09 May, 2018 Nonclinical Safety Evaluation of GalNAc-siRNA Conjugates
We presented a nonclinical safety evaluation of GalNAc-siRNA conjugates at the 8th Annual Biologics Symposium, being held May 8-9, 2018 in Plainsboro, NJ.
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We presented a nonclinical safety evaluation of GalNAc-siRNA conjugates at the 8th Annual Biologics Symposium, being held May 8-9, 2018 in Plainsboro, NJ.
We presented initial data demonstrating delivery of nove small interfering RNA (siRNA) conjugates to the central nervous system (CNS) at the TIDES: Oligonucleotides and Peptide Therapeutics 2018 Annual Meeting, being held May 7-10, 2018 in Boston, MA.
We presented new positive results from the APOLLO Phase 3 study of patisiran, an investigational RNAi therapeutic for the treatment of hereditary ATTR (hATTR) amyloidosis, at the American Academy of Neurology (AAN) 2018 Annual Meeting, being held April 21-27, 2018 in Los Angeles.
We presented new positive results from the Phase 1, Phase 1/2, and EXPLORE natural history studies of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias (AHPs), at the European Association for the Study of the Liver (EASL) 53rd Annual International Liver Congress, being held April 11-15, 2018 in Paris, France.
We presented additional results from the APOLLO Phase 3 study of patisiran, an investigational RNAi therapeutic for the treatment of hereditary ATTR (hATTR) amyloidosis, at the 16th International Symposium on Amyloidosis (ISA), held March 26-29, 2018 in Kumamoto, Japan.
In addition, we presented new data from the Phase 1 study of ALN-TTRsc02, an investigational, subcutaneously administered RNAi therapeutic for the treatment of ATTR amyloidosis.
During initial development candidate selection, a subset of chemically-modified siRNAs conjugated to trivalent GalNAc does not pass the stringent safety criteria for nonclinical evaluation due to rat hepatotoxicity. This body of work provides evidence that the observed hepatotoxicity is largely attributed to unintended base-pairing of the seed region of the siRNA antisense strand with off-target mRNAs, with little or no contribution from chemical modifications or the perturbation of RNAi pathways. Changing the sequence of the seed region or introducing thermally destabilizing modifications, such as glycol nucleic acid (GNA), in that region mitigated hepatotoxicity. Introduction of seed GNA has the potential to minimize the occurrence of hepatotoxic siRNAs across species without compromising on-target activity. This approach, among others, provides the opportunity to expand the number of initial candidates for nonclinical testing and to streamline the process of development candidate selection for RNAi therapeutics.