Compositions of peptide inhibitors of Interleukin-23 receptor
Inventors
Di Pretoro, Giustino • SUN, Dajun • Rajan, Gopal • BROECKX, Geraldine • MERTENS, Nathalie • Li, Shu • Lai, Felix • MASJEDIZADEH, Mohammad • Fourie, Anne M. • Knight, Beverly • Polidori, David • Neelamkavil, Santhosh Francis • Modi, Nishit • Bhandari, Ashok • Cheng, Xiaoli
Assignees
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Publication Number
US-11939361-B2
Publication Date
2024-03-26
Expiration Date
Abstract
The present invention relates to compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salt or solvate forms thereof, corresponding pharmaceutical compositions, methods and/or uses for treatment of autoimmune inflammation and related diseases and disorders.
Core Innovation
The invention relates to peptide inhibitors of the IL-23 receptor (IL-23R) and to an oral tablet formulation comprising a peptide of SEQ ID NO: 1, including an acetate form, or a pharmaceutically acceptable salt or solvate form thereof, together with one or more pharmaceutically acceptable excipients. Sodium caprate is used as an absorption/permeation enhancer, and the tablet is described as having a two-phase tablet core with a granulated internal phase and a silicified microcrystalline cellulose external phase to physically separate sodium caprate from an enteric coating.
The peptide content is described as from about 0.1% to about 15% (w/w) in one composition context and from about 0.1% to about 20% (w/w) in another composition context. The composition includes pharmaceutically acceptable salt or solvate forms, including acetate salt and amorphous acetate forms, and is described as an oral/systemically active pharmaceutical composition to enable IL-23R blockade in a subject.
The document provides pharmacology and pharmacokinetic evidence for orally administered SEQ ID NO: 1 peptide, including dog pharmacokinetic parameters under fasted versus fed conditions and in the presence of sodium caprate, as well as first-in-human Phase 1 results for oral solution and enteric-coated tablet formulations. Ex vivo and pharmacodynamic engagement is described using IL-23/IL-1β stimulated whole blood assays with IL-17A ELISA, and downstream rat skin pharmacodynamics are described through IL-23-related gene expression and functional ear-thickening outcomes.
Therapeutic application is supported by a rat TNBS colitis model in which GI-exposure-related attenuation of disease endpoints is described, and by Phase 1 ex vivo human PD assays using IL-23 pathway engagement readouts including IFNγ and pSTAT3 in clinically relevant dosing contexts. The treatment-use context includes inflammatory diseases such as psoriasis and inflammatory bowel disease (IBD), with IL-23/IL-23R signaling and related cytokines IL-17A, IL-17F, and IL-22 referenced.
Claims Coverage
The independent claims cover two pharmaceutical compositions containing a peptide of SEQ ID NO: 1, or a pharmaceutically acceptable salt or solvate form thereof, with one or more pharmaceutically acceptable excipients. The inventive features are the two peptide-loading ranges, 0.1% to 15% (w/w) and 0.1% to 20% (w/w); dependent claims further specify salt or solvate forms, narrower peptide amount ranges, optional absorption enhancer inclusion, and a method of treating an inflammatory disease in a subject.
Pharmaceutical composition with SEQ ID NO: 1 peptide at 0.1% to 15% (w/w)
A pharmaceutical composition comprising a peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate form thereof in an amount of from about 0.1% to about 15% (w/w) of the pharmaceutical composition, and one or more pharmaceutically acceptable excipients.
Pharmaceutical composition with SEQ ID NO: 1 peptide at 0.1% to 20% (w/w)
A pharmaceutical composition comprising a peptide of SEQ ID NO: 1 or a pharmaceutically acceptable salt or solvate form thereof in an amount of from about 0.1% to about 20% (w/w) of the pharmaceutical composition, and one or more pharmaceutically acceptable excipients.
The claim coverage is composition-level protection for SEQ ID NO: 1 peptide pharmaceutical compositions at either 0.1% to about 15% (w/w) or 0.1% to about 20% (w/w) with pharmaceutically acceptable excipients. Dependent claims refine the salt or solvate forms, narrow peptide amount ranges, optionally add an absorption enhancer, and recite treatment of an inflammatory disease in a subject.
Stated Advantages
Improved bioavailability supported by PK/PD claims, including enhancer comparisons and relative bioavailability for enteric-coated, absorption-enhanced tablets.
Reduced contact between sodium caprate and the enteric coating by using silicified microcrystalline cellulose external phase, supporting stability and intestinal delivery.
Purity, particle size, and crystallinity of sodium caprate are stated to improve bioavailability.
Performance support is described via IL-17A suppression in whole blood ex vivo and skin gene-expression inhibition.
Documented Applications
Treatment of an inflammatory disease in a subject by administering a therapeutically effective amount of the pharmaceutical composition.
Inhibition of IL-23R in inflammatory diseases, including psoriasis and inflammatory bowel disease (IBD), with IL-23/IL-23R signaling and related cytokine expression referenced.
Use of an ex vivo whole-blood assay measuring IL-17A suppression and skin gene-expression inhibition as application contexts for assessing performance.
Animal model context including a TNBS rat colitis model and PK studies in rats and dogs as described support for performance of the described compositions.
Preliminary first-in-human Phase 1 study context for assessing human PK/relative bioavailability of enteric-coated, absorption-enhanced tablets.
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