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WO2022112224A1 - Posologie de cobitolimod pour auto-administration - Google Patents

Posologie de cobitolimod pour auto-administration Download PDF

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Publication number
WO2022112224A1
WO2022112224A1 PCT/EP2021/082627 EP2021082627W WO2022112224A1 WO 2022112224 A1 WO2022112224 A1 WO 2022112224A1 EP 2021082627 W EP2021082627 W EP 2021082627W WO 2022112224 A1 WO2022112224 A1 WO 2022112224A1
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oligonucleotide
subject
use according
administered
treatment
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Arezou Zargari
Pernilla SANDWALL
Charlotte Yvonne Birgitta ADMYRE
Thomas Knittel
Peter ZERHOUNI
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Index Pharmaceuticals AB
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Index Pharmaceuticals AB
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Priority to CN202180091789.4A priority Critical patent/CN116867499A/zh
Priority to JP2023531702A priority patent/JP2023553336A/ja
Priority to KR1020237020455A priority patent/KR20230112664A/ko
Priority to EP21835160.9A priority patent/EP4251270A1/fr
Priority to CA3202097A priority patent/CA3202097A1/fr
Priority to AU2021386281A priority patent/AU2021386281A1/en
Publication of WO2022112224A1 publication Critical patent/WO2022112224A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to new therapies for treating inflammatory bowel diseases, for instance active ulcerative colitis (UC), wherein an oligonucleotide, especially cobitolimod, is administered according to an optimised dosage regime.
  • UC active ulcerative colitis
  • Ulcerative colitis is a disease characterized by chronic inflammation of the rectal and colonic mucosa, affecting the innermost lining in the first stage.
  • the disease is recurrent, with both active and inactive stages that differ in pathology, symptoms and treatment.
  • the underlying cause of UC is not understood, nor is it known what triggers the disease to recur between its inactive and active forms (Irvine, E. J. (2008) Inflamm Bowel Dis 14(4): 554-565).
  • Symptoms of active UC include progressive loose stools with blood and increased frequency of bowel movements. Active mucosal inflammation is diagnosed by endoscopy.
  • the stools contain pus, mucous and blood and are often associated with abdominal cramping with urgency to evacuate (tenesmi). Diarrhoea may have an insidious onset or, more rarely, start quite suddenly. In severe cases the symptoms may include fever and general malaise. In severe stages, deep inflammation of the bowel wall may develop with abdominal tenderness, tachycardia, fever and risk of bowel perforation. Furthermore, patients with UC may suffer extra intestinal manifestations such as arthralgia and arthritis, erythema nodosum, pyoderma gangrenosum and inflammation in the eyes. In the case of remission or inactive UC, patients are usually free of bowel symptoms.
  • ulcerative proctitis The extent of inflamed and damaged mucosa differs among patients with UC.
  • UC that affects only the rectum is termed ulcerative proctitis.
  • the condition is referred to as distal or left sided colitis when inflammatory changes are present in the left side of the colon up to the splenic flexure.
  • pancolitis designates a disease involving the entire colon.
  • Active mucosal inflammation is diagnosed by endoscopy and is characterized by a loss of vascular patterning, oedema, petechia, spontaneous bleeding and fibrinous exudates.
  • the endoscopic picture is that of continuous inflammation, starting in the rectum and extending proximally to a variable extent into the colon.
  • Biopsies obtained at endoscopy and subjected to histological examination help to diagnose the condition.
  • Infectious causes including Clostridium difficile, camphylobacter, Salmonella and Shigella, may mimic UC and can be excluded by stool cultures.
  • the medical management of UC is divided into treatment of active disease and maintenance of remission.
  • the treatment of patients with active UC aims to reduce inflammation and promote colon healing and mucosal recovery.
  • the disease may be controlled with conventional drugs including sulphasalazine, 5 -aminosalicylic acid (5-ASA) (Sutherland, L., F. Martin, S. Greer, M. Robinson, N. Greenberger, F. Saibil, T. Martin, J. Sparr, E. Prokipchuk and L. Borgn (1987) Gastroenterology 92: 1894-1898) and glucocorticosteroids (GCS) (Domenech, E., M. Manosa and E. Cabre (2014). Dig Dis 32(4): 320-327).
  • 5-ASA 5 -aminosalicylic acid
  • GCS glucocorticosteroids
  • GCS are generally used to treat disease flare-ups and are not recommended for maintenance of remission since there are significant side effects in long-term use, and the possible development of steroid dependent disease.
  • Glucocorticoid drugs act non- selectively, so in the long run they may impair many healthy anabolic processes. As a result, maintenance treatment with systemic GCS is not advised (Prantera, C. and S. Marconi (2013) Therap Adv Gastroenterol 6(2): 137-156).
  • immunomodulatory agents such as cyclosporine, 6- mercaptopurine and azathioprine may be used.
  • immunomodulators are slow- acting and the induction of remission in these patients is often temporary (Khan, K. J., M. C. Dubinsky, A. C. Ford, T. A. Ullman, N. J. Talley and P. Moayyedi (2011) Am J Gastroenterol 106(4): 630-642).
  • TNF- ⁇ inhibitors currently approved for the treatment of moderate to severe UC are infliximab, adalimumab, and golimumab. All three carry potential risks associated with their use, and should be avoided in certain patients, e.g. those with uncontrolled infections, advanced heart failure, neurologic conditions and in patients with a history of malignancy, due to a potential risk of accelerating the growth of a tumour.
  • TNF- ⁇ inhibitor therapy include neutropenia, hepatotoxicity, serum sickness, leukocytoclastic vasculitis, rash including psoriasiform rash, induction of autoimmunity, and injection or infusion site reactions, including anaphylaxis, convulsions, and hypotension.
  • TNF- ⁇ inhibitor agents All three TNF- ⁇ inhibitor agents and their related biosimilar / derivative counterparts may be used to induce and maintain clinical response and remission in patients with UC.
  • Combination therapy with azathioprine is also used for inducing remission.
  • Vedolizumab a a4b7 integrin inhibitor
  • vedolizumab was found to be more effective than placebo for inducing and maintaining clinical response, clinical remission, and mucosal healing (Feagan, B. G., P. Rutgeerts, B. E. Sands, S. Hanauer, J. F. Colombel, W. J. Sandbom, G. Van Assche, J. Axler, H. J. Kim, S. Danese, I. Fox, C. Milch, S. Sankoh, T. Wyant, J. Xu, A. Parikh and G. S. Group (2013). "Vedolizumab as induction and maintenance therapy for ulcerative colitis.” N Engl J Med 369(8): 699-710.).
  • Ulcerative colitis patients who are chronically active and refractory to known treatments pose a serious medical challenge and often the only remaining course of action is colectomy.
  • a total colectomy is a potentially curative option in severe UC, but is a life- changing operation that entails risks as complications, such as pouch failure, pouchitis, pelvic sepsis, infertility in women, and nocturnal faecal soiling, may follow. Therefore, surgery is usually reserved for patients with severe refractory disease, surgical or other emergencies, or patients with colorectal dysplasia or cancer.
  • Cobitolimod Kappaproct/DIMS0150
  • DNA deoxyribonucleic acid
  • Cobitolimod has the sequence 5'- G*G*A*ACAGTTCGTCCAT*G*G*C- 3’ (SEQ ID NO:l), wherein the CG dinucleotide is unmethylated.
  • Cobitolimod functions as an immunomodulatory agent by targeting the Toll-like receptor 9 (TLR9) present in immune cells.
  • TLR9 Toll-like receptor 9
  • These immune cells i.e., B-cells and plasmacytoid dendritic cell (pDCs) reside in high abundance in mucosal surfaces, such as colonic and nasal mucosa.
  • the immune system is the key mediator of the changes of UC.
  • the mucosa of the colon and rectum of patients with UC is chronically inflamed and contains active immune cells.
  • Cobitolimod may be topically administered in the region of inflammation, which places the drug in close contact with a high number of intended target cells, ensuring that the drug will reach an area rich in TLR9 expressing cells.
  • cobitolimod The activation of these cells by cobitolimod induces various cytokines, such as type I interferons and interleukin 10 (IL- 10) which are classical anti- inflammatory cytokines and are believed to be important factors for the clinical effect of cobitolimod.
  • cytokines such as type I interferons and interleukin 10 (IL- 10) which are classical anti- inflammatory cytokines and are believed to be important factors for the clinical effect of cobitolimod.
  • cobitolimod supports a positive benefit-risk assessment for patients with chronic UC which is in an active phase (occasionally referred to herein as “chronic active UC”).
  • Cobitolimod is safe and well tolerated and has been shown to be effective to induce clinical response and remission in patients with chronic UC which is in an active phase, as well as symptomatic and endoscopic remission in patients with treatment refractory, moderate to severe chronic UC which is in an active phase.
  • cobitolimod for treatment of inflammatory bowel diseases such as UC, administration of cobitolimod at a dosage of greater than 350mg, for instance from 351 to 650mg, typically from 400mg to 600mg, preferably around 500mg, on at least two, preferably two, separate occasions three weeks apart is optimal, for instance to induce remission and/or retain a patient in remission (i.e. act as a maintenance therapy).
  • the increase in efficacy of the drug at 500mg is more than would have been expected from the previous clinical studies carried out at lower doses.
  • this dosage is found to be safe and well-tolerated, and is effective even when faecal matter is present, despite the known propensity of cobitolimod to bind to faecal matter. Therefore, this dosage is suitable for administration to patients which have not been subjected to colonic cleaning. Further, it has surprisingly been found that this dosage is suitable for self-administration via an enema device. Thus, it is not necessary to administer the active ingredient using a spray catheter device during an endoscopy. This avoids the need for administration by a medical professional and the use of complex medical equipment and more invasive procedures.
  • the patient does not therefore need to travel to a medical centre or hospital to receive the drug and can self-administer in their own home.
  • the present invention therefore provides an oligonucleotide comprising the sequence 5 '-GGAAC AGTTCGTCC AT GGC-3 ' (SEQ ID NO:2) for use in the treatment of inflammatory bowel disease in a human subject, wherein individual doses of from 400mg to 600mg of said oligonucleotide are administered to the subject on at least two separate occasions, wherein said separate occasions are 3 weeks apart.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an oligonucleotide as defined herein, together with one or more pharmaceutically acceptable carriers, for use in the treatment of inflammatory bowel disease as defined herein in a human subject as defined herein, wherein individual administrations of said composition are administered to the subject on at least two separate occasions, wherein said separate occasions are 3 weeks apart, and wherein each administration of the composition delivers an amount of the oligonucleotide as defined herein.
  • the present invention also provides a method of treating inflammatory bowel disease as defined herein, in a human subject as defined herein, comprising administering to said subject an oligonucleotide as defined herein or a composition as defined herein, wherein individual administrations of said oligonucleotide or composition are administered to the patient on at least two separate occasions, wherein said separate occasions are 3 weeks apart, and wherein each administration of the oligonucleotide or composition delivers an amount of the oligonucleotide as defined herein.
  • the oligonucleotide has the sequence 5'- G*G*A*ACAGTTCGTCCAT*G*G*C-3' (SEQ ID NO:l ), wherein the CG dinucleotide is unmethylated.
  • the oligonucleotide is cobitolimod.
  • Figure 2 shows the results from a placebo-controlled clinical trial of the proportion of the treatment and placebo groups reporting weekly stool frequency ⁇ 18 (summary of patient reported outcome during 7 days) by week following administration of an oligonucleotide of the invention, or placebo (added to standard of care (S.o.C.)).
  • Figure 3 shows the results from a placebo-controlled clinical trial of the proportion of the treatment and placebo groups reporting weekly stool frequency ⁇ 35 (summary of patient reported outcome during 7 days) by week following administration of an oligonucleotide of the invention, or placebo (added to standard of care (S.o.C.)).
  • Figure 4 shows the results from a placebo-controlled clinical trial of the proportion of the treatment and placebo groups reporting daily stool frequency ⁇ 3 (mean daily patient reported outcome during 7 days) by week following administration of an oligonucleotide of the invention, or placebo (added to standard of care (S.o.C.)) ⁇
  • Figure 5 shows the results from a placebo-controlled clinical trial of the proportion of the treatment and placebo groups reporting daily stool frequency ⁇ 4 (mean daily patient reported outcome during 7 days) by week following administration of an oligonucleotide of the invention, or placebo (added to standard of care (S.o.C.)) ⁇
  • Figure 6 shows the results from a placebo-controlled clinical trial of the proportion of the treatment and placebo groups reporting daily stool frequency ⁇ 5 (mean daily patient reported outcome during 7 days) by week following administration of an oligonucleotide of the invention, or placebo (added to standard of care (S.o.C.)).
  • the term “subject” refers to a human subject/patient.
  • the terms “subject” and “patient” are used interchangeably herein.
  • IBD inflammatory bowel disease
  • Ulcos disease refers to a group of inflammatory conditions of the colon and the gastrointestinal tract.
  • the major types of IBD are ulcerative colitis (UC) and Crohn’s disease.
  • UC ulcerative colitis
  • Crohn's disease can affect any part of the gastrointestinal tract, from mouth to anus, while UC is restricted to the colon and the rectum.
  • a definitive diagnosis of either Crohn’s disease or UC cannot be made due to idiosyncrasies in the presentation. In these cases a diagnosis of indeterminate colitis may be made.
  • Other forms of IBD include, but are not limited to, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Beliefs disease and indeterminate colitis.
  • the inflammatory bowel disease is ulcerative colitis (UC).
  • UC ulcerative colitis
  • Ulcerative colitis treated in accordance with the present invention may involve treatment of ulcerative proctitis, distal or left sided colitis, extensive colitis, pancolitis and pouchitis. Typically, the patient is suffering from left sided ulcerative colitis.
  • Patients with UC typically present with a spectrum of disease severity ranging from remission to severely active.
  • Clinical assessment can be used to classify UC patients into 4 disease activity subgroups as defined in D’Haens, Gastroenterology 2007; 132: 763-786, the entirety of which is incorporated herein by reference: (1) remission ( ⁇ 2 or 3 stools/ day, without the presence of blood and/or pus in the stools, with no systemic symptoms); (2) mildly active disease (3 or 4 stools/day and/or presence of blood and/or pus in the stools less than daily, with no systemic symptoms of fever or weight loss); (3) moderately active disease (>4 stools/day and/or daily presence of blood and/or pus) with minimal systemic symptoms; and (4) severely active disease (>6 bloody stools/day, and evidence of toxicity, as demonstrated by fever, tachycardia, anemia, or an erythrocyte sedimentation rate ESR).
  • the patient is suffering from moderate to severe UC.
  • the patient is suffering from moderate to severe UC as defined above.
  • the patient may be suffering from moderate to severe left sided UC.
  • treatment and “treating” are to be understood as embracing treatment and/or amelioration and/or prevention of or reduction in aggravation/worsening of symptoms of a disease or condition as well as treatment of the cause of the disease or condition, and may include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilise a subject's condition.
  • “treating” typically refers to inducing response or remission in a patient having active ulcerative colitis.
  • the oligonucleotide is for inducing response or remission of active ulcerative colitis in a patient.
  • Inducing response means improving the condition of a patient by e.g. reducing and/or arresting the symptoms and clinical signs of the active disease.
  • Inducing remission means transitioning a patient from a state where they are considered to be in an active stage of the disease to a state where they are considered to be in remission.
  • Induction of response or remission in UC patients is typically assessed by one or more of endoscopy, histology, patient recorded outcomes and quality of life outcomes.
  • reference to induction of response or remission includes induction of one or more of endoscopic remission, endoscopic response, histological remission, histological response, response or remission as determined by physician or by patient recorded outcomes, and response or remission as determined by quality of life. This can typically be assessed by reference to one or more standard indices.
  • ulcerative colitis is chronic active ulcerative colitis, i.e. the patient is suffering from chronic ulcerative colitis which is in an active phase.
  • chronic active ulcerative colitis refers to patients with ulcerative colitis that is both active and chronic. Active ulcerative colitis is typically as defined herein, i.e. the patient is not in remission. Ulcerative colitis is typically a chronic (long- term) condition which cycles between active and less active phases . As the skilled person would understand, a patient suffering from chronic ulcerative colitis goes through active phases (“flare ups” or relapses) with more extreme symptoms interspersed with periods where the patient experiences milder symptoms or is in remission. Thus, the term “chronic active UC” typically refers to a patient with chronic UC who is in an active disease state.
  • the patient may be suffering from chronic active moderate to severe UC.
  • the patient may be suffering from chronic active moderate to severe left sided UC.
  • reference herein to “treating” refers to inducing response or remission in a patient having chronic active ulcerative colitis.
  • the oligonucleotide is for inducing response or remission of chronic active ulcerative colitis in a patient.
  • Induction of response or remission in UC patients may be determined in accordance with one or more standard disease indices.
  • Typical disease indices include but not limited to the ones mentioned below; (i) disease activity determined by clinical and biochemical disease activity, (ii) disease activity determined by endoscopic disease activity, (iii) disease activity determined by composite clinical and endoscopic disease activity indices, (iv) quality of life, (v) histologic disease activity. These indices are discussed in D’Haens (ibid).
  • Indices based on disease activity determined by clinical and biochemical disease activity include the Truelove and Witts Severity Index; Powell-Tuck (St. Mark’s) Index; Clinical Activity (Rachmilewitz) Index; Activity (Seo) Index; Physician Global Assessment; Lichtiger (Modified Truelove and Witts Severity) Index; Investigators Global Evaluation; Simple Clinical Colitis Activity Index; Improvement Based on Individual Symptom Scores; Ulcerative Colitis Clinical Score; and Patient-defined remission. These indices are discussed in D’Haens (ibid).
  • Indices based on disease activity determined by endoscopic disease activity include the Truelove and Witts Sigmoidoscopic Assessment; Baron score; Powell-Tuck Sigmoidoscopic Assessment; Endoscopic (Rachmilewitz Endoscopic) Index; Sigmoidoscopic Index; Sigmoidoscopic Inflammation Grade Score; Mayo Score Flexible Proctosigmoidoscopy Assessment; Sutherland Mucosal Appearance Assessment; and Modified Baron Score. These indices are discussed in D’Haens (ibid).
  • Indices based on disease activity determined by composite clinical and endoscopic disease activity indices include the Mayo Score (Mayo Clinic Score/Disease Activity Index); Modified Mayo Score and Sutherland Index (Disease Activity Index/UC Disease Activity Index). Mayo Score and Sutherland Index are discussed in D’Haens (ibid). Indices based on quality of life include the Rating Form of IBD Patient Concerns; and the Inflammatory Bowel Disease Questionnaire (IBDQ). These indices are discussed in D’Haens (ibid).
  • Indices based on histologic disease activity include those discussed in D’Haens (ibid) such as Geboes Index and Riley Index and further indices such as Nancy Index and Robarts Index.
  • Preferred indices for assessing UC patients include the Clinical Activity (Rachmilewitz) Index, Mayo Score and Modified Mayo Score.
  • the Clinical Activity (Rachmilewitz) Index is an index taking into account 7 variables: number of stools, blood in stools, investigator’s global assessment of symptomatic state, abdominal pain or cramps, temperature due to colitis, extraintestinal manifestations, and laboratory findings. This is discussed further in D’Haens (ibid) and Rachmilewitz D., BMJ 1989; 298: 82-86, the entirety of which is incorporated herein by reference. Determination of the Clinical Activity (Rachmilewitz) Index produces a score for a patient ranging from 0 to 29 points (higher scores meaning more severe disease).
  • Clinical remission may be considered as a Clinical Activity (Rachmilewitz) Index score ⁇ 4 points.
  • Response as determined by the Clinical Activity (Rachmilewitz) Index means the patient has a lower score after treatment than before treatment.
  • the Mayo Score is an index taking into account 4 items: stool frequency, rectal bleeding, findings of lower GI endoscopy, and Physician’s Global Assessment (PGA). This is discussed further in D’Haens (ibid) and Schroeder KW et al, N Engl J Med 1987; 317: 1625-1629, the entirety of which is incorporated herein by reference. Determination of the Mayo Score produces a score ranging from 0 to 12 points (higher scores meaning more severe disease). In addition to the four specific items, a patient’s functional assessment is also measured that is not meant to be included in the 12 -point index calculation but should be used as a measure of general well-being when determining the PGA score.
  • Mayo scoring for each of the 4 items is determined as set out in the Table below. b
  • Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
  • the daily bleeding score represents the most severe day of bleeding d
  • the physician’s global assessment acknowledges the 3 other criteria, the patient’s daily record of abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the patient's performance status.
  • Remission according to the Mayo Score maybe defined as complete resolution of (1) stool frequency (normal stool frequency), (2) rectal bleeding (no rectal bleeding), (3) patient’s functional assessment score (generally well), (4) endoscopy findings (normal), and a PGA score of 0.
  • Response as determined by Mayo Score typically requires improvement (a minimum 1 -point decrease from baseline) in the PGA score and improvement in at least one other clinical assessment (stool frequency, rectal bleeding, patient’s functional assessment, endoscopy findings) and no worsening in any other clinical assessment.
  • clinical remission may be defined as a Mayo Score of 0 and clinical improvement (response) as a decrease from baseline in the Mayo Score ⁇ 3 points.
  • clinical remission may be defined as a Mayo Score of 0 and clinical improvement (response) as a decrease from baseline in the Mayo Score ⁇ 3 points (or a decrease of ⁇ 2 points if the baseline Mayo Score was ⁇ 3 points).
  • remission as determined by Mayo Score may be defined as requiring subscores of 0 for both sigmoidoscopy and rectal bleeding and a score of 0 or 1 for stool frequency and PGA subscores.
  • clinical remission may be defined as a total Mayo score of ⁇ 2 points with no individual subscore >1 point
  • clinical response may be defined as a decrease from baseline in the total Mayo score ⁇ 3 points and ⁇ 30% and a decrease in the rectal bleeding subscore ⁇ 1 point or an absolute rectal bleeding subscore of 0 or 1
  • mucosal healing may be defined as an absolute endoscopy subscore of 0 or 1.
  • patients having active ulcerative colitis have a Mayo Score >2.
  • Patients who are in a remission phase of ulcerative colitis typically have a Mayo Score ⁇ 2.
  • Modified Mayo Score is related to the Mayo Score, which is defined above. Modified Mayo Score differs from Mayo Score in that the Colonoscopy/sigmoidoscopy scoring takes less account of friability. Thus, the scoring table for the Modified Mayo Score is as set out below. b Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency. c The daily bleeding score represents the most severe day of bleeding d The physician’s global assessment acknowledges the 3 other criteria, the patient’s daily record of abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the patient's performance status.
  • Modified Mayo Score Remission and response values for the Modified Mayo Score are as set out above for the Mayo Score. Modified Mayo Score is typically assessed in accordance with the FDA’s draft guidance document “Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry” found at http ://www. fda. gov/ downloads/Drugs/ GuidanceComplianceRegulatorylnformation/ Guidan ces/UCM515143.pdf
  • Modified Mayo Score may differ from Mayo Score in that the Colonoscopy/sigmoidoscopy scoring takes less account of friability and also in that Physician’s Global Assessment is not determinative.
  • the scoring table for the Modified Mayo Score may also be as follows. b Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency. c The daily bleeding score represents the most severe day of bleeding
  • Remission and response values for this alternative Modified Mayo Score are typically as set out above for the Mayo Score.
  • remission may be defined in accordance with this alternative Modified Mayo Score by sub-scores of i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), and iii) endoscopy score of 0 or 1 (excluding friability).
  • Induction of remission of UC may be in accordance with the criteria set out in S. P. L. Travis, Aliment Pharmacol Ther 2011; 34: 113-124, the entirety of which is incorporated herein by reference, i.e. complete cessation of rectal bleeding, urgency and increased stool frequency, preferably confirmed by endoscopic mucosal healing.
  • induction of response or remission may be in accordance with the criteria set out in E.F. Stange, Journal of Crohn's and Colitis (2008) 2, 1-23; S.P.L. Travis, Journal of Crohn's and Colitis (2008) 2, 24-62; K Geboes, Gut 2000; 47: 404-409; the entirety of which are incorporated herein by reference.
  • Induction of response or remission in Crohn’s disease patients may be determined in accordance with one or more standard disease indices.
  • Typical indices include the Crohn’s Disease Activity Index (CDAI).
  • CDAI Crohn’s Disease Activity Index
  • the CDAI is discussed in Love, “Pharmacotherapy for Moderate to Severe Inflammatory Bowel Disease: Evolving Strategies”, Am J Manag Care. 2016;22:S39-S50; Peyrin-Biroulet et al “Defining disease severity in inflammatory bowel diseases: current and future directions” Clin Gastroenterol Hepatol. 2015; pii:
  • CDAI is a composite score taking into account a large number of symptoms associated with Crohn’s disease, including number of liquid or soft stools; abdominal pain; general well-being; presence of complications (the presence of joint pains (arthralgia) or frank arthritis; inflammation of the iris or uveitis; presence of erythema nodosum, pyoderma gangrenosum, or aphthous ulcers; anal fissures, fistulae or abscesses; other fistulae; fever during the previous week); use of lomotil or opiates for diarrhea; presence of an abdominal mass; hematocrit value; and percentage deviation from standard weight. Clinical remission according to the CDAI is typically indicated by a score of ⁇ 150.
  • Clinical remission may be any of the definitions of clinical remission as described herein.
  • the subject is in clinical remission at week 6, following commencement of treatment with the oligonucleotide at week 0, wherein clinical remission is as defined by the 3- component Mayo scores: i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), and iii) endoscopy score of 0 or 1.
  • the subject exhibits an endoscopic improvement at week 6, following commencement of treatment with the oligonucleotide at week 0.
  • the subject is in symptomatic remission at week 6, following commencement of treatment with the oligonucleotide at week 0.
  • Symptomatic remission is typically defined as a blood in stool score of 0 and stool frequency score of 0 or 1 according to the Mayo scoring system .
  • the subject treated in accordance with the present invention is typically refractory or responds insufficiently or is intolerant to anti-inflammatory therapy and/or demonstrates or has previously demonstrated an inadequate response, loss of response, or intolerance to at least one immunomodulator, TNF- ⁇ inhibitor, anti-integrin, JAK inhibitors or IL-12/IL-23 inhibitor.
  • the subject treated in accordance with the present invention is typically refractory or responds insufficiently or is intolerant to anti-inflammatory therapy.
  • the subject treated in accordance with the present invention is typically refractory or responds insufficiently or is intolerant to at least one immunomodulator.
  • the subject treated in accordance with the present invention is typically refractory or responds insufficiently or is intolerant to at least one TNF- ⁇ inhibitor.
  • the subject has previously received or is currently receiving anti- inflammatory therapy, preferably anti-inflammatory therapy for UC and/or immunomodulatory, TNF- ⁇ inhibitor or anti-integrin therapy, preferably such therapy for UC.
  • anti- inflammatory therapy preferably anti-inflammatory therapy for UC and/or immunomodulatory, TNF- ⁇ inhibitor or anti-integrin therapy, preferably such therapy for UC.
  • Anti-inflammatory therapies for UC are discussed herein and typically include oral corticosteroids, and glucocorticosteroids (GCS), sulfasalazine and 5-ASA.
  • GCS glucocorticosteroids
  • sulfasalazine typically include oral corticosteroids, and glucocorticosteroids (GCS), sulfasalazine and 5-ASA.
  • GCS glucocorticosteroids
  • 5-ASA sulfasalazine
  • the subject treated in accordance with the present invention is typically refractory or responds insufficiently or is intolerant to oral corticosteroids.
  • Immunomodulators, TNF- ⁇ inhibitors and anti-integrins are discussed herein and typically include azathioprine, 6-mercaptopurine and biologicals including the TNF- ⁇ inhibitors infliximab and biosimilars and derivatives thereof, golimumab and biosimilars and derivatives thereof, adalimumab and biosimilars and derivatives thereof and anti-integrins vedolizumab and biosimilars and derivatives thereof.
  • the subject treated in accordance with the present invention is typically refractory or responds insufficiently or is intolerant to azathioprine, 6-mercaptopurine, infliximab and biosimilars and derivatives thereof, golimumab and biosimilars and derivatives thereof, adalimumab and biosimilars and derivatives thereof and anti-integrin vedolizumab and biosimilars and derivatives thereof.
  • the subject treated in accordance with the present invention is refractory or responds insufficiently or is intolerant to azathioprine and/or 6- mercaptopurine.
  • the subject treated in accordance with the present invention is refractory or responds insufficiently or is intolerant to infliximab and/or adalimumab.
  • the subject treated in accordance with the present invention may be refractory or respond insufficiently or is intolerant to JAK inhibitors (for instance tofacitinib).
  • JAK inhibitors for instance tofacitinib
  • IL-12/IL23 inhibitor for instance ustekinumab
  • a refractory disease or disease that responds insufficiently to therapy is typically a disease where signs and symptoms of active disease persist despite a history of at least one course of therapy, for instance anti-inflammatory therapy or immunomodulatory therapy, in the context of the present invention.
  • signs and symptoms of active disease persist despite a history of two or more courses of anti- inflammatory therapy or immunomodulatory therapy.
  • a typical course of treatment with anti-inflammatory or immunomodulatory therapy for UC would be well understood by a person skilled in the art, and would typically involve a sufficient number of doses at sufficient dosage to induce remission in a typical patient.
  • Intolerance to therapy for instance anti-inflammatory therapy or immunomodulatory therapy, in the context of the present invention, means that the therapy has caused side effects in the subject that are not tolerated, e.g. that typically lead to discontinuation of therapy.
  • the subject has previously received or is currently receiving Aminosalicylic acid (5-ASA), preferably 5-ASA therapy for UC.
  • 5-ASA Aminosalicylic acid
  • the subject has previously received or is currently receiving oral Glucocorticosteroids (GCS), preferably oral GCS therapy for UC.
  • GCS oral Glucocorticosteroids
  • the subject has previously received or is currently receiving budesonide, for instance oral MMX Budesonide therapy.
  • budesonide for instance oral MMX Budesonide therapy.
  • the subject has previously received or is currently 5 -aminosalicylic acid and/or Salazopyrin compounds.
  • the subject has previously received or is currently receiving azathioprine and/or 6-merc aptopurine .
  • the subject who is refractory or responds insufficiently or is intolerant to anti- inflammatory therapy shows or has previously shown an inadequate response to, or loss of response to (i.e. is refractory to) or intolerance of rectal, oral, and/or parenteral GCS treatment (including no GCS treatment due to earlier side effect).
  • the subject who is refractory or responds insufficiently or is intolerant to anti- inflammatory therapy has a history of or current status of an inadequate response (e.g. steroid refractory) to, OR steroid dependency, OR loss of response to, OR intolerance of GCS treatment.
  • the steroids/GCS will typically have been received by the subject in the course of treating ulcerative colitis.
  • Steroid-refractory typically refers to a subject lacking a meaningful clinical response, i.e. showing signs and symptoms of persistently active ulcerative colitis, despite a history of at least one course of steroid treatment, for instance an induction regimen that included a dose equivalent to prednisone 40-60 mg daily over a period of 30 days for oral administration or over a period of 7 to 10 days for intravenous (IV) administration.
  • a meaningful clinical response i.e. showing signs and symptoms of persistently active ulcerative colitis
  • Steroid dependence typically refers to a patient who is either unable to reduce steroids below the equivalent of prednisolone 10 mg/d within 3 months of starting steroids, without recurrent active ulcerative colitis, or who has a relapse within 3 months of stopping steroids.
  • Intolerance of GCS treatment typically means the subject has experienced side effects not tolerated by the subject following GCS treatment, such as but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, or infection.
  • the subject who is refractory or responds insufficiently or is intolerant to an immunomodulator shows or has previously shown an inadequate response to, or loss of response to (i.e. is refractory to) or intolerance of an immunomodulator.
  • the subject who is refractory or responds insufficiently or is intolerant to a TNF- ⁇ inhibitor shows or has previously shown an inadequate response to, or loss of response to (i.e. is refractory to) or intolerance of a TNF- ⁇ inhibitor.
  • An inadequate response, or loss of response to an immunomodulator typically means signs and symptoms of active ulcerative colitis persist despite previous treatment with at least one immunomodulator, for instance one 8 Week regimen of oral azathioprine ( ⁇ 1.5 mg/kg) or 6-mercaptopurine ( ⁇ 0.75 mg/kg).
  • Intolerance to an immunomodulator typically means the subject has experienced nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, lymphopenia, Thiopurine Methyltransferase (TPMT) genetic mutation, or infection or other side effects after receiving an immunomodulator.
  • LFT liver function test
  • TPMT Thiopurine Methyltransferase
  • An inadequate response, or loss of response to a TNF- ⁇ inhibitor means signs and symptoms of active ulcerative colitis persist despite previous treatment with at least one TNF- ⁇ inhibitor, such as 4-Week induction regimen (or doses as recommended according to the current labels) of infliximab (5 mg/kg (IV), 2 doses at least 2 weeks apart) or a biosimilar or derivative thereof; golimumab (200 /100 mg (SC), 2 doses at least 2 weeks apart) or a biosimilar or derivative thereof; or adalimumab (160/80 mg (SC), 2 doses at least 2 weeks apart) or a biosimilar or derivative thereof or recurrence of symptoms during maintenance dosing following prior clinical benefit.
  • 4-Week induction regimen or doses as recommended according to the current labels
  • Intolerance to a TNF- ⁇ inhibitor means an infusion-related reaction, demyelination, congestive heart failure, infection or other side effects following receipt of a TNF- ⁇ inhibitor.
  • An inadequate response, or loss of response to an anti-integrin means signs and symptoms of active ulcerative colitis persist despite previous treatment with an anti-integrin, for instance at least 10 weeks regimen of vedolizumab 300 mg (IV) or a biosimilar or derivative thereof, or as recommended in the current label, or recurrence of symptoms during maintenance dosing following prior clinical benefit.
  • the subject has been diagnosed with left sided ulcerative colitis, i.e. distal colitis, including proctosigmoiditis.
  • the subject may have been diagnosed with moderate to severe left sided ulcerative colitis.
  • said subject is elective for colectomy.
  • colectomy refers to surgical resection of any extent of the large intestine (colon).
  • colectomy includes, but is not limited to, right hemicolectomy, left hemicolectomy, extended hemicolectomy, transverse colectomy, sigmoidectomy, proctosigmoidectomy, Hartmann operation, "double-barrel” or Mikulicz colostomy, total colectomy (also known as Lane's Operation), total procto-colectomy and subtotal colectomy.
  • the phrase "elective for colectomy” refers to a subject who may choose to undergo the procedure of non-emergency colectomy based on physician and surgeon assessment.
  • Subjects elective for colectomy may be, but are not limited to, subjects refractory to available therapy (for ulcerative colitis) or intolerant of available therapy (for ulcerative colitis). This differs from emergency colectomy, which is an acute intervention for subjects with acute illnesses or injuries and who require immediate medical attention.
  • emergency colectomy which is an acute intervention for subjects with acute illnesses or injuries and who require immediate medical attention.
  • the phrase also includes subjects that are elected for colectomy.
  • oligonucleotide refers to a polynucleoside formed from a plurality of linked individual nucleoside units. Such oligonucleotides can be obtained from existing nucleic acid sources, including genomic DNA or cDNA, plasmids, vectors, or bacterial DNA, but are preferably produced by synthetic methods. The nucleoside residues can be coupled to each other by any of the numerous known intemucleoside linkages.
  • Such intemucleoside linkages include, without limitation, the natural intemucleoside phosphodiester bond or indeed modified internucleosides such as, but not limited to, phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy, acetamidate, carbamate, morpholino, borano, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate, and sulfone intemucleoside linkages.
  • internucleosides such as, but not limited to, phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy, acetamidate, carbamate,
  • oligonucleotide also encompasses polynucleosides having one or more stereospecific intemucleoside linkages (e. g., (Rp)- or (Sp)-phosphorothioate, alkylphosphonate, or phosphotriester linkages).
  • stereospecific intemucleoside linkages e. g., (Rp)- or (Sp)-phosphorothioate, alkylphosphonate, or phosphotriester linkages.
  • the terms “oligonucleotide” and “dinucleotide” are expressly intended to include polynucleosides and dinucleosides having any such intemucleoside linkage, whether or not the linkage comprises a phosphate group.
  • these intemucleoside linkages may be phosphodiester, phosphorothioate, or phosphorodithioate linkages, or combinations thereof.
  • oligonucleotide also encompasses polynucleosides having additional substituents including, without limitation, protein groups, lipophilic groups, intercalating agents, diamines, folic acid, cholesterol and adamantane.
  • oligonucleotide also encompasses any other nucleobase containing polymer, including, without limitation, peptide nucleic acids (PNA), peptide nucleic acids with phosphate groups (PHONA), locked nucleic acids (LNA), morpholino-backbone oligonucleotides, and oligonucleotides having backbone sections with alkyl linkers or amino linkers.
  • the alkyl linker may be branched or unbranched, substituted or unsubstituted, and chirally pure or a racemic mixture.
  • the oligonucleotides of the invention can include naturally occurring nucleosides, modified nucleosides, or mixtures thereof.
  • modified nucleoside is a nucleoside that includes a modified heterocyclic base, a modified sugar moiety, or a combination thereof.
  • the modified nucleoside is a non-natural pyrimidine or purine nucleoside, as herein described.
  • the modified nucleoside is a 2'-substituted ribonucleoside, an arabinonucleoside or a 2'- deoxy-2'- substituted-arabinoside.
  • a hybrid oligonucleotide is an oligonucleotide having more than one type of nucleoside.
  • oligonucleotide includes hybrid and chimeric oligonucleotides.
  • a "chimeric oligonucleotide” is an oligonucleotide having more than one type of internucleoside linkage within its sequence structure.
  • a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region and non-ionic linkages such as alkylphosphonate or alkylphosphonothioate linkages (US5635377 and US5366878).
  • oligonucleotide also includes circularized variants and circular oligonucleotides.
  • the oligonucleotide comprises at least one naturally occurring phosphodiester, or one modified phosphorothioate, or phosphorodithioate internucleoside linkage, however preferred linkages or indeed backbone modifications including, without limitation, methylphosphonates, methylphosphonothioates, phosphotriesters, phosphothiotriesters, phosphorothioates, phosphorodithioates, triester prodrugs, sulfones, sulfonamides, sulfamates, formacetal, N-methylhydroxylamine, 2’ OMe (OxyM ethyl group at 2 ’position), carbonate, carbamate, morpholino, boranophosphonate, phosphoramidates, especially primary amino-phosphoramidates, N3 phosphoramidates and N5 phosphoramidates, and stereospecific linkages (e. g., (Rp)-or (Sp)-phosphorothioate, al
  • the sugar moiety of the nucleoside can be a non-naturally occurring sugar moiety.
  • a "naturally occurring sugar moiety” is a sugar moiety that occurs naturally as part of a nucleic acid, e. g., ribose and 2'- deoxyribose
  • a "non-naturally occurring sugar moiety” is any sugar that does not occur naturally as part of a nucleic acid, but which can be used in the backbone for an oligonucleotide, for example but not limited to hexose.
  • Arabinose and arabinose derivatives are examples of preferred sugar moieties.
  • Modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases.
  • An oligonucleotide is usually comprised of more than ten (10) and up to one hundred (100) or more deoxyribonucleotides or ribonucelotides, although preferably between about eight (8) and about forty (40), most preferably between about eight (8) and about twenty (20). The exact size will depend on many factors, which in turn depends on the ultimate function or use of the oligonucleotide.
  • the oligonucleotide may be generated in any manner, including chemical synthesis, DNA replication, reverse transcription, or a combination thereof.
  • the oligonucleotide for use in the present invention comprises the sequence 5'- GGAAC AGTTCGTCC ATGGC-3 ’ (SEQ ID NO:2). Typically, at least one CG dinucleotide is unmethylated.
  • At least one nucleotide in said oligonucleotide has a backbone modification.
  • at least one nucleotide in said oligonucleotide has a phosphate backbone modification.
  • the backbone modification is typically a phosphorothioate or a phosphorodithioate modification.
  • Phosphorothioate linkages can be illustrated with asterisks (*) in a sequence, e.g. in the sequence:
  • said oligonucleotide has the sequence
  • oligonucleotide is cobitolimod.
  • the present invention therefore preferably provides cobitolimod for use in the treatment of active ulcerative colitis as defined herein in a human subject as defined herein, wherein individual doses of an amount as defined herein of cobitolimod are administered to the subject on at least two separate occasions, wherein said separate occasions are 3 weeks apart.
  • individual doses of from 400mg to 600mg of said oligonucleotide, preferably cobitolimod are administered.
  • the same dosage of oligonucleotide is administered in each individual dose/administration, but different dosages may also be used.
  • individual doses of greater than 350mg of said oligonucleotide, preferably cobitolimod are administered.
  • individual doses of greater than 350 mg, for instance from 351 up to 650mg of said oligonucleotide, preferably cobitolimod are administered.
  • oligonucleotide preferably cobitolimod
  • each dose/administration preferably from 450mg to 550mg, more preferably from 460 to 540, still more preferably from 470 to 530, yet more preferably from 480 to 520, even more preferably from 490 to 510, even more preferably from 495 to 505, even more preferably from 499 to 501mg.
  • oligonucleotide preferably cobitolimod
  • about 500mg of said oligonucleotide, preferably cobitolimod is administered on each of the at least two occasions.
  • “about” as used herein means +/- 10%, typically +/- 5%, preferably +/- 1%.
  • oligonucleotide preferably cobitolimod
  • individual doses (of an amount as specified herein) of said oligonucleotide are administered to the patient on at least two separate occasions, wherein said separate occasions are 3 weeks apart.
  • the patient does not receive any additional oligonucleotide between the specified doses/administrations three weeks apart.
  • the patient does not receive an oligonucleotide as defined herein, but may receive one or more additional therapeutic agents for the treatment of ulcerative colitis.
  • doses of said oligonucleotide are administered to the patient on more than two occasions, then typically each occasion is three weeks after the previous occasion.
  • doses (of an amount as specified herein) of said oligonucleotide are administered to the patient on, for instance, 2, 3, 4, 5, 6, 7, 8, 9, or 10 separate occasions, each occasion being three weeks after the previous occasion.
  • doses of said oligonucleotide are administered to the patient until that patient is in remission, as defined above.
  • individual doses are administered to the subject on only two separate occasions, the separate occasions being 3 weeks apart.
  • reference to administration on at least two separate occasions, where said separate occasions are 3 weeks apart refers to a single treatment regime for inducing remission.
  • further treatment with the oligonucleotide is not ruled out in the future, e.g. following relapse to an active disease state after remission.
  • a first dose would be delivered at day zero, and a second dose would be delivered three weeks after that.
  • a first dose would be delivered at day zero, a second dose would be delivered three weeks after that, and a third dose would be delivered a further three weeks after that, i.e. six weeks from day zero.
  • 3 weeks apart means in certain embodiments administration of the doses exactly 21 days apart, i.e. a first dose is administered on day zero and a further dose is administered on day twenty one.
  • a first dose is administered on day zero
  • a further dose is administered on day twenty one.
  • 3 weeks apart means administration 14-28 days apart, typically 18-24 days apart, alternatively 19-23 days apart, or 20-22 days apart.
  • the present invention provides an oligonucleotide, as defined herein, for use in the treatment of ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of an amount as defined herein of said oligonucleotide are administered to the patient on at least two, for instance two, separate occasions, wherein said separate occasions are 18-24 days apart, 19-23 days apart, or 20-22 days apart.
  • the drugs for use in the present invention may be administered as monotherapy treatment for the indication or with other drug(s) as adjunct therapy for the indication, as described in more detail below.
  • the drugs for use in the present invention may be administered simultaneously, separately or sequentially with the other drug(s), for example in fixed dose combination or in separate doses.
  • additive-on refers to administering of said oligonucleotide in addition to a current therapy or drug regime, without discontinuing the current therapy or drug regime.
  • the oligonucleotide may be administered as a monotherapy, or in combination with one or more additional therapeutic agents for the treatment of ulcerative colitis.
  • the oligonucleotide may be administered as a monotherapy, or in combination with one or more additional therapeutic agents for the treatment of ulcerative colitis chosen from anti- inflammatories, immunomodulatory drugs, anti-TNF therapy drugs or other suitable drugs for treating ulcerative colitis.
  • drugs suitable for use in combination with said oligonucleotide include, but are not limited to GCS or derivatives; prednisolone, Decortin, anti-TNF or derivative; infliximab and biosimilars and derivatives thereof, adalimumab and biosimilars and derivatives thereof, golimumab and biosimilars and derivatives thereof, anti-integrin or derivatives; vedolizumab and biosimilars and derivatives thereof, natural IFN- ⁇ , thiopurine or derivatives; azathioprine, 6-mercaptopurine, 5-ASA, sulphasalazine, methotrexate, cylclosporine, and equivalents thereof.
  • the subject receiving said oligonucleotide also receives one or more other drugs chosen from GCS, Decortin, 5-ASA, azathioprine, 6-mercaptopurine, sulphasalazine, methotrexate, prednisolone and equivalents thereof or derivatives.
  • one or more other drugs chosen from GCS, Decortin, 5-ASA, azathioprine, 6-mercaptopurine, sulphasalazine, methotrexate, prednisolone and equivalents thereof or derivatives.
  • the subject receiving said oligonucleotide also receives one or more other drugs chosen from GCS, 5-ASA, azathioprine, 6-mercaptopurine, sulphasalazine and methotrexate.
  • the subject receiving said oligonucleotide also receives one or more other drugs chosen from oral GCS, oral 5-ASA, oral MMX budesonide, azathioprine, 6- mercaptopurine, and oral methotrexate.
  • the subject receiving said oligonucleotide also receives one or more steroid drugs, for example corticosteroids and glucocorticosteroids.
  • one or more steroid drugs for example corticosteroids and glucocorticosteroids.
  • the terms "in combination with” and “add-on” mean in the course of treating the same disease in the same patient, and include administering the oligonucleotide and one or more additional therapeutic agents in any order, including simultaneous administration, as well as temporally spaced order of up to several months apart.
  • said oligonucleotide is administered topically, such as topically to the mucous membrane.
  • said oligonucleotide is administered intracolonically.
  • Intracolonical administration is typically effected rectally.
  • Intracolonical administration is typically effected using an enema or catheter.
  • Intracolonical administration may involve administration by a rectal enema.
  • Intracolonical administration may be topical, for example performed during colonoscopy with the aid of a spraying catheter, or other suitable medical equipment, inserted though the colonoscopies biopsy channel.
  • the oligonucleotide is administered intracolonically by rectal enema.
  • the rectal enema is typically suitable for self-administration by the subject.
  • the oligonucleotide may be administered without a medical professional present allowing the subject to administer the oligonucleotide at home, without travelling to and from a clinic or hospital. Further, this avoids the use of more complex and expensive equipment such as a spray catheter device during an endoscopy.
  • the oligonucleotide is self-administered rectally by the subject.
  • the oligonucleotide may be self-administered by rectal enema by the subject.
  • typically topical administration is effected via an enema which is suitable for self- administration by the subject.
  • the subject has not been subjected to colonic cleaning prior to said administration.
  • the subject has not been subjected to colonic cleaning prior to said administration.
  • reference to a subject “which has not been subjected to colonic cleaning” is intended to define a subject which has not been subject to colonic cleaning in a time period prior to the administration of the oligonucleotide to reduce the amount of faecal matter in the colon treated with the oligonucleotide.
  • the subject has not been subjected to colonic cleaning for 1 hour prior to the treatment with the oligonucleotide, typically for 4 hours prior to the treatment with the oligonucleotide, preferably for 8 hours prior to the treatment with the oligonucleotide, more preferably for 12 hours prior to the treatment with the oligonucleotide, more preferably for 24 hours prior to the treatment with the oligonucleotide, most preferably for 48 hours prior to the treatment with the oligonucleotide.
  • said colonic cleaning can be effected by any method known in the art, for example administration of a laxative.
  • said subject has luminal faecal material.
  • said subject has faecal material which coats or is proximal to the colonic epithelial cells treated with the oligonucleotide.
  • Said subject may have faecal material in the lumen which is not directly in contact with the colonic epithelial cells treated with the oligonucleotide.
  • Said subject may have faecal material in the lumen which is coats or is proximal to the colonic epithelial cells treated with the oligonucleotide and faecal material in the lumen which is not directly in contact with the colonic epithelial cells treated with the oligonucleotide. More preferably, the amount of said faecal material is the normal amount which would be expected in a patient which had never been subjected to colonic cleaning.
  • said topical administration is effected via an enema which is suitable for self- administration by the patient.
  • the enema has an elongate tip configured so as to enable insertion into the rectum.
  • said tip is from 4 to 15 cm long, typically from 4 to 10 cm long, preferably 5 to 6 cm long.
  • the cobitolimod is administered via a method which involves the insertion into the rectum only of an elongate enema tip which is from 4 to 15 cm long, preferably from 4 to 10 cm long.
  • the said oligonucleotide may be delivered to the upper portion of the descending colon or to the transverse region of the colon; however other regions are also possible when suited. Topical administration to other parts of the gastrointestinal tract is also possible.
  • the said oligonucleotide can be administered by any appropriate administration route, such as, but not limited to, inhalation, intranasal, parenteral, oral, intradermal, subcutaneous, vaginal and rectal administration. Further, in certain embodiments, systemic administration of said oligonucleotide may be used.
  • the oligonucleotide may be administered in the form of a pharmaceutical composition comprising the oligonucleotide as defined herein together with one or more pharmaceutically acceptable carriers.
  • carrier encompasses any excipient, diluent, fdler, salt, buffer, water, stabilizer, solubilizer, lipid, or other material well known in the art for use in pharmaceutical formulations. It will be understood that the characteristics of the carrier will depend on the route of administration for a particular application.
  • the term "pharmaceutically acceptable” refers to a material that does not interfere with the effectiveness of the immunomodulatory oligonucleotide and is compatible with a biological system such as a cell, cell culture, tissue, organ, or organism.
  • a biological system such as a cell, cell culture, tissue, organ, or organism.
  • the biological system is a living organism, such as a vertebrate.
  • the composition is a solution of the oligonucleotide in a liquid carrier.
  • the carrier is water, preferably sterile water.
  • the composition comprises the oligonucleotide as defined herein and water.
  • the carrier is water and the oligonucleotide (in the form of a composition) is administered intracolonically, for instance as a rectal enema.
  • concentration of an oligonucleotide in a pharmaceutical composition will vary depending on several factors, including the dosage of the oligonucleotide to be administered. Typical concentrations of oligonucleotides in compositions that are solutions are 1 mg/ml to 20 mg/ml, preferably 5 to 15 mg/ml, , preferably 8 mg/ml to 12 mg/ml, more preferably about 10 mg/ml.
  • the present invention provides cobitolimod for use in the treatment of ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on only two separate occasions, said separate occasions being 3 weeks apart.
  • the present invention provides cobitolimod for use in the treatment of ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on two or more separate occasions 3 weeks apart until the subject is in remission, typically remission as determined by an index as defined herein. More preferably the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on only two separate occasions, said separate occasions being 3 weeks apart, wherein cobitolimod is administered in the form of a pharmaceutical composition comprising cobitolimod and water.
  • the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on two or more separate occasions 3 weeks apart, wherein cobitolimod is administered intracolonically or rectally.
  • the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on two or more separate occasions 3 weeks apart, wherein cobitolimod is self-administered rectally by the subject.
  • the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on two or more separate occasions 3 weeks apart, wherein cobitolimod is self-administered by rectal enema by the subject.
  • the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on only two separate occasions, said separate occasions being 3 weeks apart, wherein cobitolimod is administered intracolonically or rectally.
  • the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on only two separate occasions, said separate occasions being 3 weeks apart, wherein cobitolimod is self-administered rectally by the subject.
  • the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on only two separate occasions, said separate occasions being 3 weeks apart, wherein cobitolimod is self-administered by rectal enema by the subject.
  • the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on only two separate occasions, said separate occasions being 3 weeks apart, wherein cobitolimod is administered intracolonically or rectally in the form of a pharmaceutical composition comprising cobitolimod and water.
  • the present invention provides cobitolimod for use in the treatment of chronic active ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein individual doses of about 500mg of cobitolimod are administered to the patient on only two separate occasions, said separate occasions being 3 weeks apart, wherein cobitolimod is administered intracolonically or rectally in the form of a pharmaceutical composition comprising cobitolimod and water.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an oligonucleotide as defined herein, together with one or more pharmaceutically acceptable carriers, for use in the treatment of an inflammatory bowel disease as defined herein in a human subject as defined herein, wherein individual administrations of said composition are administered to the subject on at least two separate occasions, wherein said separate occasions are 3 weeks apart, and wherein each administration of the composition delivers an amount of the oligonucleotide as defined herein.
  • oligonucleotide for use as defined above are also preferred features of the composition for use.
  • the present invention also provides use of an oligonucleotide as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in treating an inflammatory bowel disease as defined herein, in a human subject as defined herein, wherein individual administrations of said oligonucleotide or composition are administered to the patient on at least two separate occasions, wherein said separate occasions are 3 weeks apart, and wherein each administration of the oligonucleotide or composition delivers an amount of the oligonucleotide as defined herein.
  • oligonucleotide for use as defined above are also preferred features of the use of the oligonucleotide or composition.
  • the present invention also provides a method of treating an inflammatory bowel disease as defined herein, in a human subject as defined herein, comprising administering to said subject an oligonucleotide as defined herein or a composition as defined herein, wherein individual administrations of said oligonucleotide or composition are administered to the patient on at least two separate occasions, wherein said separate occasions are 3 weeks apart, and wherein each administration of the oligonucleotide or composition delivers an amount of the oligonucleotide as defined herein.
  • the present invention also provides a method of treating an inflammatory bowel disease as defined herein, in a human subject as defined herein, which method comprises:
  • the invention also provides an oligonucleotide for use in preventing the recurrence of active ulcerative colitis in a patient, wherein the oligonucleotide comprises the sequence 5 '-GGAAC AGTTCGTCC AT GGC-3 ' (SEQ ID NO:2).
  • the oligonucleotide maybe any oligonucleotide of SEQ ID NO:2 as described herein.
  • Preferably said oligonucleotide is cobitolimod.
  • the oligonucleotide may be for use as a maintenance therapy.
  • reference to preventing the recurrence of active ulcerative colitis is intended to refer to preventing recurrence of the active phase of the disease, i.e. maintaining a patient in remission and providing a maintenance therapy.
  • the present invention relates to the use of an oligonucleotide as defined herein to prevent the recurrence of or relapse into the active phase of ulcerative colitis.
  • the oligonucleotide as herein above can be used as maintenance therapy to prevent the recurrence of or relapse into symptoms associated with active ulcerative colitis, and/or to improve the patient’s condition.
  • the patient may be any patient or subject as described herein.
  • the patient may be suffering with any type of ulcerative colitis as described herein.
  • the subject has been diagnosed with left-sided ulcerative colitis, i.e. distal colitis, including proctosigmoiditis.
  • the patient has previously been treated for active ulcerative colitis, for instance the patient may have previously received one or more therapeutic agents for the treatment of active ulcerative colitis.
  • the one or more therapeutic agents may comprise the oligonucleotide of SEQ ID NO:2 as described herein.
  • the patient may have received the oligonucleotide as described herein, wherein individual doses of from 400mg to 600mg of said oligonucleotide are administered to the subject on at least two separate occasions, wherein said separate occasions are 3 weeks apart to bring the patient into remission (i.e. to treat active ulcerative colitis).
  • the one or more therapeutic agents may comprise any other therapeutic agent used to treat ulcerative colitis, as described herein.
  • individual doses of said oligonucleotide are administered to the patient with regular intervals between those individual doses.
  • the interval between individual doses maybe from 1 week to 12 months, for instance, the interval between individual doses is 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 6 months or 12 months.
  • the interval between individual doses is 3 weeks.
  • the individual doses are doses of from lOmg to 600mg of said oligonucleotide.
  • the individual doses maybe from 150 to 350 mg of said oligonucleotide.
  • the individual doses may be about 250 mg of said oligonucleotide.
  • the individual doses may be from 350 to 600 mg of said oligonucleotide, preferably from 400 to 600 mg of said oligonucleotide.
  • the individual doses may be from 425mg to 575mg of said oligonucleotide, from 450mg to 550mg, from 460 to 540, from 470 to 530, from 480 to 520, preferably from 490 to 510, more preferably from 495 to 505, even more preferably from 499 to 501 mg.
  • the individual doses may be about 500 mg of said oligonucleotide.
  • the above dosage regime i.e. of administering individual doses of said oligonucleotide to the patient at regular intervals is continued for a time period such that it provides an ongoing maintenance therapy.
  • ulcerative colitis is chronic condition that cannot be cured
  • patients will generally receive the regimes as described herein for extended periods of time, typically for at least 6 months, preferably for at least 1 year or 2 years, for example for at least 5 year or 10 years.
  • some patients may need to be administered the regimes as described herein for as long as needed (as determined e.g. by a physician) or indefinitely.
  • the patient may be administered the individual doses at regular intervals for at least 6 months, preferably for at least 1 year or 2 years, more preferably for at least 5 years or 10 years or indefinitely.
  • the patient may receive multiple doses of the said oligonucleotide at regular intervals, the individual doses of said oligonucleotide are between 150 and 350 mg, and interval between those individual doses is 1 week, 2 weeks, 3 weeks or 4 weeks.
  • the patient receives multiple doses of the said oligonucleotide at regular intervals, the individual doses of said oligonucleotide are about 250mg, and interval between those individual doses is 3 weeks.
  • These regimes are typically continued for at least 6 months, preferably for at least 1 year or 2 years, for example for at least 5 year or 10 years or indefinitely.
  • the patient may receive multiple doses of the said oligonucleotide at regular intervals, the individual doses of said oligonucleotide are between 400 and 600 mg, and interval between those individual doses is 1 week, 2 weeks, 3 weeks or 4 weeks, with 3 weeks preferred.
  • the patient receives multiple doses of the said oligonucleotide at regular intervals, the individual doses of said oligonucleotide are about 500mg, and interval between those individual doses is 3 weeks.
  • These regimes are typically continued for at least 6 months, preferably for at least 1 year or 2 years, for example for at least 5 year or 10 years or indefinitely.
  • the oligonucleotide may be for use as a monotherapy.
  • the patient may receive one or more additional therapeutic agents for preventing the recurrence of active ulcerative colitis.
  • the additional therapeutic agents may be any therapeutic agents as described herein used in treating ulcerative colitis.
  • the patient may receive one or more additional anti-inflammatory agents for preventing the recurrence of active ulcerative colitis.
  • the oligonucleotide may be administered combination with one or more additional therapeutic agents for the prevention of recurrence of active ulcerative colitis chosen from anti-inflammatory drugs, immunomodulatory drugs, anti- integrin therapy drugs, TNF- ⁇ inhibitors, immunosuppressive drugs, JAK inhibitors or other suitable drugs for treating ulcerative colitis or other suitable drugs for treating ulcerative colitis.
  • additional therapeutic agents for the prevention of recurrence of active ulcerative colitis chosen from anti-inflammatory drugs, immunomodulatory drugs, anti- integrin therapy drugs, TNF- ⁇ inhibitors, immunosuppressive drugs, JAK inhibitors or other suitable drugs for treating ulcerative colitis or other suitable drugs for treating ulcerative colitis.
  • Examples of such drugs suitable for use in combination with said oligonucleotide include, but are not limited aminosalicylates (such as 5 -ASA [also known as mesalamine], sulfasalazine, olsalazine and balsalazide), GCS (such as prednisone, methylprednisolone, hydrocortisone and budesonide), azathioprine (AZA), 6- mercaptopurine (6-MP), tacrolimus, methotrexate, cyclosporine, infliximab (REMICADE®), etanercept (ENBREL ®), adalimumab (HUMIRA®), certolizumab (CIMZIA®), golimumab (SIMPONI®), ustekinumab (STELARA®), vedolizumab (ENTYVIO®), SMAD7 antisense oligonucleotide (Mongersen
  • the terms "in combination with” and “add-on” mean in the course of treating the same disease in the same patient, and include administering the oligonucleotide and one or more additional therapeutic agents in any order, including simultaneous administration, as well as temporally spaced order of up to several months apart.
  • the oligonucleotide may be administered via any administration route as described herein.
  • said oligonucleotide is administered topically, such as topically to the mucous membrane.
  • said oligonucleotide is administered intracolonically.
  • Intracolonical administration is typically effected rectally.
  • Intracolonical administration is typically effected using an enema or catheter.
  • Intracolonical administration preferably involves administration by an enema (i.e. by rectal enema).
  • the oligonucleotide administered by rectal enema preferably the oligonucleotide is self-administered by rectal enema.
  • the subject has not been subjected to colonic cleaning prior to said administration.
  • Patients in the treatment group and placebo group monitored the maximum amount of blood in their stool by week (as none, a little, or a lot), weekly stool frequency (as ⁇ 18, 18- 35, 36-60 or 61+) and daily stool frequency (as ⁇ 1, 1-1.99, 2-2.99, 3-3.99, 4-4.99, 5-5.99, 6-6.99, 7-7.99 or 8+) using an e-diary for twelve weeks.
  • Figure 2 shows the proportion of the treatment and placebo groups reporting weekly stool frequency ⁇ 18 (summary of patient reported outcome during 7 days) by week.
  • Figure 3 shows the proportion of the treatment and placebo groups reporting weekly stool frequency ⁇ 35 (summary of patient reported outcome during 7 days) by week.
  • Figure 4 shows the proportion of the treatment and placebo groups reporting daily stool frequency ⁇ 3 (mean daily patient reported outcome during 7 days) by week.
  • Figure 5 shows the proportion of the treatment and placebo groups reporting daily stool frequency ⁇ 4 (mean daily patient reported outcome during 7 days) by week.
  • Figure 6 shows the proportion of the treatment and placebo groups reporting daily stool frequency ⁇ 5 (mean daily patient reported outcome during 7 days) by week.
  • a randomised double-blind, placebo controlled, trial assesses the efficacy and safety of topical cobitolimod in moderate to severe active ulcerative colitis patients in accordance with established methods.
  • Immunomodulators e.g. cyclosporine, methotrexate, AZA/6-MP, tacrolimus o
  • previous intolerance including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, lymphopenia, TPMT genetic mutation, infection
  • TNF- ⁇ inhibitors and/or anti-integrins o Signs and symptoms of persistently active disease despite previous treatment with at least one induction regimen with 2 doses at least 2 weeks apart (or doses as recommended according to the current labels) of for e.g.:
  • Vedolizumab 300 mg (IV) or o History of intolerance including but not limited to infusion-related reaction, demyelination, congestive heart failure, infection
  • Oral GCS therapy ( ⁇ 20 mg prednisone or equivalent/daily) providing that the dose has been stable for 2 weeks prior to visit la (Day -14)
  • Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks before visit 1
  • Oral 5-ASA/SP compounds providing that the dose has been stable for 2 weeks prior to visit la and initiated at least 8 weeks before visit la
  • AZA/6-MP providing that the dose has been stable for 8 weeks prior to visit lb and been initiated at least 3 months before visit la
  • Gastrointestinal infections including positive Clostridium difficile stool assay 11. Currently receiving parenteral nutrition or blood transfusions
  • Cobitolimod or placebo was administered topically to the colon via rectal enema which is suitable for self- administration. Unlike in the COLLECT study, no special steps were taken to ensure the colon was clean prior to enema administration.
  • the primary outcome measure was established as follows:
  • the secondary outcome measures are as follows: • Proportion of patients with induction of symptomatic remission, at Week 4 or 6, defined by the Mayo subscores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline)
  • the percentage of patients receiving two doses of 250 mg cobitolimod in remission at week 6 was also higher than the percentage of patients in remission for the other dosage regimes (2x31 mg, 2x125 mg and 4x125 mg).
  • the percentage of patients in remission who received two doses of 250 mg cobitolimod was higher than for the patients who received four doses of 125 mg cobitolimod. This is a surprising outcome in that it shows that administration of the same total amount of active ingredient via a reduced number of higher doses provides an improved clinical outcome.
  • results demonstrate that, surprisingly, clinical efficacy can be obtained without removal of faecal material from the colon and/or colonic epithelial cells. Further, clinical efficacy can be achieved by administration from an enema device which is suitable for self-administration.
  • Cobitolimod will be administered rectally with a prefilled enema, which places the drug in close contact with a high number of intended target cells.
  • Cobitolimod has been studied in treatment refractory UC patients administered rectally.
  • the target groups for treatment are patients with chronic active left-sided UC in whom previous treatments with conventional drugs, have not resulted in adequate response. Results from the clinical studies showed that cobitolimod can induce remission in these patients.
  • Non-clinical safety studies in rodents and cynomolgus monkey have indicated that cobitolimod is well tolerated and no evidence of systemic or local toxicity has been found.
  • Safety assessments from the five placebo-controlled trials with cobitolimod have not indicated any significant toxicity.
  • Administration of cobitolimod is straightforward and drug compliance has been reported as excellent. Overall, cobitolimod has been well tolerated.
  • the induction study will target participants with moderate to severe active left-sided UC who demonstrate an inadequate response or failure to tolerate conventional or biological therapy.
  • the study will have two parts (la and lb), where the objective in the first part is to explore a clinically relevant and the most efficacious dose between cobitolimod 250 and 500 mg versus placebo.
  • Study treatment will be administered rectally using an enema.
  • Endpoints including the Mayo sub scores of blood in stool and stool frequency will be derived using eDiary data.
  • Participant eligibility should be reviewed and documented by an appropriately qualified member of the investigator's study team prior to inclusion in the study. Endoscopic eligibility and PR02 criteria eligibility will be approved centrally and communicated to investigator before final randomization occur. If participant fails to fulfil the inclusion/exclusion criteria, participant can be considered to be re-screened at a later time if eligible.
  • Moderate to severe active left-sided UC (disease should extend 15 cm or more above the anal verge and not beyond the splenic flexure) determined by a 3- component Mayo score of 5 to 9 with an endoscopic sub score ⁇ 2 (in sigmoid or descending segments) assessed by central reading of endoscopy, and the stool frequency and rectal bleeding sub scores, assessed by e-diary, individually ⁇ 1
  • UC drugs Allowed to receive a therapeutic dose of following UC drugs during the study: a. Oral GCS therapy ( ⁇ 20 mg prednisone or equivalent/ daily) providing that the dose has been stable for 2 weeks prior to visit lb b. Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks before visit lb. c. Oral 5-ASA/SP compounds, providing that the dose has been stable for 2 weeks prior to visit la and initiated at least 8 weeks before visit lb. d. AZA/6-MP providing that the dose has been stable for 8 weeks prior to visit lb and been initiated at least 3 months before visit lb. 6.
  • Oral GCS therapy ⁇ 20 mg prednisone or equivalent/ daily
  • Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks before visit lb.
  • Oral 5-ASA/SP compounds providing that the dose has been stable for 2 weeks prior to visit la and initiated at least 8 weeks before visit lb.
  • Serious active infection including; history of latent or active tuberculosis, documented history of past or current tuberculosis, participants living with or having frequent close contact with people with active tuberculosis or with a positive tuberculosis test according to current regulations for 12 weeks preceding randomisation.
  • Chronic Human Immunodeficiency Virus (HIV); Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infections including; history of latent or active tuberculosis, documented history of past or current tuberculosis, participants living with or having frequent close contact with people with active tuberculosis or with a positive tuberculosis test according to current regulations for 12 weeks preceding randomisation.
  • Chronic Human Immunodeficiency Virus (HIV); Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infections including; history of latent or active tuberculosis, documented history of past or current tuberculosis, participants living
  • Gastrointestinal infections including positive Clostridium difficile stool assay
  • Participants in the Induction study 1 will initially be randomised to one of three treatment arms in a 1:1:1 ratio. After interim analysis, and selection of “winning” dose randomization will be done in a 1:1 ratio. Randomisation will be stratified for the following factors: concomitant use of GCS treatment (Yes/No) and previously treated with “modern’/targeted therapies (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab) and JAK inhibitors (tofacitinib) (Yes/No). A computer-generated randomisation schedule will be used to assign participants to treatment sequences. Treatment assignments will be obtained through the interactive voice response system (IVRS). Information regarding the treatment assignments will be kept secure.
  • IVRS interactive voice response system
  • Oral GCS therapy ( ⁇ 20 mg prednisone or equivalent/daily) providing that the dose has been stable for 2 weeks prior to visit lb and need to be kept stable up to primary endpoint (Week 6).
  • Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks before screening visit lb and need to be kept stable up to primary endpoint (Week 6). Tapering should start after Week 6 visit, if participants are in remission, see suggested tapering scheme below.
  • Oral 5 -ASA and/or SP compounds providing that the dose has been stable for 2 weeks prior to visit lb and initiated at least 8 weeks before visit lb. Stable dose up to end of study (Week 54).
  • Example 2 Dextran sulfate sodium (DSS) induced colitis mouse model
  • mice Balb/c mice are obtained from Charles River Laboratories, Research Models and
  • DSS induced colitis 2% or 3% (w/v) Dextran sulfate sodium (DSS) is administrated for 10 days to the drinking water of 8 week old female Balb/c mice. An additional control group of mice which were completely untreated is also part of the experimental set up. Food uptake and bodyweight are monitored.
  • Rectal administration of cobitolimod 1000 ⁇ g, 2000 ⁇ g or 4000 ⁇ g cobitolimod per mouse is rectally administered twice (on days 4 and 8).
  • a dose of 1000 ⁇ g in mice is approximately equivalent to a 250mg dose in a human (see “Guidance for Industry - Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Health Volunteers” , US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, July 2005).
  • the results observed in this mouse model could be considered predictive of the effects observed in humans administered with individual doses of 250mg, 500 mg and 1000 mg of cobitolimod on two separate occasions, 3 weeks apart.
  • Dose A 1000 ⁇ g (250 mg human equivalent)
  • Dose B 2000 mg (500 mg human equivalent)
  • Dose C 4000 ⁇ g (1000 mg human equivalent)
  • DAI Disease Activity Index

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Abstract

La présente invention concerne un oligonucléotide comprenant la séquence 5'-GGAACAGTTCGTCCATGGC-3' (SEQ ID NO:2), destiné à être utilisé dans le traitement d'une maladie inflammatoire de l'intestin chez un sujet humain, des doses individuelles allant de 400 mg à 600 mg dudit oligonucléotide étant administrées au sujet à au moins deux reprises, à au moins trois semaines d'intervalle.
PCT/EP2021/082627 2020-11-24 2021-11-23 Posologie de cobitolimod pour auto-administration Ceased WO2022112224A1 (fr)

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CN202180091789.4A CN116867499A (zh) 2020-11-24 2021-11-23 用于自我施用的可比托莫德用量
JP2023531702A JP2023553336A (ja) 2020-11-24 2021-11-23 自己投与のためのコビトリモド用量
KR1020237020455A KR20230112664A (ko) 2020-11-24 2021-11-23 자가-투여를 위한 코비톨리모드 투여량
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