Method for prevention of colectomy
Inventors
Admyre, Charlotte • Zargari, Arezou • Von Stein, Oliver • Von Stein, Petra
Assignees
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Publication Number
US-9795627-B2
Publication Date
2017-10-24
Expiration Date
Abstract
A method of treating chronic active ulcerative colitis in a subject that is refractory or responds insufficiently or is intolerant to anti-inflammatory therapy, comprises administering to a patient in need thereof an effective exposure of an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO.2), wherein at least one CG dinucleotide is unmethylated. The oligonucleotide is not administered with corticosteroids or glucocorticosteroids.
Core Innovation
The invention relates to methods and compositions for preventing or delaying colectomy and for treating inflammatory bowel disease using repetitively administered immunomodulatory oligonucleotides. The treatment is described for chronic active ulcerative colitis and Crohn’s disease, including subjects that are refractory or respond insufficiently or are intolerant to anti-inflammatory therapy. The oligonucleotide comprises the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2) and includes at least one unmethylated CG dinucleotide.
The invention defines an exposure-based administration approach in which the oligonucleotide is administered as an effective exposure, including single exposure and repeated exposures. Repeated exposures are described using exposure intervals on the order of weeks, including separate occasions spaced within a 4 to 70 week interval window. The document further includes dosing amounts and regimens in which relapse re-dosing is considered.
In addition, the oligonucleotide is described as not being administered in combination with corticosteroid or glucocorticosteroid. The oligonucleotide chemistry is described with options for phosphate backbone modifications, including phosphorothioate and phosphorodithioate modifications, and with oligonucleotide sequence variants based on the core sequence. Administration is described as including intracolonic and topical delivery to mucosal membrane, including delivery during colonoscopy, and the document reports clinical outcomes using CAI score, endoscopic score (Rachmilewitz), and histological score (Geboes).
Claims Coverage
The independent claim is directed to treating chronic active ulcerative colitis in a subject refractory or insufficiently responding or intolerant to anti-inflammatory therapy by administering an effective exposure of a specific unmethylated-CG-containing oligonucleotide sequence, while excluding corticosteroid/glucocorticosteroid co-administration. The independent claim is refined by dependent claims adding defined dose ranges, multi-dose timing intervals, oligonucleotide backbone modification requirements, and specific administration routes, among other constraints.
Unmethylated CG oligonucleotide for chronic active ulcerative colitis treatment
Administering an effective exposure of an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2) wherein at least one CG dinucleotide is unmethylated.
Exclude corticosteroid or glucocorticosteroid combination
Administering the oligonucleotide such that it is not administered in combination with corticosteroid or glucocorticosteroid.
Dose around 30 mg
Administering the oligonucleotide at an amount of about 30 mg.
Dose range from 0.3 mg to 100 mg
Administering the oligonucleotide in an amount ranging from about 0.3 mg to about 100 mg.
Repeated dosing spaced 4 to 70 weeks apart
Administering two or more doses of the specified oligonucleotide on separate occasions spaced 4 to 70 weeks apart.
Phosphate backbone modification with phosphorothioate or phosphorodithioate
Using a phosphate backbone modification selected from phosphorothioate or phosphorodithioate modifications.
Intracolonic administration
Administering the oligonucleotide intracolonically.
Across the claim set, the core coverage centers on treating chronic active ulcerative colitis using an effective exposure of SEQ ID NO:2 containing at least one unmethylated CG dinucleotide, expressly excluding corticosteroid/glucocorticosteroid combination therapy, with dependent claim refinements including specific dose amounts/ranges, multi-dose spacing (4 to 70 weeks), required phosphate backbone modification chemistry (phosphorothioate or phosphorodithioate), and intracolonic administration.
Stated Advantages
Preventing or delaying colectomy.
Treating chronic active ulcerative colitis (including refractory/insufficient response/intolerance) using an effective exposure regimen with reported improvements in clinical response/remission metrics.
Improving colectomy-free outcomes over a period described in the document.
Documented Applications
Preventing or delaying colectomy in inflammatory bowel disease, including chronic active ulcerative colitis and Crohn’s disease.
Treating chronic active ulcerative colitis in subjects refractory or insufficiently responding or intolerant to anti-inflammatory therapy.
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