Oral delivery of antisense conjugates targeting PCSK9
Inventors
OERUM, Henrik • Noble, Stewart Alwyn • SHEAR, Charles Lester
Assignees
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Publication Number
US-12291708-B2
Publication Date
2025-05-06
Expiration Date
Abstract
The present disclosure provides pharmaceutic compositions for oral delivery comprising an antisense oligonucleotide (e.g., CIVI 008) and an oral delivery agent such as 5-CNAC. In some aspects, the disclosure provides a capsule comprising a dry blend of CIVI 008 and 5-CNAC, and optionally a statin.
Core Innovation
The invention relates to pharmaceutical compositions for oral delivery to a subject that include an antisense oligonucleotide of formula I (SEQ ID NO: 19) and N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) or a salt thereof. The composition is presented as a tablet or capsule and includes a pH-sensitive enteric coating, formulated to release the antisense oligonucleotide of formula I in the subject's small intestine following oral administration.
A core aspect is the pairing of the PCSK9-targeting antisense oligonucleotide conjugate chemistry with an oral delivery agent system described as SNAC/C10/5-CNAC. The antisense oligonucleotide is characterized as a LNA gapmer design over a 16-22 contiguous nucleotides target region, having a phosphorothioate internucleoside linkage pattern, and being defined by target region sequences identified by SEQ ID NOs.
The described compositions further specify modulation endpoints related to PCSK9 expression/activity and PCSK9-related lipid endpoints. They also include nucleotide-analogue and linker/conjugate definitions, with disclosed nucleotide-analogue options including LNA variants and modifications and additional disclosures of duplex RNA variations and bicyclic nucleoside structural formulas.
Claims Coverage
The independent claim covers an oral pharmaceutical composition composed of an antisense oligonucleotide of formula I (SEQ ID NO: 19) and 5-CNAC (or a salt), within a tablet or capsule having a pH-sensitive enteric coating configured for small-intestine release. The inventive features are directed to the oral delivery format and pH-sensitive release arrangement, as well as the specific pairing of formula I antisense oligonucleotide with 5-CNAC.
Oral delivery composition with formula I antisense oligonucleotide and 5-CNAC
A pharmaceutical composition for oral delivery to a subject comprising an antisense oligonucleotide of formula I (SEQ ID NO: 19) and N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) or a salt thereof.
Tablet or capsule with pH-sensitive enteric coating for small-intestine release
The pharmaceutical composition is formulated as a tablet or capsule comprising a pH-sensitive enteric coating, wherein the composition is formulated to release the antisense oligonucleotide of formula I in the subject's small intestine following oral administration.
Across the independent claim, the main coverage is the specific oral composition that combines the formula I antisense oligonucleotide (SEQ ID NO: 19) with 5-CNAC (or salt) and uses a pH-sensitive enteric-coated tablet or capsule configured to release the antisense oligonucleotide in the small intestine after oral administration.
Stated Advantages
Provides a pharmaceutical composition formulated for oral delivery with release in the subject’s small intestine following oral administration.
Enables reduction of expression levels and/or activity of PCSK9 or reduction of cholesterol levels in a subject.
Documented Applications
Oral administration of a pharmaceutical composition to reduce expression levels and/or activity of PCSK9 or cholesterol levels in a subject.
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