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Oligonucleotide–based therapeutics have long formed the third major drug development platform, specifically focused on modulating gene expression by targeting RNA or the genome itself. A key distinguishing attribute of nucleic acids as therapeutic agents is their ability to access the “undruggable” space left by small molecules and biologics, allowing drug developers to address a wider range of diseases, and particularly those with limited or no therapeutic options. This has generated significant interest in this field; however, first generation molecules exhibiting potency and safety issues have hindered the potential of oligonucleotide therapies dramatically impacting the drug development landscape. Recent advances in nucleic acid chemistry and delivery to improve stability, bioavailability, specificity and potency are now driving the rapid development and clinical evaluation of a new generation of therapies poised for success.

The Oligonucleotide Therapeutics and Delivery conference, April 4-5, in Cambridge, MA will gather leading drug developers and discovery scientists to discuss technological and scientific advances in oligonucleotide-based therapeutics.

FINAL AGENDA

Monday, April 4th

7:00am Registration and Morning Coffee

ADVANCES IN OLIGONUCLEOTIDE THERAPEUTICS

8:10 Chairperson’s Opening Remarks

Dmitry Samarsky, Ph.D., Senior Vice President, Technology Development, RiboBio Co, China

8:15 Keynote Presentation: GalNAc-Conjugated siRNAs as a New Paradigm in Oligonucleotide Therapeutics

Muthiah (Mano) Manoharan, Ph.D., Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.

During this presentation, I will discuss the progress in the advancement of RNAi therapeutics and review delivery of RNAi and where the field is going. I will also discuss conjugated delivery of oligonucleotides to the liver and combining novel chemical modifications with conjugation strategies.

8:45 Development of Stereopure Nucleic Acid Therapeutics

Chandra Vargeese, Ph.D., Senior Vice President and Head, Drug Discovery, WAVE Life Sciences

WAVE Life Sciences is utilizing its innovative and proprietary synthetic chemistry drug development platform to design, develop and commercialize stereopure nucleic acid therapeutics that precisely target the underlying cause of rare genetic diseases, delivering exceptional treatment options for patients. Given the unique versatility of its chemistry platform, WAVE’s pipeline will span multiple oligonucleotide modalities including antisense, exon-skipping and single-stranded RNAi.

9:15 Novel Phosphorodiamidate Oligomers (PMOs) for the Treatment of Genetic and Infectious Diseases

Bruce Wentworth, Ph.D., Vice President, Biology, Sarepta Therapeutics

PMOs are being tested in advanced clinical trials for the treatment of patients with Duchenne muscular dystrophy (DMD), a rare, X-linked disease that results in progressive muscle loss and premature death. Research has shown that for other disorders, including viral and bacterial infection as well as rare diseases such as Pompe disease, modified PMOs may be more appropriate due to their potential for enhanced delivery and tissue targeting. The PMO-based technology has the potential to be a versatile, modifiable, and widely applicable treatment in any number of disease states.

9:45 Sponsored Presentation (Opportunity Available)

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

SYNTHESIS AND MEDICINAL CHEMISTRY

10:45 Featured Presentation: Structure Activity Relationships of Trivalent GalNAc Conjugated Antisense Oligonucleotides

Punit Seth, Ph.D., Executive Director, Medicinal Chemistry, Isis Pharmaceuticals

Trivalent GalNAc, a high affinity ligand for the hepatocyte-specific Asialoglycoprotein receptor (ASGR), enhances the potency of antisense oligonucleotides (ASOs) for inhibiting gene targets expressed in hepatocytes. We undertook a comprehensive structure-activity relationship study to determine the optimal structural requirements for enhancing ASO potency via ASGR mediated delivery to hepatocytes. As part of this effort, GalNAc clusters assembled from six distinct branched or amino acid scaffolds were synthesized and attached to ASOs using simplified solution-phase or phosphoramidite based methods. Within each cluster, the length and hydrophobicity of the linker attaching the GalNAc sugar to the branching point on the scaffold was varied. The effect of reducing backbone phosphorothioate content (PS) and changing the linker moiety between the GalNAc cluster and the ASO was also evaluated. Details from this work which resulted in the selection of a simplified trivalent GalNAc ASO conjugate for evaluation in human trials will be presented.

11:15 Phosphorodithioate RNA for RNA-Based Therapeutics

Xianbin Yang, Ph.D., Director, R&D, AM Biotechnologies

During this presentation I will discuss the chemistry for synthesizing phosphorodithioate (PS2)-modified siRNAs, aptamer, and anti-miRNAs; crystal structures of PS2-modified siRNAs and protein-RNA complexes; therapeutic aptamers with remarkably improved binding affinity (from nM to pM) with a single PS2 substitution; and in vitro and in vivo gene silencing activity of PS2-substituted RNA.

Lipid Modification of c-MYC Promoter Targeted Oligonucleotide Stabilizes G-Quadruplex Formation and Enhances Its Growth Inhibitory Activity in Leukemia Cells

Gilles Tapolsky, Ph.D., CSO, Advanced Cancer Therapeutics

We have shown that Pu27 reduces c-MYC transcription in leukemia cell lines and consequently inhibits cell growth and promotes apoptosis. In this study, we evaluated the effect of Pu27 modification using polyethylene glycol (PEG), tocopherol (Toco) and the lipid palmitate in order to increase G-quadruplex stability and lessen blood clearance. Our finding suggests that modification of the c-MYC targeted oligonucleotide by addition of lipids stabilizes the 3D structure (G-quadruplex) and improve its function at inhibiting cell growth most likely by down-regulating c-MYC.

Luncheon Presentation (Sponsorship Opportunity Available) or Lunch On Your Own

CANCER IMMUNOTHERAPY AND COMBINATIONS

1:25 Chairperson’s Remarks

Art Krieg, M.D., Founder and CEO, Checkmate Pharma

1:30 Featured Presentation: Prospects for Increasing the Response Rates to Checkpoint Inhibition: The Role of TLR9

Art Krieg, M.D., Founder and CEO, Checkmate Pharma

Many immunologists have speculated that combining a strong Th1 immune activator known to be capable of inducing multifunctional anti-tumor CD8+ T cell responses in cancer patients together with anti-PD-1/PD-L1 would greatly increase the response rates to therapy compared to either agent alone. Checkmate’s TLR9 agonist program has shown such a response in humans with excellent safety, and will be moving into clinical development in combination with an anti-PD-1 antibody in advanced cancer patients in early 2016.

2:00 Modulation of Tumor Microenvironment with Use of Intratumoral Imo-2125, a TLR9 Agonist, for Effective Therapy in Combination with Checkpoint Inhibitors

Sudhir Agrawal, D.Phil., President, Research, Idera Pharmaceuticals

2:30 CureVac’s Sequence-Optimized mRNA – En Route to the Next Generation Biologicals

Mariola Fotin-Mleczek, Ph.D., CSO, CureVac

Recent advances strongly suggest that mRNA is the basis for a new class of vaccines and drugs. RNActive®, one of CureVac’s technologies has been developed on this basis and provides potent prophylactic vaccines and novel immunotherapies against cancer. These successes could be extended preclinically to mRNA protein and gene replacement therapy. The production of mRNA-based vaccines and drugs is highly flexible, scalable and cost competitive, and eliminates the requirement of a cold chain. Furthermore CureVac’s proprietary optimization process allows the generation of sequence optimized yet natural mRNA that provides a safe and efficient method for enabling the human body to produce its own medicine.

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

3:30 Silencing Immune Checkpoints Using RNAi

Alexey Wolfson, Ph.D., Founder and CSO, MirImmune

4:00 Immunomodulatory Spherical Nucleic Acids

David Giljohann, Ph.D., CEO, Exicure

Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.

4:30 Sponsored Presentation (Opportunity Available)

5:00 Welcome Reception in the Exhibit Hall with Poster Viewing

6:00 End of Day

Tuesday, April 5th

7:30am Roundtable Discussions with Continental Breakfast

ANTIVIRAL DEVELOPMENT

8:25 Chairperson’s Remarks

Andrew Vaillant, Ph.D., CSO, Replicor Inc.

8:30 Nucleic Acid Polymers: Antiviral Mechanisms and Application in the Treatment of Chronic HBV and HBV / HDV Infection

Andrew Vaillant, Ph.D., CSO, Replicor Inc.

Nucleic acid polymers (NAPs) are a newly emerging antiviral technology for the treatment of chronic HBV infection and HBV / HDV co-infection. NAPs have the unique ability to clear HBsAg from the blood of human patients, a critical step in achieving a functional cure in HBV and HBV / HDV infection. Replicor will present its current mechanistic data underlying the basis for this unique antiviral effect of NAPs as well as updated clinical data showing Replicor’s progress in using NAP-based combination therapy in patients with chronic HBV infection and HBV / HDV co-infection towards achieving functional cure for these infections.

9:00 Using DPC Technology in RNAi Therapeutics for Chronic HBV Infection and Factor 12-Mediated Diseases

David Lewis, Ph.D., CSO, Arrowhead Research Corporation

9:30 Sponsored Presentation (Opportunity Available)

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

ADVANCES IN RNA THERAPEUTICS AND DELIVERY

10:25 Chairperson’s Remarks

Balkrishen (Bal) Bhat, Ph.D., Vice President, Chemistry, RaNA Therapeutics

10:30 Long Non-Coding RNAs (lncRNAs): A New Frontier for Drug Development

Balkrishen (Bal) Bhat, Ph.D., Vice President, Chemistry, RaNA Therapeutics

The ss-siRNA activity in vivo requires a metabolically stable 5’-phosphate analog. Here, we used crystal structure of the 5’-phosphate binding pocket of Ago-2 bound with guide strand to design and synthesize ss-siRNAs containing various 5’-phosphate analogs. Chemically modified ss-siRNA targeting human apoC III mRNA demonstrated good potency for inhibiting ApoC III mRNA and protein in transgenic mice. Moreover, ApoC III ss-siRNAs were able to reduce the triglyceride and LDL cholesterol in transgenic mice demonstrating pharmacological effect of ss-siRNA.

12:00 Development of Novel Breakthrough Cancer Therapies Based on the Unique Functions of Proprietary miRNAs

Roel Q.J. Schaapveld, Ph.D., MBA, CEO, InteRNA Technologies BV

To explore miRNAs as therapeutic angiogenesis-inhibitors, we performed a functional screen to identify miRNAs that are able to decrease EC viability. We identified miRNA-7 (miR-7) as a potent negative regulator of angiogenesis. This study provides a comprehensive validation of miR-7 as novel anti-angiogenic therapeutic miRNA that can be systemically delivered to both EC and tumor cells and offers promise for miR-7 as novel anti-tumor therapeutic.

11:30 Development of Lipid-Based Oligonucleotide Delivery Systems

Volker Fehring, Ph.D., Director, Formulation Development, Silence Therapeutics GmbH

Posttranscriptional gene silencing by RNA interference can be therapeutically exploited to inhibit pathophysiological gene expression. However, in contrast to the established effectiveness of RNAi in vitro, safe and effective delivery of siRNAs to specific organs and cell types in vivo remains the major hurdle. Here, we report the development and in vivo characterization of a novel siRNA delivery system (DACC lipoplex) suitable for modulating target gene expression.

12:00pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch On Your Own

DELIVERY TO THE CNS

1:00 Chairperson’s Remarks

Dong-ki Lee, Ph.D., Professor, Sungkyunkwan University, South Korea; CEO, OliX Pharmaceuticals

1:05 Therapeutic Antidepressant Potential of a Conjugated siRNA Silencing the Serotonin Transporter after Intranasal Administration

Andres Montefeltro, Ph.D., CEO, nLife Therapeutics, S.L.

nLife Therapeutics has developed different nucleic acid chemical modifications with the aim to optimize cell specific delivery capabilities to neurons. We have combined siRNAs and antisense oligonucleotides (ASOs) with some specific and potent small molecule ligands to neuronal receptors or transporters, named nOligos (neuronal specific oligonucleotides). These combinations proved to deliver the nucleic acid to the target neuron in an effective way. Also, the intranasal administration of the modified nucleic acids reached the targeted brain area and neurons in mice and monkeys.

1:35 Exosome Mediated Delivery of Therapeutic Oligonucleotides for Treatment of Neurodegenerative Disorders

Anastasia Khvorova, Ph.D., Professor, Molecular Medicine, RNA Therapeutics Institute, University of Massachusetts Medical School

Oligonucleotide therapeutics is a new class of drugs, the clinical utility of which has been limited by inefficient tissue distribution and cellular uptake. Through our research, we have developed a novel methodology that enables the loading of hydrophobically modified oligonucleotides (hsiRNA) into exosomes. These hsiRNAs show efficient cellular uptake in vitro as well as broad brain distribution and in vivo efficacy. Exosome-formulated oligonucleotide therapeutics might be a solution for the development of novel therapeutics for the treatment of neurodegenerative disorders.

NOVEL AND EMERGING APPROACHES FOR IN VIVO DELIVERY

2:05 Featured Presentation: Therapeutic Development Using the Second Generation RNAi Triggers

Dong-ki Lee, Ph.D., Professor, Sungkyunkwan University, South Korea; CEO, OliX Pharmaceuticals

Recent studies came up with novel RNAi triggering molecular structures with unique structural features and functional advantages compared with the conventional siRNA. During this presentation I will introduce novel RNAi triggers developed in my laboratory, with improved features over conventional siRNA, such as reduced off-target effects, enhanced cellular delivery when complexed with cationic delivery vehicles, and specific target gene silencing combined with immunostimulation. One of these second generation RNAi triggers, asymmetric siRNAs (asiRNAs), were combined with specific set of chemical modifications to generate cell-penetrating asiRNAs (cp-asiRNAs), which can execute gene silencing without delivery vehicle both in vitro and in vivo. I will introduce current therapeutic development programs based on the cp-asiRNA structures.

2:35 A Novel Nano-Medicine Platform for Oligonucleotide Discovery and Delivery

Art Levin, Ph.D., Executive Vice President, Research and Development, Avidity NanoMedicines

Despite the considerable promise, delivery has proven to be one of the central challenges of oligonucleotide-based therapeutics. Oligonucleotides are large, hydrophilic and highly negatively charged, so they don’t cross cell membranes. We have pioneered the development of Precision NanoMedicines, which are targeted, polymeric nanoparticles encapsulating siRNA drug payloads for delivery to specific tumor types. These self-assembling nanoparticles can be decorated with antibodies, proteins, peptides and small molecules to bind to extracellular receptors and facilitate cellular uptake.

3:05 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Delivery of Dicer-Substrate siRNAs (DsiRNAs) to Multiple Patient-Derived Xenograft Tumors

Bob Brown, Ph.D., CSO, Dicerna Pharmaceuticals

Lipid Nanoparticle (LNP) technology is an elegant solution for delivery of RNAi triggers, since it enables both bioavailability to target organs as well as the ability to transfect target cells. However, while LNPs are well characterized for delivery of RNA oligonucleotides to the normal liver, much remains to be explored regarding the mechanisms of LNP-mediated delivery to tumors. In this study, we investigated the ability of Dicerna’s unique LNP platform, termed EnCore, to deliver Dicer- substrate siRNAs (DsiRNAs) to xenograft tumors of diverse origin.

4:15 Translation of Messenger RNA Therapeutics from Preclinical Research into Clinical Studies

Pad Chivukula, Ph.D., CSO & COO, Arcturus Therapeutics

Arcturus has developed a novel, potent and safe RNA Therapeutics platform called LUNAR™, a proprietary lipid-enabled delivery system for RNA medicines including small interfering RNA, messenger RNA, antisense and microRNA oligotherapeutics. In addition, we incorporate Unlocked Nucleic Acid (UNA) chemistry into the oligonucleotide drug candidate enabling the targeting of any gene in the human genome. This presentation will provide an update on our lead asset, an UNA-modified, LUNAR-formulated siRNA targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis.

4:45 Clinical Development of RXI-109 to Reduce the Formation of Scars

Pamela Pavco, Ph.D., Chief Development Officer, RXi Pharmaceuticals Corp‬.

RXI-109 is a self-delivering RNAi compound (sd-rxRNA®) in development as a therapeutic to target and reduce connective tissue growth factor (CTGF) in order to impede the fibrotic pathway. Preliminary results from Phase 2a dermal clinical trials indicate a better outcome (reduced scar formation) following hypertrophic scar revision surgery when the incision site is treated by intradermal injections of RXI-109. A summary of the ongoing dermal trials and an overview of a Phase 1/2 trial to prevent subretinal fibrosis in subjects with neovascular age-related macular degeneration will be discussed.

5:15 Small Molecules that Enhance the Pharmacological Effects of Oligonucleotides

Rudolph L. Juliano, Ph.D., Boshamer Distinguished Professor, Department of Pharmacology, University of North Carolina

Endosomal trapping is a key impediment to the effective use of oligonucleotides in therapy. We have used high throughput screening to identify small molecules that selectively release oligonucleotides from the late endosome compartment thus increasing access to the cytosol and nucleus. These compounds substantially enhance pharmacological effects of several types of oligonucleotides both in cell culture and in mouse models.

5:45 Close of Conference

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