Mark Schlegel, Director at Alnylam Pharmaceuticals, presented on advancements in siRNA therapeutic designs, focusing on improving specificity and therapeutic indices. Schlegel played a key role in developing the ESC+ siRNA design platform, which enhances safety and efficacy by mitigating off-target effects.
Alnylam's GalNAc siRNA conjugate platform has successfully delivered multiple clinical candidates, resulting in five approved drugs. Recent advancements include targeting extrahepatic tissues, such as the central nervous system, by converting GalNAc siRNAs into lipid-conjugated forms.
The ESC+ design strategy addresses safety challenges by introducing chemical modifications in the seed region to selectively destabilise off-target seed interactions while preserving on-target knockdown. This strategy has shown significant improvements in safety and efficacy in both preclinical and clinical studies.
One key modification is the incorporation of glycol nucleic acid (GNA), which thermally destabilises RNA duplexes and reduces off-target binding. This modification has demonstrated enhanced safety without compromising potency in rat toxicology studies.
The ESC+ strategy was successfully translated into humans, showing robust pharmacology and improved safety profiles in clinical trials. Structural studies revealed that GNA nucleotides invert hydrogen bond donor-acceptor pairs, affecting base pairing differently depending on the nucleotide, which can influence in vivo activity.
Alnylam continues to evolve its siRNA conjugate platform through clinical experience and mechanistic insights. The ESC+ approach, incorporating GNA and 2’-5’-RNA modifications, effectively mitigates seed-mediated off-target effects, improves therapeutic specificity, and expands the safety window of siRNA therapeutics. Multiple ESC+ conjugates have progressed into clinical development, with further data forthcoming.
