Therapy
Inventors
Zargari, Arezou • Admyre, Charlotte • Sandwall, Pernilla • Knittel, Thomas • Zerhouni, Peter
Assignees
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Publication Number
US-11795462-B2
Publication Date
2023-10-24
Expiration Date
Abstract
The present invention provides an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2) for use in the treatment of inflammatory bowel disease in a human subject, wherein individual doses of from 100 mg to 350 mg of said oligonucleotide are administered to the subject on at least four separate occasions, wherein the separate occasions are each a week apart.
Core Innovation
The invention relates to a method of treating moderate-to-severe active ulcerative colitis in a human subject. The method administers an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), with individual doses of from 100 mg to 350 mg administered on at least four separate occasions, each occasion being a week apart.
The method is directed to subjects who are refractory or respond insufficiently or are intolerant to anti-inflammatory therapy and/or who are elective for colectomy. In related embodiments, the oligonucleotide is cobitolimod (SEQ ID NO:1), which includes an unmethylated CG dinucleotide and phosphorothioate/phosphorodithioate backbone modifications. The approach is positioned as an immunomodulatory agent for inflammatory bowel disease and ulcerative colitis.
The document provides support through a randomized double-blind placebo-controlled topical cobitolimod trial with weekly rectal administration on four occasions, with outcomes including clinical, endoscopic, and histologic remission. Additional support is provided using a DSS-induced colitis mouse model in which rectal cobitolimod reduced weight loss and disease activity index, improved endoscopic colitis grading, and reduced Th17/IL-17+ CD4+ cells and Gr1+CD11b+ myeloid-derived suppressor cells.
Claims Coverage
The independent claims identified are claim 1, claim 14, and claim 17. Across these claims, the inventive coverage centers on administering a specific oligonucleotide sequence (SEQ ID NO:2) to treat moderate-to-severe active ulcerative colitis, with defined dosing amounts over weekly administrations and defined subject eligibility based on anti-inflammatory therapy response or colectomy status, including formulation and treatment-duration variations.
Specific oligonucleotide sequence with weekly spaced dosing for moderate-to-severe active ulcerative colitis
Administering an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2) to treat moderate-to-severe active ulcerative colitis, wherein individual doses of from 100 mg to 350 mg are administered on at least four separate occasions, with the separate occasions each a week apart, to subjects who are refractory or respond insufficiently or are intolerant to anti-inflammatory therapy and/or who are elective for colectomy.
Pharmaceutical composition including SEQ ID NO:2 with carriers and weekly administrations delivering 100 mg to 350 mg
Administering a pharmaceutical composition comprising an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2) together with one or more pharmaceutically acceptable carriers, wherein individual administrations of the composition are administered on at least four separate occasions each a week apart, and wherein each administration delivers an amount of from 100 mg to 350 mg of the oligonucleotide, for subjects who are refractory or respond insufficiently or are intolerant to anti-inflammatory therapy and/or are elective for colectomy.
Weekly dosing of SEQ ID NO:2 until remission
Administering a pharmaceutical composition comprising an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), wherein individual doses of from 100 mg to 350 mg are administered every week until the subject is in remission, for subjects who are refractory or respond insufficiently or are intolerant to anti-inflammatory therapy and/or are elective for colectomy.
The independent claims collectively cover treatment of moderate-to-severe active ulcerative colitis using an oligonucleotide having sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), with dosing defined as 100 mg to 350 mg given on at least four weekly administrations or every week until remission. They further restrict use to subjects refractory or insufficiently responsive or intolerant to anti-inflammatory therapy and/or subjects elective for colectomy, and claim 14 additionally specifies administration as a pharmaceutical composition with pharmaceutically acceptable carriers.
Stated Advantages
Improved clinical, endoscopic, and histologic remission outcomes in a randomized double-blind placebo-controlled topical cobitolimod trial.
Reduced weight loss and reduced disease activity index and improved endoscopic colitis grading in a DSS-induced colitis mouse model.
Reduced Th17/IL-17+ CD4+ cells and reduced Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) in the DSS-induced colitis mouse model.
Documented Applications
Treating moderate-to-severe active ulcerative colitis in a human subject who is refractory or responds insufficiently or is intolerant to anti-inflammatory therapy and/or is elective for colectomy.
Topical administration of cobitolimod via rectal administration in a randomized double-blind placebo-controlled trial with four weekly administrations.
Using a DSS-induced colitis mouse model to assess rectal cobitolimod effects, including disease activity and immune-cell changes.
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