Cambridge Healthtech Institute’s 4^th Annual

Oligonucleotide Discovery and Delivery

Optimizing Design, Delivery and Performance

March 26-27, 2019

CHI’s Oligonucleotide Discovery and Delivery conference reveals the latest strategies at the forefront of discovery, chemistry and delivery with in-depth sessions on new chemistries, novel delivery mechanisms and the most important preclinical and clinical advances. Leading oligonucleotide scientists deliver detailed case studies on antisense, RNA, aptamers and conjugates – helping you develop the next generation of targeted oligonucleotide therapeutics.

Final Agenda

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

OPTIMIZING DESIGN, DELIVERY AND PERFORMANCE

10:45 Chairperson’s Remarks

Patrick Lu, PhD, President & CEO, Sirnaomics

10:50 FEATURED PRESENTATION: Advancing RNA Therapeutics: New Molecular Designs and Discovery Concepts

Peter Hagedorn, Senior Principal Scientist and Group Leader, Roche Innovation Center Copenhagen

Over the past two decades, RNA therapeutics has experienced major success. Our understanding of RNA biology and knowledge of RNA as a drug target has expanded tremendously, as has the translation fidelity of pre-clinical in vitro/vivo discovery models. The link between disease/target intervention and the principles for safe drug design are also well established. The presentation will focus on new ways to design antisense drugs, strategies and discovery concepts. It will show how structural elements of antisense oligonucleotides can be used for bespoke tailoring LNA oligonucleotide designs.

11:20 Oligonucleotide Therapeutics Now on Target: Activity of Oligonucleotide Antibody Conjugates

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

Using monoclonal antibodies or Fab fragments, we can deliver both siRNA payloads and single stranded oligonucleotides to specific cell types and tissues. We observed > 90% reduction in the expression of a muscle specific gene after a single 3 mg/kg dose of an siRNA conjugated to an antibody to the transferrin receptor, suggesting that the technology can be used for reducing the expression of disease-related genes in muscle. Similarly, using oligonucleotides designed to induce exon skipping, a single dose of 10 mg oligonucleotide/kg conjugated to the anti-transferrin receptor antibody induced exon skipping in wild type mice and exon skipping and dystrophin expression in the mdx mouse model of muscular dystrophy. For both the siRNA and exon skipping oligo, the activity was related to the concentration of oligonucleotide in muscle. This presentation will explore how we are using antibody oligonucleotide conjugates to develop drug candidates for multiple disease indications.

11:50 Site Specific Incorporation of Chemical Modifications in the DNA-Gap Improves the Therapeutic Index of Gapmer ASOs

Michael T. Migawa, PhD, Director, Medicinal Chemistry, Ionis Pharmaceuticals

The overall activity of antisense oligonucleotides (ASOs) is determined by its sequence, backbone, and particular combination of chemical modification. Recently, we replaced one or more of the phosphorothioate (PS) backbone modifications with a neutral methoxypropyl (MOP) modification or replaced the deoxy sugar with a 2’-OMe substituted monomer in the DNA gap-region and profoundly reduced ASO toxicity, while having only a small effect on potency.

12:20 New Generation STING Agonists for Cancer Immunotherapy

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

12:50 pm Enjoy Lunch on Your Own

2:00 Novel siRNA Therapeutics for Immune Oncology Therapeutics

Patrick Lu, PhD, President & CEO, Sirnaomics

Using a proprietary and optimized polypeptide nanoparticle-based delivery technology, we have developed the novel anti-fibrosis and anti-cancer therapeutics with siRNAs targeting both TGFβ1 and Cox-2 simultaneously (STP705), resulting apoptosis of human fibroblasts, for initial clinical indication of skin hypertrophic scar (in clinical Phase II study in US). STP705 was further advanced for liver fibrosis (Primary Sclerosing Cholangitis, PSC) treatment and received Orphan drug designation by US FDA. Among Sirnaomics anti-cancer programs, STP705 for treatment of cholangiocarcinoma (CCA) has received not only IND approval but Orphan drug designation by US FDA. Recent report for immune oncology study using dual targeting PD-L1/PD-1 and TGFβ1 and resulting in promising clinical outcome inspired us for an attempt using STP705 in combination with immune checkpoint inhibitory mAb therapy for treatment of liver cancers. I will discuss the unique advantage of our Polypeptide Nanoparticle (PNP) technology platform for safe and efficient siRNA delivery, and our strategy for advancing multiple clinical studies in both China and USA in near future.

2:30 From Stereopurity to Precision Medicine: Optimizing the Properties of Antisense Nucleic Acid Therapeutics

David Butler, PhD, Vice President, Medicinal Chemistry, Wave Life Sciences

We have developed proprietary synthetic chemistry and manufacturing capabilities that we are using to design and produce stereopure antisense oligonucleotides (ASOs) for patients with serious, genetically defined disease. We will highlight how our chemistry platform allows us to optimize ASOs for mechanism (e.g., gene knockdown or splicing), properties in vitro and in vivo, and distribution to an array of tissues.

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

3:45 Breakthrough Technology for Intrathecal Delivery of Antisense Oligonucleotides

Krishna Subramanian, PhD, Senior Scientist, Research & Development, Alcyone Lifesciences Inc

Delivery to the CNS through generic methods results in variable, sub-optimal treatment requiring use of higher doses of ASOs (antisense oligonucleotides) to provide maximum therapeutic benefit. We demonstrate for the first time, a consistent, optimal delivery system designed specifically to enhance the effectiveness of ASO therapies for CNS disorders.

4:15 A New Twist to GalNAc-Conjugated siRNA for Treatment of Liver-Related Disorders

Marie Wikstrom Lindholm, PhD, VP, Head of Technology Innovation, Silence Therapeutics

Silence Therapeutics explores different options for GalNAc conjugated siRNA design such as modification patterns, end stabilisation, linker chemistry, and number and location of GalNAc units. Two single GalNAc units, positioned a distance apart on the sense strand, demonstrated increased activity and duration of action in wild type mice compared to a GalNAc triantennary design. Novel design elements have shown great promise as a tool box for new pipeline projects.

4:35 siRNA Clinical Development Based on the TRiM Platform

James Hamilton, MD, Vice President Clinical Development, Arrowhead Pharmaceuticals

4:55 Case Study from Quark Pharmaceuticals

Elena Feinstein, MD, PhD, CSO, Quark Pharmaceuticals

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.

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.

9:15 Chairperson’s Remarks

Marie Wikstrom Lindholm, PhD, Vice President, Head of Technology Innovation, Silence Therapeutics

OPPORTUNITIES AND CHALLENGES WITH miRNA

9:20 FEATURED PRESENTATION: MicroRNA Therapeutics: Targeting the Genomic Dark Matter in Human Disease

Ekkehard Leberer, PhD, Senior Director, R&D Alliance Management, Sanofi

The non-coding genome (“genomic dark matter”) makes up 98.8% of the human genome. Most of this non-coding genome is transcribed into non-coding RNAs that may play an important role in cellular regulation in health and disease; these non-coding RNAs could be novel targets for future medicines. MicroRNAs are short non-coding RNAs that regulate biochemical pathways and networks of pathways by the mechanism of RNA interference (RNAi). MicroRNA-21 has been implicated in multiple organs as a microRNA associated with fibrotic diseases and cancer. The presentation will summarize the opportunities and challenges of developing microRNA-based drugs and will illustrate the successful generation of an anti-fibrotic microRNA-based therapeutic approach by targeting microRNA-21 with an antisense oligonucleotide (anti-miR-21).

9:50 Novel miRNA-targeting Therapeutic for Non-Alcoholic Fatty Liver Disease

Hyung J. Chun, MD FAHA, Associate Professor of Medicine and Pathology, Yale School of Medicine

MicroRNA based therapeutics offer an attractive treatment modality for liver disease.  A novel microRNA based therapeutic target that regulates both inflammation and fatty acid absorption into the liver will be discussed.

10:20 siRNA Science Journey as Reflected by the Patent Literature

Alison Gallafent, Patent Director, Patent Attorney, HGF Limited

Starting with patents that initially reflected manufacturing constraints, moving to patents reflecting greater understanding of chemical modifications, and later product specific patents.  Advantages and potential challenges are associated with patent protection at the different stages of this journey.  Close interaction between Research and Attorney can help to address potential challenges.

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

ADVANCES IN mRNA 

11:35 Advances in mRNA Delivery to Support Therapeutic Applications

Thomas Madden, PhD, President & CEO, Acuitas Therapeutics

Therapeutic applications of messenger RNA (mRNA) are currently being advanced into clinical development. However, mRNA requires a delivery system in order to enter cells and access the cytoplasmic compartment. Acuitas is developing lipid nanoparticle systems (LNP) that allow the efficient delivery and expression of mRNA via different routes of administration. Characteristics of both the LNP carrier and mRNA payload that facilitate efficient delivery and provide a favorable safety profile will be discussed. In addition, we will present preclinical results illustrating the potential application of mRNA-LNP therapeutics in several clinical areas.

11:55 pm The Epitranscriptome: The New Frontier in mRNA Therapeutic Development

Anton McCaffrey, PhD, Senior Director of Emerging Science and Innovation, TriLink BioTechnologies

mRNA therapeutics is one of the hottest new areas in nucleic acid therapeutics. mRNAs are post-transcriptionally modified at the 5’ cap and at internal bases. These epitranscriptome modifications license the mRNA as self and prevent activation of innate immune sensors. Recently we developed a novel capping method called CleanCap™ that allows co-transcriptional incorporation of various natural cap forms. These endogenous cap forms have improved activity in mice.

12:15 Nucleoside-modified mRNA Immunization Elicits Durable Protective Immune Responses Against Infectious Diseases

Norbert Pardi, PhD, Assistant Professor of Medicine, University of Pennsylvania

Nucleoside-modified, lipid nanoparticle (LNP)-encapsulated mRNA vaccines demonstrated safety and protective efficacy against various infectious pathogens (influenza, Ebola and Zika viruses) in small and large animals. This vaccine platform has the unique ability to develop potent T follicular helper cell and durable, broadly protective neutralizing antibody responses. This presentation will highlight some of the most recent findings on nucleoside-modified mRNA-LNP vaccines. 

12:35 Enjoy Lunch on Your Own

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

2:00 mRNA Therapies: Momentum and Progress of a Disruptive Technology

Ingmar Hoerr, PhD, Founder and Chairman of the Supervisory Board, CureVac

This talk will cover 1) approaches for the application (delivery) of mRNA. Encapsulation through packaging in LNP (lipid nanoparticles) and other delivery options 2) mRNA optimization: Protein therapies, like enzyme replacement, require a high and steady expression for longer term therapeutic benefit 3) production of mRNA – upscaling of an industrial pharmaceutical process with high throughput and lowest possible production costs as significant challenge.

2:30 PANEL DISCUSSION: Examining Developments in the Discovery and Delivery of mRNA Therapies

Moderator: Marie Wikstrom Lindholm, PhD, Vice President, Head of Technology Innovation, Silence Therapeutics

Panellists:

Anton McCaffrey, PhD, Senior Director of Emerging Science and Innovation, TriLink BioTechnologies

Ingmar Hoerr, PhD, Founder and Chairman of the Supervisory Board, CureVac

Norbert Pardi, PhD, Assistant Professor of Medicine, University of Pennsylvania

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 Discovery and Delivery

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.