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Key Sessions

Muthiah (Mano) Manoharan

RNAi Therapeutics Delivered: From Principles to Patients

Alnylam Pharmaceuticals, Inc.

Troels Koch, M.Sc., Ph.D.

LNA, Antisense, Pre-Clinical Updates

Roche Innovation Center Copenhagen

Nov 07
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08:00 - 09:00

Registration

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09:00 - 09:10

Chairperson's Opening Remarks

  • Arthur A. Levin - Executive Vice President, Research and Development, Avidity NanoMedicines
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Showing of Streams
10:30 - 11:15

Morning Coffee and Networking

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Showing of Streams
12:45 - 13:45

Lunch and Networking

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Showing of Streams
16:00 - 16:30

Afternoon Coffee and Networking

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Showing of Streams
18:00 - 19:30

End of Day 2 and Networking Evening Reception in the Exhibition Hall

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08:00 - 09:00 60 mins
Registration
09:00 - 09:10 10 mins
Chairperson's Opening Remarks
  • Arthur A. Levin - Executive Vice President, Research and Development, Avidity NanoMedicines
09:10 - 09:50 40 mins
Info
Opening Keynote Plenary Session
RNAi Therapeutics Delivered: From Principles to Patients
  • Muthiah (Mano) Manoharan - Senior Vice President of Drug Discovery, Alnylam Pharmaceuticals, Inc.

Advances in RNAi Therapeutics: Discovery, delivery, development and performance of patisiran, inclisiran, givosiran and other pipeline compounds.

09:50 - 10:30 40 mins
Info
Opening Keynote Plenary Session
LNA, Antisense, Pre-Clinical Updates
  • Troels Koch, M.Sc., Ph.D. - Vice President and Head of Research, RNA Therapeutics, Roche pRED, Roche Innovation Center Copenhagen

RNA therapeutics is a rapidly expanding field. The reasons are many, not least a particular focus on targets and tissues which are well validated for oligonucleotide drugs. Advances have also been made by introducing new oligonucleotide designs and chemistries. Targeting ligands conjugated to oligonucleotides for delivery purposes are now widely used, and with the development of sophisticated pharmacologically relevant assays, subtle variations in nucleoside and phosphorothioate chemical composition can result in significant drug improvements. The presentation will illustrate how disrupted discovery concepts, molecular modelling and bespoke tailoring of LNA oligonucleotide designs contribute to RNA therapeutic advancements.

10:30 - 11:15 45 mins
Morning Coffee and Networking
11:15 - 11:45 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
From Stereopurity To Precision Medicine: Optimising The Properties Of Antisense Nucleic Acid Therapeutics
  • Chandra Vargeese - Senior VP, Head of Drug Discovery, 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.

11:15 - 11:45 30 mins
Info
TRACK 2: Manufacturing and Scale Up Strategies
Launching Clinical Antisense Oligonucleotide Manufacturing Capability in a Biologics Company
  • Sheron Branham - Associate Director, Biogen

Biogen is the first innovator to invest internal capital on an ASO facility, 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.  Because Biogen has historically been a protein therapeutic company, there were many challenges associated with this project which required creative solutions.  Among those challenges were upskilling resources, defining a new organizational structure, culture building and working within conservative quality systems.

11:45 - 12:15 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
New Discoveries within Stereodefined Phosphorothioate LNA
  • Erik Daa Funder - Senior Scientist, Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen A/S

This talk will focus on the chemistry optimizations which have been done in the context of stereodefined LNA phosphorothioate oligonucleotide synthesis. Furthermore, the talk will highlight some of the consequences of having a stereodefined backbone as compared to the LNA parent random mixture in terms of e.g. in vitro and in vivo efficacy, toxicity, and cellular uptake.

11:45 - 12:15 30 mins
TRACK 2: Manufacturing and Scale Up Strategies
Considerations of Process Design for the Solid Phase Oligonucleotide Synthesis
  • Jale Müslehiddinoğlu - Senior Principal Engineer, Janssen Pharmaceuticals of Johnson & Johnson, Belgium
12:15 - 12:45 30 mins
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
Understanding ASO Trafficking
  • Emily Linnane - Postdoctoral Researcher, AstraZeneca, UK
12:15 - 12:45 30 mins
TRACK 2: Manufacturing and Scale Up Strategies
Insights into the Sequence Fidelity of Chemically Synthesised Oligonucleotides
  • Hüseyin Aygün - CSO, BioSpring GmbH
12:45 - 13:45 60 mins
Lunch and Networking
13:45 - 14:15 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
Oligonucleotide Therapeutics Now on Target: Activity of Oligonucleotide Antibody Conjugates
  • Arthur A. Levin - Executive Vice President, Research and Development, Avidity NanoMedicines

The widespread use of oligonucleotides as therapeutics has been limited by delivery to target tissues.  Numerous approaches have been taken and only a few have succeeded clinically to date.  Local delivery to the eye and the CNS have produced clinical successes and drug registrations.  Lipid nanoparticles and ligands for the asialoglycoprotein receptor (ASGPR) can effectively deliver oligonucleotide payloads to the liver and hepatocytes, respectively, and are being used in the clinic.  However, technologies for delivering oligonucleotides to other cell types and tissues have lagged behind these approaches.

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.

13:45 - 14:15 30 mins
Info
TRACK 2: Manufacturing and Scale Up Strategies
Developments In The Manufacturing Of Tricyclo-DNA Oligonucleotides
  • Branislav Dugovic - CTO, Synthena AG, Switzerland

Tricyclo-DNA is a conformationally constrained analogue of DNA with significantly enhanced binding affinity for the complementary RNA. It has been shown that antisense efficacy of the tricyclo-DNA oligonucleotides was superior to that of the corresponding LNA-oligonucleotides. Moreover, it displayed unique pharmacological properties and unprecedented uptake both in tissue and various organs after systemic administration in mice. Therefore tricyclo-DNA is a modification which deserves broader study in animal models for improved antisense effects. In order to supply the material for our preclinical studies, we have scaled-up the process of production of all four tricyclo-DNA phosphoramidites, which delivers the tricyclo-DNA building-blocks in consistent quality on kilogram-scale. The fully modified tricyclo-DNA oligonucleotides for in-vivo studies have been produced on various scales up to 1 mmol. Various aspects related to CMC of tricyclo-DNA oligonucleotides will be discussed during the proposed presentation.

14:15 - 14:45 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
Ligand Conjugates for Targeting of Viral and Endogenous Gene Targets
  • Kieu Lam - Director, Technology Development, Genevant Sciences Corp.

Genevant has developed a ligand conjugate platform for delivery of RNAi molecules. New data will be presented that highlights the potential of the platform in different indications.

14:15 - 14:45 30 mins
Info
TRACK 2: Manufacturing and Scale Up Strategies
A Systematic Approach Towards Development of a Robust Process for Oligonucleotide Manufacturing
  • Ramesh Rajeswaran, PhD - Senior Group Leader, Syngene International Ltd.

The oligonucleotide therapeutics field has progressed exponentially over the last three decades and till date regulatory guidelines are not well defined for oligonucleotide development. Due to non-availability of guidelines it is obvious that various problems are faced during different stages of process/analytical development, scale up as well as manufacturing. In this talk we will attempt to discuss Syngene’s approach to devise a platform technology for development and manufacture of different therapeutic oligonucleotides.

14:45 - 15:15 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
CriPec® Nanomedicines: rationally designed oligonucleotide therapeutics for superior tumour treatments
  • Jimmy Weterings, PhD - Principal Scientist Chemistry, Cristal Therapeutics, The Netherlands

The CriPec® polymeric platform enables the design of customised nanomedicines for superior tumour targeting, as already demonstrated by the clinical candidate CriPec® docetaxel. The pharmaceutical compatibility of CriPec® with miRNA, siRNA and antisense has already been demonstrated, whilst significantly improved tumour uptake upon intravenous administration as compared to naked oligonucleotide has been achieved. The various key parameters of CriPec® composition are currently being optimised, whilst assuring easy manufacturability and aiming for an improved therapeutic profile.

14:45 - 15:15 30 mins
Info
TRACK 2: Manufacturing and Scale Up Strategies
Enzyme Catalysed Assembly Of Oligonucleotides
  • David Tew - Project Leader & GSK Senior Fellow, Biological Technologies RD Management, GlaxoSmithKline, UK

Although solid phase phosphoramidite based chemistry is a well controlled and high yielding process for manufacturing oligonucleotides, the multiple rounds of iterative synthesis ultimately erode overall yields and purity. We have developed an enzyme catalysed process where multiple short oligonucleotides are brought together in a single assembly step to generate the final product oligonucleotide. This assembly process provides the opportunity to use unpurified short oligonucleotides and also offers the potential to eliminate chromatography from the overall process. Overall process yields are significantly improved compared to standard solid phase synthesis followed by chromatography.

15:15 - 15:45 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
Advances in RNA delivery using the Viromer Technology
  • Steffen Panzner - Managing Director, Lipocalyx GmbH

The talk will inform about recent advances in the development of our Viromer® delivery platform. We will present on delivery chemistry, formulation science and in vivo efficacy and safety.

15:15 - 15:30 15 mins
TRACK 2: Manufacturing and Scale Up Strategies
Enzymatic DNA Synthesis, a Novel Approach for Therapeutic Nucleic Acid Synthesis
  • Elise Champion - VP Research, DNA Script
15:30 - 16:00 30 mins
Info
TRACK 2: Manufacturing and Scale Up Strategies
AJIPHASE® Track Record in Europe: Recent Developments and Scale Up Experience at Ajinomoto OmniChem
  • Geert Schelkens - R&D Manager Pharmaceutical Fine Chemicals, Aji Bio Pharma Services

As AJIPHASE® technology has been recognised as a practical alternative technology to solid phase for both oligonucleotides and peptides, the number of inquiries to AJIPHASE® has been drastically increasing. Ajinomoto OmniChem, a member of Ajinomoto group, is a production site of AJIPHASE® in Europe. I will give the presentation on our experience with AJIPHASE® in large scale.

16:00 - 16:30 30 mins
Afternoon Coffee and Networking
16:30 - 17:00 30 mins
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
Next Generation R&D Strategies and Innovative Chemistries and Modifications
  • Michael E. Østergaard - Research Fellow, Ionis Pharmaceuticals
16:30 - 17:00 30 mins
Info
TRACK 2: Manufacturing and Scale Up Strategies
High Purity Liquid Phase Oligonucleotide Synthesis with Nanostar Sieving
  • Jack Cordrey - PhD Student, Imperial College

Oligonucleotides (oligos, 18 to 25-mers) are difficult to prepare at high purity using solid phase oligo synthesis (SPOS), and extensive chromatography of the crude full-length oligo is required to reach acceptable purity for pharmaceutical applications. We have developed a liquid phase oligo synthesis (LPOS) strategy that allows in-line monitoring of the coupling efficiency throughout the synthesis, so that any incomplete reactions detected can be driven to completion. After each chain extension the growing oligo is separated from reaction debris using two-stage nanofiltration for molecular sieving. To enhance the separation, three independently growing oligos are linked to a central hub molecule to create a three-arm oligo-star. The purified oligo-star is then concentrated, again using molecular sieving, ready for the next chain extension. This strategy enables LPOS to be integrated into a standard chemical process plant, and for building block usage to be minimised. A new class of membranes was developed to efficiently retain oligo-stars whilst allowing large reactant debris (MW ca. 600 Da) present in strong organic solvents to permeate and demonstrated over more than 19 synthesis cycles. The synthesis cycle was repeated up to a 20-mer using a 5’-methoxyisopropyl protecting group. Current work, now using commercial phosphoramidites, seeks to reach greater than 95% crude purity. This technology is being commercialised by EXACTMER, a new start-up from Imperial College London.

17:00 - 17:30 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
Lipophilic LNA-based Antisense Oligonucleotides
  • Jesper Wengel - Professor, Center Director, BioNEC - A VKR Center of Excellence, FKF - University of Southern Denmark

It will be presented how Lipo-LNAs, ie. lipophilic 2’-amino-LNA-based antisense compounds. can be designed towards optimising plasma half-life, biodistribution and gene knock-down in cell culture and in vivo. Importantly, the Lipo-LNA antisense technology offers the opportunity of using phosphorodiester instead of phosphorothioate linkages.

17:00 - 17:30 30 mins
TRACK 2: Manufacturing and Scale Up Strategies
Is Solution API Right For You – Practical and Strategic Considerations
  • Robert Simler, Ph.D. - Associate Director, Engineering and Technology, Biogen
17:30 - 18:00 30 mins
Info
TRACK 1: Delivery of Oligonucleotides and R&D Strategies
Overview of Next-generation Approaches for Rapid Production of Nanoparticles for Use in Gene and Cell Therapies
  • Samuel Clarke - Director of Research & Development, Precision NanoSystems, Inc.

This presentation will highlight recent advances across PNI’s NanoAssemblr platform for the discovery, development and cGMP production of nanoparticles for use in gene and cell therapies. PNI's lipid nanoparticle technology and µL-scale microfluidic manufacturing instrument are combined to rapidly screen nanoparticles for nucleic acid delivery to different cell types including iPSCs, neurons and T cells. PNI's next-generation microfluidics technology is introduced for the scale-up and large-scale manufacturing of nucleic acid lipid nanoparticle therapeutics.

17:30 - 18:00 30 mins
Info
TRACK 2: Manufacturing and Scale Up Strategies
GMP Manufacturing of RNA/DNA Containing Liposomal Formulations - From Microfluidics to Large-Scale
  • Charalampos Koutsoulas, PhD - Head of Liposome R&D, Polymun Scientific GmbH

Polymun Scientific GmbH is a pioneer in the formulation and large-scale production of liposomal dosage forms. Various oligonucleotides such as siRNA, saRNA, DNA and numerous mRNAs have been formulated using Polymun’s proprietary solvent injection technology. Additional to short and long nucleic acids, various small molecular weight compounds and various liposomal vaccine products have been successfully produced by Polymun's fully scalable solvent injection technology. The present study demonstrates the ability of Polymun Scientific to transfer, optimize and manufacture with its proprietary solvent injection technology liposomal formulations developed in a lab-scale microfluidic system.

18:00 - 19:30 90 mins
End of Day 2 and Networking Evening Reception in the Exhibition Hall