyretin (TTR) for the treatment of hereditary ATTR amyloidosis. Patisiran comprises a double stranded RNA API in a lipid nanoparticle formulation for intravenous administration. The presentation will discuss the development of the CMC strategy for patisiran from early stage to approval.

11:20 Stage 3 Continued Process Verification of Commercial Oligonucleotide Synthesis: Monitoring Strategy and Process Observations

Francis Ring, Assistant Director, Manufacturing & Operations, Ionis Pharmaceuticals

As more Oligonucleotide Therapies are approved, it is important to develop appropriate Continued Process Verification procedures, both to satisfy regulatory requirements and to inform future process development. Since 2010, across three compounds, Ionis has been performing validated solid-phase syntheses. The process data collection, analysis, and reporting strategy will be described, along with their evolution over time. Additionally, notable process trends and observations will be presented.

11:50 Enabling Rapid Start-Up with End-to-End Antisense Oligonucleotide Capability and Streamlined Business Processes

Sheron Branham, Associate Director, ASO Process Engineering and Manufacturing, Biogen

Biogen is the first innovator to internalize end-to-end ASO manufacturing capability while others have chosen to outsource. By vertically integrating their ASO supply chain, Biogen has been able to significantly reduce turnaround time and supply risk. The presentation will highlight how the facility and the business processes were designed to maximize flexibility and prepare for potential rapid growth in the future.

12:20 Enjoy Lunch on Your Own

2:00 siRNA Case Study: Development and Implementation of Late Stage CMC Strategies

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

Assay testing or weight-based determination of API content is an important aspect of release testing. Determining the assay of double-stranded oligonucleotide therapeutics is complicated. Because the duplex is formed by annealing two single strands, there will likely be closely related duplex variants arising from annealing of the impurities of the single strands thus making it difficult to discriminate variants from the parent duplex. This presentation will discuss findings from a comparative assessment of specific denaturing and non-denaturing chromatographic methods for assay measurement of a siRNA duplex and implications for release testing.

2:30 Combining siRNA and Peptides for Improved Delivery – CMC Aspects

Marc Lemaitre, PhD, COO, Sirnaomics and ML_Consult

Branched peptides containing histidines and lysines (HK) have been shown to be effective carriers for DNA and siRNA. We will discuss the specific aspects of CMC for the development of such a product.

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Late Breaking Presentation

4:15 CMO Outsourcing: An Integrated Approach

Joe DeCourcey, Head Manufacturing Science and Technology, Sarepta Therapeutics

4:45 CMC Challenges Associated with Oligonucleotide Products for Intravitreal Administration

Bianca Matthee, Vice President, Manufacturing & Pharmaceutics, ProQR Therapeutics

Oligonucleotide product design for intravitreal administration can be challenging from a formulation, analytical and manufacturing perspective. There are stringent specifications these products need to adhere to for the purpose of safely delivery the oligo into the eye. This presentation will elaborate on CMC challenges to overcome in manufacturing and will include some examples.

5:15 Welcome Reception in the Exhibit Hall with Poster Viewing

6:15 Dinner Short Course Registration*

6:30-9:30 SC2: Oligonucleotide-Based Drugs for Cancer Immunotherapy - Detailed Agenda

Oligonucleotide-based therapies are now gaining attention as an alternative to antibody and small molecule-based therapies for cancer immunotherapy. In cancers where current treatment options are limited by efficacy and specificity, oligonucleotide-based drug modalities are offering a better alternative. This course will bring together experts who will share their perspectives on the opportunities and challenges underlying the generation of novel, more targeted and effective oligonucleotide-based therapies for cancer immunotherapy. Some topics that will be discussed include:

• Modulating the tumor microenvironment using novel approaches and drug modalities
• Emerging immuno-oncology targets (TLRs, STING, RIG-1 and more) for intervention using oligos
• Preclinical and clinical evaluation of new immunomodulatory pathways and nucleic acids
• Synthesis and delivery of oligonucleotides (siRNA, antisense, aptamers and others) for cancer immunotherapy

Instructors:

Shanthi Ganesh, PhD, Associate Director, Preclinical Oncology, Dicerna Pharmaceuticals, Inc.

Ekambar R. Kandimalla, PhD, CSO, Exicure, Inc.

Additional Instructors to be Announced

*Separate registration required.

Day 1 | Day 2 | Download Brochure

WEDNESDAY, MARCH 27

8:00 am Breakfast Breakout Roundtable Discussions

Grab breakfast and join a roundtable discussion. These are moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic.

Table 1: New Target Election for RNAi Medicines

Moderator: David Horn Solomon, PhD, Chief Executive Officer (CEO), Silence Therapeutics

Table 2: How to Prepare for a Regulatory Submission and Overcome Common Regulatory Hurdles

Moderator: Jennifer Franklin, Director, CMC Regulatory Affairs, Ionis Pharmaceuticals

• Managing project requirements and timelines
• Leveraging available stability data to satisfy regulatory submission and review requirements
• Process validation: Information required for submission versus GMP inspection
• Setting specifications with limited data

Table 3: Recent Developments and Future Outlook of Antisense Therapeutics

Moderator: Troels Koch, Oligonucleotide Expert and Former VP & Head of Research, Roche Innovation Center Copenhagen

• Where are the areas of innovation likely to come from?
• Chemistry and chemical modifications, drug design, ligand conjugation, “chimeric molecules”
• Delivery and formulation
• Routes of administration: Systemic vs. local/topical administration, etc.
• In the long chain of events – where will improvement provide most impact: Drug design, delivery, target selection and/or development path?
• How do we get a better - or the best - match between modality and indication selection?
• Platform related competition: How to position the single stranded approach best in the RNA therapeutic market and disease space versus: siRNA, mRNA, CRISP/Cas (editing)
• Personal healthcare: Particular opportunities of antisense - or not?

Table 4: Can we Push for siRNA Cancer Therapeutics Similar to Experiences with mAbs?

Moderator: Patrick Lu, PhD, President & CSO, Sirnaomics

• How to improve siRNA delivery beyond liver
• Target selection for siRNA therapeutics to treat cancer
• Potential immune oncological application using siRNA therapeutics

Table 5: Adoption and Implementation of Innovative Technologies Used in CMC And Manufacturing

Moderator: Francis Ring, Assistant Director, Manufacturing & Operations, Ionis Pharmaceuticals

• Evaluating and implementing PAT monitoring strategies in the synthesis of oligonucleotides
• Temperature during synthesis
• Conductivity during synthesis
• Multiple downstream pathways: Determining the appropriate purification and isolation strategies for different oligonucleotide chemistries

Table 6: Can New Generation ONs with Tunable Properties Contribute to the Development of the Optimal Oligotherapeutics?

Moderator: David Tabatadze, PhD, President, ZATA Pharmaceuticals

• Are currently used major ON platforms versatile enough to satisfy complex criteria of the optimal oligotherapeutics?
• Absence of what particular properties limits current ONs to be materialize into a new class of therapeutics? As ASOs? As siRNAs? As CRISPR? Other?
• Overview of the novel ON platform enabling a tun-up of the currently used ONs through the modulation of the net-charges in their backbone will be discussed.

CRITICAL FEEDBACK ON REGULATORY SUBMISSIONS

9:40 Chairperson’s Remarks

Paul Manley, President & Principal Consultant, Orvieto Consulting

9:50 FEATURED PRESENTATION: Regulatory CMC Experience for OnpattroTM (patisiran), a First-in-Class siRNA Therapeutic

Saraswathy (Sara) Nochur, PhD, Chief Regulatory Officer, Alnylam Pharmaceuticals

OnpattroTM (patisiran) became the first FDA/EMA-approved treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR), and the first regulatory approval of a new class of drugs called small interfering ribonucleic acid (siRNA). CMC development of OnpattroTM involved extensive innovation, challenges due to complexity of the product (consisting of double-stranded siRNA and lipid components including novel excipients), and well-planned interactions with regulatory agencies. Regulatory CMC experience on Onpattro development and registration will be provided.

10:20 Late Breaking Presentation

10:50 Coffee Break in the Exhibit Hall with Poster Viewing

11:35 Strategies for Identity Testing of Oligonucleotide Therapeutics

Hong Jiang, Scientist II, Analytical Development, Biogen

Due to their polymeric nature and high molecular weight, establishing identity of oligonucleotide therapeutics is significantly more challenging compared to synthetic small molecules. The commonly accepted identity tests for small molecules, such as IR spectrum and retention time matching with a reference standard, are generally insufficient for identity confirmation of an oligonucleotide. In this presentation I will discuss various risk factors during the manufacturing process that can potentially lead to an oligonucleotide of an incorrect structure, along with currently available analytical methods that can detect certain structural changes and confirm the identity. A risk-based framework for the selection of identity tests and how it can be integrated into a robust control strategy will be proposed.

12:05 pm Regulatory Agency Questions and Learnings from Recent Commercial Submissions

Jennifer Franklin, Director, CMC Regulatory Affairs, Ionis Pharmaceuticals

Recent CMC questions received from global regulatory agencies for an antisense oligonucleotide drug will be detailed, along with a discussion of the response strategies that led to their successful resolution, and ultimately, to drug approval. Regulatory challenges and learnings from the review and approval process in the US, EU, and Canada will also be examined.

12:35 Enjoy Lunch on Your Own

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

2:00 Accelerating Pathway to Approval: Points to Consider in Conducting Productive Regulatory Interactions and Making Successful IND/CTA Submissions

Paul Manley, President & Principal Consultant, Orvieto Consulting

FDA and EU National Authorities have similar approaches to how they review and approve clinical trial applications, however key areas of difference need to be appreciated in order to achieve successful applications. This presentation provides advice for oligonucleotide companies covering: pre-submission dialogue, differences in application content and Regulatory Agency review approaches and commitments during and after trial completion.

2:30 PANEL DISCUSSION: How to Successfully Prepare for a Regulatory Submission and Overcome Common Hurdles

Moderator: R.P. (Kris) Iyer, PhD, Co-Founder & CSO, Spring Bank Pharmaceuticals
Panelists: Jennifer Franklin, Director, CMC Regulatory Affairs, Ionis Pharmaceuticals

Saraswathy (Sara) Nochur, PhD, Chief Regulatory Officer, Alnylam Pharmaceuticals

Paul Manley, President & Principal Consultant, Orvieto Consulting

3:15 Refreshment Break in the Exhibit Hall with Poster Viewing

CLOSING PLENARY SESSION

3:55 Chairperson's Remarks

R.P. (Kris) Iyer, PhD, Co-Founder & CSO, Spring Bank Pharmaceuticals

4:00 Synthesis and Biological Activity of Thiomorpholino Oligonucleotides

Marvin Caruthers, PhD, Distinguished Professor, University of Colorado

The synthesis and biological activity of thiomorpholino DNA will be presented. Recently thiomorpholino oligonucleotides have been found to be far more active than any other tested analogue in exon skipping assays involving a mouse model for Duschenne Muscular Dystrophy. This analogue is also extremely active in a dual luciferase cell culture assay.

4:20 The Development of Nucleic Acid Delivery Platforms: A Pan-RNA Approach

Bo Rode Hansen, President & CSO, GeneVant Sciences

At Genevant, we are pursuing a modality agnostic “pan-RNA” approach to develop a diverse pipeline of RNA therapeutics; including delivery of RNAi payloads targeting both viral and endogenous gene targets, and mRNA in vaccine applications. 

4:40 Implementing the Use of Antisense in the Brain

Jonathan Watts, PhD, Associate Professor, UMass Medical School

5:00 Close of Oligonucleotide CMC and Regulatory Strategies”

5:00 Dinner Short Course Registration*

5:30-8:30 SC3: CRISPR-Based Gene Editing for Targeted Therapies - Detailed Agenda

While the challenges and risks associated with oligonucleotide therapies still remain, there is a new and better understanding of how genes can be effectively manipulated and delivered. With the rise of gene editing tools and enhanced knowledge of targeted delivery, these therapeutic modalities are once again being embraced with renewed hope and enthusiasm. This course helps you understand how gene editing – particularly the one enabled by the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 system – works, and how it can be used to help develop targeted therapies with good efficacy and delivery.

Instructors:

Clifford Steer, MD, Professor of Medicine and Genetics, Cell Biology and Development; Director, Molecular Gastroenterology Program, University of Minnesota Medical School

Ciro Bonetti, PhD, Scientist, Regeneron Pharmaceuticals

Eric Kmiec, PhD, Director, Gene Editing Program and Senior Research Scientist, Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System

*Separate registration required.

Day 1 | Day 2 | Download Brochure