Synthesis and Biological Activity Assessment of Different Diastereomers in siRNA Drug LEQVIO (Inclisiran) (U01) Clinical Trial Not Allowed

The purpose of this research is to systematically evaluate the diastereomeric composition of LEQVIO (Inclisiran), an FDA-approved, N-acetyl galactosamine (GalNAc)-conjugated siRNA drug, and to understand the biological/pharmacological activity of each diastereomer in LEQVIO through stereo chemically controlled synthesis and biological activity assessment using in vitro and animal models. The proposed studies will focus on 1) synthesis of each diastereomer of LEQVIO (Inclisiran) in stereo chemically pure form; 2) assessment of the biological activity of each stereo chemically pure diastereomer in inhibiting PCSK9 activity using in vitro assays and in a transgenic mouse model; 3) development of analytical methods to identify and characterize the stereochemical structure of each diastereomer in LEQVIO; and 4) assessment of the individual contribution of each diastereomer to the overall pharmacological activity of LEQVIO. Tools developed in this research can also be applied to other similar GalNAc-conjugated siRNAs specifically, and other siRNAs in general. Knowledge gained from this research will also contribute to the sameness evaluation of generic siRNAs, and to the quality control of oligonucleotide drugs.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The FDA will not accept duplicate or highly overlapping applications under review at the same time per 2.3.7.4 Submission of Resubmission Application. This means that the NIH or FDA will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application. An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Read the full announcement on Grants.gov before you start. Federal applications are submitted through Grants.gov (or the agency's own system) and require a Unique Entity ID from SAM.gov. Registration can take several weeks, so start early. Contact: Terrin Brown Grantor · terrin.brown@fda.hhs.gov · (240) 402-7610