Day Two

• Novel ligand-mediated approaches for selectively targeting adipocytes, muscle, and other metabolic compartments are needed to realize the potential of RNAi for obesity therapy
• LEADTM technology is a new ligand-and-enhancer conjugation approach that enables improved specificity and potency for obesity targets across multiple biological mechanisms
• In this presentation, we will share clinical and preclinical data demonstrating the potential for best-in-class RNAi payloads, differentiated pharmaceutical properties, and therapeutic proof-of-concept to treat obesity and metabolic disorders

• Exploring the role of DELiveri® as a powerful product engine to enable functional screens of millions of delivery molecules in human cells in a one-pot reaction, for improved specificity of RNAi therapies 
• Evaluating the quantitative output of the screen, providing a score for each molecule, and setting the basis to train AI algorithms 
• Sharing insights from over 30 screens conducted across multiple primary human cell types, along with in-vivo validation data for novel compounds, to establish a robust predictive framework for translating in vitro results into effective in vivo therapies

• Exploiting a novel RNAi delivery modality due to unique uptake and release kinetics for the development of acute RNAi therapeutics
• Leveraging direct tissue targeting of RNAi therapeutics to unlock previously inaccessible conditions for improved therapeutic outcomes
• Using selective translational models to derisk RNAi therapeutic development for pipeline acceleration

• Engineering multi-valent delivery vehicles to optimize cellular uptake and endosomal escape to avoid the limitations of conventional lipid nano particles
• Leveraging programmable nanoscale architecture and enabling modular assembly of nano particles for precision delivery of siRNa Payloads
• Demonstrating potent efficacy of DNA origami-siRNA constructs in preclinical models of disease

• Leveraging advanced chemical modifications to develop novel conjugate platforms, to enable delivery beyond the liver with high specificity, to expand treatable diseases to include neurological disorders and rare cancers
• Applying bespoke chemical modifications to peptide-based and other conjugate systems to improve endosomal escape and intracellular siRNA bioavailability to boost gene silencing efficacy while reducing dose frequency and toxicity
• Implementing a next-generation, data-rich platform for the rapid design and optimization of novel ligand-siRNA chemistries to accelerate optimization of delivery chemistries for unmet clinical needs, for future-proofing Alnylam’s pipeline against GalNAc’s limitations

• Understanding how the STRIKE™ platform utilizes proprietary ligand-siRNA conjugates (STRIKERs) for precise, receptor-mediated uptake in target kidney cells, minimizing systemic exposure and off-site toxicity.
• Exploring how megalin-STRIKERs are engineered to enhance cellular internalization into proximal tubule cells, improving the efficiency of gene silencing
• Evaluating how this targeted delivery approach enables potent and durable silencing, providing a long-term therapeutic strategy

• Antibody-siRNA conjugates enable muscle-selective uptake, treating myopathies with minimal off-target effects
• Enhanced endosomal escape increases cytoplasmic siRNA release, improving dystrophin restoration in Duchenne MD
• Modular platform allows rapid re-targeting, accelerating therapies for multiple rare muscle disorders

The breakthroughs in RNAi delivery are no longer confined to the liver, with a new generation of platforms, from antibody conjugates and DNA nanostructures to novel ligands and chemical modifications, enabling precise targeting of metabolic, muscular, and renal tissues. This roundtable unites pioneers to discuss:

• Weighing the advantages of modular platforms against bespoke conjugate strategies for specific tissue targets, considering factors like valency, manufacturability, and immunogenicity.
• Addressing the unique synthesis, characterization, and manufacturing challenges of complex delivery modalities to ensure quality, stability, and scalability for clinical and commercial supply.
• Strategizing on how to design platforms with inherent adaptability to rapidly retarget new tissues and diseases, maximizing platform value and accelerating development timelines.
• n selection for optimal risk/reward, ensuring portfolio companies can attract pharma partnerships or IPO success

• Featuring a proprietary tumor-directed protein, which mediates potent and selective biodistribution to tumors, as validated by higher payload concentration
• Demonstrating efficient functional delivery in vitro and in vivo of siRNA molecules to cancer cells for therapeutic application, achieving robust oncogene silencing and a profound anti-tumor effect
• Exploring the utility of siRNA delivery as an adjunct therapy to drug conjugates to sequentially disrupt oncogenic pathways and eradicate tumor cells, thereby overcoming mechanism-based resistance

• Showcasing early preclinical evidence of tumor-selective siRNA activity with minimized off-target effects through aptamer-based targeting
• Introducing the Antibody-Oligonucleotide Conjugate (AOC) platform and proof-ofconcept studies validating precision tumor delivery
• Presenting data from lead candidate selection and in-depth characterization to demonstrate potency and durability
• Exploring future opportunities to integrate Sebastian BioPharma’s RNAi platforms with checkpoint inhibitors and precision medicine strategies to expand patient benefit

The therapeutic window of RNAi is defined by the intricate balance between potent silencing and off-target effects, driven by advances in chemical modifications, novel conjugate strategies, and a deeper understanding of RNAi pharmacology. This roundtable convenes experts pioneering these chemical and biological innovations to define the principles for building better, safer RNAi therapeutics by discussing:

• How are novel phosphorothioate patterns, 2’-modifications, and scaffold designs being used to actively direct biodistribution, improve cellular uptake, and facilitate endosomal escape
• Comparing the advantages, limitations, and unique pharmacological profiles of emerging delivery vehicles.
• Integrating predictive tools for immunogenicity and off-target effects early in candidate selection.

The future of RNAi lies at the intersection of precision medicine, AI-driven innovation, and strategic combination approaches. This panel explores how integrating cutting-edge technologies like AI target discovery with synergistic modalities can unlock new therapeutic potential. Experts will discuss multi-target silencing strategies, new target molecule classes, and how to future-proof RNAi pipelines to lead the next wave of transformative treatments. Join us to gain actionable insights on positioning your RNAi therapeutics at the forefront of precision medicine by discussing:

• Exploring AI-driven target discovery and combination therapies with CAR-T or radiotherapy to accelerate identification of disease-specific genes with high clinical relevance to enable faster precision RNAi therapy development
• Predicting future combination therapy strategies to stay ahead of emerging trends in multi-target silencing, for the expansion of treatment options for complex diseases
• Strategizing how to position pipelines at the forefront of next-gen RNAi innovation