JP2023553336A - Cobitolimod dosage for self-administration - Google Patents

Abstract

The present invention relates to an oligonucleotide for use in the treatment of inflammatory bowel disease in human subjects, comprising the sequence 5'-GGAACAGTTCGTCCATGGC-3' (SEQ ID NO: 2), comprising: The oligonucleotide is administered to the subject on at least two separate occasions, with the separate occasions providing the oligonucleotide three weeks apart. [Selection diagram] Figure 1

Description

The present invention relates to a new therapy for treating inflammatory bowel diseases, such as active ulcerative colitis (UC), in which oligonucleotides, especially cobitolimod, are administered according to an optimized dosing regimen.

Ulcerative colitis (UC) is a disease characterized by chronic inflammation of the rectal and colonic mucosa, affecting the innermost membranes in the first stage. The disease has both active and inactive phases with different pathology, symptoms and treatments, and it recurs. The underlying cause of UC is unknown, nor is it known what triggers the disease to cycle between inactive and active forms (Irvine, E. J. (2008) Inflamm Bowel Dis 14(4): 554- 565). Symptoms of active UC include progressively loose stools with blood and increased frequency of bowel movements. Active mucosal inflammation is diagnosed by endoscopy.

Stools contain pus, mucus and blood and are often accompanied by abdominal cramps with an urgency to defecate (tenesmi). Diarrhea may have an insidious onset, and in rare cases, the onset may be completely sudden. In severe cases, symptoms may include fever and general malaise. In severe stages, abdominal tenderness, tachycardia, fever and deep inflammation of the intestinal wall with risk of intestinal perforation can occur. In addition, patients with UC may also suffer from extraintestinal symptoms such as arthralgia and arthritis, erythema nodosum, pyoderma gangrenosum, and ocular inflammation. In cases of remitted or inactive UC, patients usually have no intestinal symptoms.

The degree of inflammation and damaged mucosa varies among patients with UC. UC that affects only the rectum is called ulcerative proctitis. If inflammatory changes are present on the left side of the colon up to the splenic flexure, the condition is called distal or left-sided colitis. In extensive UC, the transverse colon is also affected, and pancolitis refers to disease involving the entire colon.

Active mucosal inflammation is diagnosed by endoscopy and is characterized by loss of vascular visibility, edema, petechiae, spontaneous bleeding, and fibrous exudate. Endoscopic images are continuous images of inflammation starting in the rectum and extending proximally to varying degrees into the colon. A biopsy obtained during endoscopy and examined histologically helps diagnose the condition. Infectious causes such as Clostridium difficile, campylobacter, Salmonella and Shigella can mimic UC and can be excluded with stool culture.

Medical management of UC is divided into treating active disease and maintaining remission.

Treatment of patients with active UC aims to reduce inflammation and promote colonic healing and mucosal recovery. In mild cases, sulfasalazine, 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- Conventional drugs such as 327) can control the disease.

GCS is typically used to treat disease flares, but is not recommended for maintaining remission because long-term use has significant side effects and the potential for steroid-dependent disease. Because glucocorticoid drugs act non-selectively, they can impair many healthy anabolic processes in the long term. As a result, maintenance treatment with systemic GCS is not recommended (Prantera, C. and S. Marconi (2013) Therap Adv Gastroenterol 6(2): 137-156).

For patients who become resistant to GCS and suffer from severe or moderate attacks of UC, additional immunomodulatory agents such as cyclosporine, 6-mercaptopurine, and azathioprine may be used. However, immunomodulatory drugs 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).

Additional treatment options for UC include biological agents (Fausel, R. and A. Afzali (2015) Ther Clin Risk Manag 11:63-73). The three TNF-α inhibitors currently approved for the treatment of moderate to severe UC are infliximab, adalimumab, and golimumab. All three have potential risks associated with their use, including in certain patients, such as those with uncontrolled infections, advanced heart failure, neurological symptoms and the potential to promote tumor growth. It should be avoided in patients with a history of malignancy due to potential risk. Other potential adverse effects of TNF-α inhibitor therapy include neutropenia, hepatotoxicity, serum sickness, leukocytoclastic vasculitis, rashes such as psoriasiform rash, induction of autoimmunity and anaphylaxis, convulsions and injection or infusion site reactions such as hypotension.

All three TNF-α inhibitors and their related biosimilar/derivative counterparts may be used to induce and maintain clinical response and remission in UC patients. Combination therapy with azathioprine is also used to induce remission. However, more than 50% of patients receiving TNF-α inhibitors do not respond to induction therapy or lose response to TNF-α inhibitors over time (Fausel, R. and A. Afzali (2015) Ther. Clin Risk Manag 11: 63-73).

Vedolizumab, an α4β7 integrin inhibitor, was recently approved for the treatment of UC. In the GEMINI1 trial, vedolizumab was found to be more effective than placebo in 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. Sandborn, 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.).

Patients with ulcerative colitis are chronically active and resistant to known treatments, posing a serious medical challenge, and often the only remaining treatment option is colectomy. Total colectomy is a potentially curative option in severe UC, but complications such as pouch failure, pouchitis, pelvic sepsis, female infertility and nocturnal fecal soiling may follow. It is a life-changing surgery that comes with risks. Therefore, surgery is usually reserved for patients with severe refractory disease, surgical or other emergencies, or patients with colorectal dysplasia or cancer.

The emergency third-line treatment for UC is covitolimod (Kappaproct/DIMS0150), a modified single-stranded deoxyribonucleic acid (DNA)-based synthetic oligonucleotide 19 bases in length. Covitolimod has the sequence 5'-G ^* G ^* A ^* ACAGTTCGTCCAT ^* G ^* G ^* C-3' (SEQ ID NO: 1), where the CG dinucleotide is unmethylated.

Cobitolimod functions as an immunomodulator by targeting Toll-like receptor 9 (TLR9) present on immune cells. These immune cells (ie, B cells and plasmacytoid dendritic cells (pDCs)) are abundant on mucosal surfaces such as the colon and nasal mucosa. The immune system is an important mediator of changes in UC. The mucosa of the colon and rectum of UC patients is chronically inflamed and contains active immune cells. Covitolimod may be administered locally to the area of inflammation, which brings the drug into close contact with a large number of target cells of interest and ensures that the drug reaches areas rich in TLR9-expressing cells. . Activation of these cells by cobitolimod is associated with a variety of classical anti-inflammatory cytokines, such as type I interferon and interleukin 10 (IL-10), which are thought to be important factors in the clinical efficacy of cobitolimod. induces cytokines.

The clinical efficacy of covitolimod was determined by the ``COLLECT'' (CSUC-01/10) clinical trial, which involved administering 30 mg doses of covitolimod to patients at four-week intervals, and the ``CONDUCT'' clinical trial, which involved testing different dosing regimens. (CSUC-01/16) Proven in clinical trials. Details of the "COLLECT" test are published in the Journal of Crohns and Colitis (Atreya et al. J Crohns Colitis, May 20, 2016) and summarized in Reference Example 1. Details of the CONDUCT clinical trial are published in The Lancet Gastroenterology and Hepatology (Atreya et al 2020. Lancet Gastroenterol Hepatol. 2020 Dec;5(12):1063-1075) and summarized in Reference Example 2. . Overall, the data regarding covitolimod support a positive benefit-risk assessment for patients with chronic active UC (sometimes referred to herein as "chronic active UC"). Covitolimod is safe and well-tolerated, with clinical responses and remissions in patients with active chronic UC, as well as symptomatic and endoscopic responses in patients with treatment-resistant, moderately to severely active chronic UC. It was shown to be effective in inducing clinical remission. Despite the clinical trial results obtained to date, there is still a need for additional effective doses of covitolimod that exhibit both good efficacy and safety.

In the COLLECT study, which involved administration of a relatively low dose (30 mg) of cobitolimod, local administration of cobitolimod was performed using a spray catheter device and administered during endoscopy. This is an invasive medical procedure that must be performed by medical professionals. In addition, each patient's colon was cleaned to remove fecal material before administering cobitolimod locally to the patient. This was done to allow cobitolimod to reach the intestinal epithelial cells within the colon and allow the endoscopist to view the colonic mucosa. Thus, it is well known in the art that oligonucleotides such as covitolimod bind organic matter such as feces. Therefore, it was considered necessary to remove the fecal coating, fecal material, etc. from the colon so that cobitolimod could reach the target intestinal epithelial cells within the colon.

As mentioned above, patients with chronic ulcerative colitis who are in an active disease phase and are resistant to known treatments have serious medical challenges, and often the only remaining treatment is Colectomy. Therefore, despite the inconvenience and discomfort associated with such invasive treatments, patients tolerate medical interventions that require both colonic irrigation to remove fecal material and local administration via spray catheter. There is. However, it would be therapeutically desirable to provide ulcerative colitis patients with a topical treatment that does not require colonic irrigation to remove fecal material and that preferably can be self-administered by the patient.

SUMMARY OF THE INVENTION Surprisingly, for the treatment of inflammatory bowel diseases such as UC, at least two doses of covitolimod greater than 350 mg, such as from 351 mg to 650 mg, typically from 400 mg to 600 mg, preferably about 500 mg. have found that administration on two separate occasions, preferably three weeks apart, is optimal for, for example, inducing remission and/or maintaining a patient in remission (i.e., acting as a maintenance therapy). Ta. The increased efficacy of the drug at 500 mg is more than expected from previous clinical studies conducted at lower doses. Furthermore, this dose was found to be safe, well-tolerated, and effective even in the presence of fecal material, despite the known propensity of cobitolimod to bind to fecal material. Therefore, this dose is suitable for administration to patients who have not undergone colon cleansing. Furthermore, it has surprisingly been found that this dosage is suitable for self-administration via an enema device. Therefore, there is no need to administer the active ingredient using a spray catheter device during endoscopy. This avoids the need for administration by medical personnel and the use of complex medical equipment and more invasive procedures. Therefore, patients do not need to go to a medical center or hospital to receive the drug; they can self-administer it at home.

The invention therefore provides an oligonucleotide comprising the sequence 5'-GGAACAGTTCGTCCATGGC-3' (SEQ ID NO: 2) for use in the treatment of inflammatory bowel disease in human subjects, comprising 400 mg to 600 mg of each oligonucleotide. of the oligonucleotide is administered to the subject on at least two separate occasions, the separate occasions being three weeks apart.

The present invention also provides a method for treating inflammation as defined herein in a human subject as defined herein comprising an oligonucleotide as defined herein together with one or more pharmaceutically acceptable carriers. A pharmaceutical composition for use in the treatment of genital disorders, wherein separate doses of said composition are administered to a subject on at least two separate occasions, said separate occasions being three weeks apart; Compositions are provided in which each administration of the composition delivers an amount of oligonucleotide as defined herein.

The present invention also provides a method of treating an inflammatory bowel disease, as defined herein, in a human subject, comprising: an oligonucleotide as defined herein or an oligonucleotide as defined herein; administering to said subject a composition as defined, wherein separate administrations of said oligonucleotide or composition are administered to said patient on at least two separate occasions, said separate occasions being three weeks apart; Each administration of oligonucleotide or composition provides a method of delivering an amount of oligonucleotide as defined herein.

In a preferred embodiment, the oligonucleotide has the sequence 5'-G ^* G ^* A ^* ACAGTTCGTCCAT ^* G ^* G ^* C-3' (SEQ ID NO: 1) in which the CG dinucleotide is unmethylated. Therefore, in a preferred embodiment, the oligonucleotide is cobitolimod.

Figure 1 shows the treatment and placebo groups reporting no bloody stools (maximum of 7-day patient-reported results) weekly after administration of oligonucleotides of the invention or placebo (added to standard of care (S.o.C.)). Figure 2 shows the results of a placebo-controlled clinical trial on proportions. Figure 2 shows treatment groups reporting less than 18 weekly bowel movements (total of 7-day patient-reported results) after administration of oligonucleotides of the invention or placebo (added to standard of care (S.o.C.)). The results of the placebo-controlled clinical trial are presented for the proportions in the and placebo groups. Figure 3 shows treatment groups reporting less than 35 weekly bowel movements (total of patient-reported results over 7 days) after administration of oligonucleotides of the invention or placebo (added to standard of care (S.o.C.)). and the proportion of the placebo group in a placebo-controlled clinical trial. Figure 4 shows fewer than 3 bowel movements per week (daily average of 7-day patient-reported results) after administration of oligonucleotides of the invention or placebo (added to standard of care (S.o.C.)). Results of placebo-controlled clinical trials are presented for the proportion of treatment and placebo groups reporting . Figure 5 shows that fewer than 4 bowel movements per day (7-day patient-reported daily average of ) shows the results from placebo-controlled clinical trials of the proportion of treatment and placebo groups reporting Figure 6 shows that fewer than 5 bowel movements per day (7-day patient-reported daily average of ) shows the results from placebo-controlled clinical trials of the proportion of treatment and placebo groups reporting

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications and publications cited herein are incorporated by reference in their entirety.

As used herein, the term "subject" refers to a human subject/patient. The terms "subject" and "patient" are used interchangeably herein.

As used herein, the term inflammatory bowel disease (IBD) refers to a group of inflammatory conditions of the colon and gastrointestinal tract. The main types of IBD are ulcerative colitis (UC) and Crohn's disease. The main difference between UC and Crohn's disease is the location and nature of the inflammatory changes. Crohn's disease affects any part of the gastrointestinal tract, from the mouth to the anus, whereas UC is limited to the colon and rectum. In some cases, a definitive diagnosis of either Crohn's disease or UC cannot be made because of the specificity of the symptoms. In these cases, an uncertain diagnosis of colitis may be made. Other forms of IBD include, but are not limited to, collagenous colitis, lymphocytic colitis, ischemic colitis, diverting colitis, Behcet's disease, and indeterminate colitis.

Typically, the inflammatory bowel disease is ulcerative colitis (UC).

The disease ulcerative colitis (UC) is well known to those skilled in the art. Ulcerative colitis treated according to the present invention may include treatment of ulcerative proctitis, distal or left-sided colitis, pancolitis, pancolitis, and pouchitis. Typically, patients have left-sided ulcerative colitis.

Patients with UC typically exhibit a spectrum of disease severity, ranging from remission to severe activity. Using clinical assessment, UC patients can be classified into four disease activity subgroups as defined by D'Haens, Gastroenterology 2007; 132: 763-786, incorporated herein by reference in its entirety. : (1) Remission (less than 2 or 3 stools/day, no blood and/or pus in the stool, no systemic symptoms); (2) Mild active disease (3 or 4 stools/day); (3) moderately active disease (more than 4 stools/day and/or blood); (3) moderately active disease (more than 4 stools/day and/or blood); and (4) severe active disease (more than 6 bloody stools/day, and toxicity indicated by fever, tachycardia, anemia, or erythrocyte sedimentation rate ESR); evidence).

Typically, patients suffer from moderate to severe UC. Preferably, the patient suffers from moderate to severe UC as defined above. For example, a patient may have moderate to severe left-sided UC.

As used herein, the terms "treatment" and "treating" refer to the treatment and/or amelioration and/or prevention of a disease or condition or the reduction of the severity/exacerbation of symptoms of a disease or condition, and or the treatment of the cause of the condition, including reversing, alleviating or preventing the symptoms, clinical signs and underlying pathology of the condition in a manner that improves or stabilizes the subject's condition. good.

Specifically in the context of ulcerative colitis, "treating" typically refers to inducing a response or remission in a patient with active ulcerative colitis. Thus, typically the oligonucleotide is for inducing a response or remission of active ulcerative colitis in a patient. Inducing a response means improving the patient's condition, eg, by reducing and/or preventing symptoms and clinical signs of active disease. Induction of remission means that the patient moves from what is considered to be an active stage of the disease to what is considered to be remission.

Response or induction of remission in UC patients is typically assessed by one or more of endoscopy, histology, patient record results, and quality of life outcomes. Thus, reference to induction of response or remission includes endoscopic remission, endoscopic response, histological remission, histological response, response or remission as determined by physician- or patient-recorded results; and one or more induction of response or remission as determined by quality of life. This can typically be assessed with reference to one or more standard indicators.

Typically, the ulcerative colitis is chronic active ulcerative colitis, ie, the patient has chronic ulcerative colitis that is in the active phase.

As used herein, the term "chronic active ulcerative colitis" refers to patients with ulcerative colitis that is both active and chronic. Active ulcerative colitis is typically as defined herein, ie, the patient is not in remission. Ulcerative colitis is typically a chronic (long-term) condition with alternating active and inactive periods. As those skilled in the art will appreciate, patients with chronic ulcerative colitis experience periods of active disease (“flare-ups”) with more extreme symptoms, interspersed with periods in which the patient experiences milder symptoms or is in remission. (flare up) or relapse). Accordingly, the term "chronic active UC" typically refers to patients with chronic UC who are in an active disease state.

The patient may have chronic active moderate to severe UC. The patient may have chronic active moderate to severe left-sided UC.

Preferably, reference herein to "treating" refers to inducing a response or remission in a patient with chronic active ulcerative colitis. Thus, typically 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 according to one or more standard disease indicators. Typical disease indicators include: (i) disease activity as determined by clinical and biochemical disease activity; (ii) disease activity as determined by endoscopic disease activity; (iii) disease activity as determined by endoscopic disease activity; ) disease activity as determined by a composite clinical and endoscopic disease activity index, (iv) quality of life, and (v) histological disease activity. These indicators are explained in D'Haens (ibid.).

Disease activity-based indices determined by clinical and biochemical disease activity include the Truelove and Witts Severity Index; the Powell-Tuck (St. Mark's) Index); Clinical Activity (Rachmilewitz) Index; Activity (Seo) Index; Physician Global Assessment; Rich Tiger (revised) Lichtiger (Modified Truelove and Witts Severity) Index; Investigators Global Evaluation; Simple Clinical Colitis Activity Index; Individual Symptom Score Improvement Based on Individual Symptom Scores; Ulcerative Colitis Clinical Score; and Patient-defined remission. Described in Haens (ibid.).

Disease activity-based indicators determined by endoscopic disease activity include Truelove and Witts Sigmoidoscopic Assessment; Baron score; Powell-Took sigmoidoscopy. 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 indicators are explained in D'Haens (ibid.).

An index based on disease activity determined by a composite clinical and endoscopic disease activity index is the Mayo Score (Mayo Clinic Score/Disease Activity Index). ;Modified Mayo Score and Sutherland Index (Disease Activity Index/UC Disease Activity Index). The Mayo score and Sutherland index are explained in D'Haens (ibid.).

Quality of life-based indicators include the Rating Form of IBD Patient Concerns; and the Inflammatory Bowel Disease Questionnaire (IBDQ). These indicators are explained in D'Haens (ibid.).

Indices based on histological disease activity include those described by D'Haens (ibid.), such as the Geboes Index and Riley Index, as well as the Nancy Index and Robert's Index. Other indicators include (Robarts Index).

Preferred indicators for evaluating UC patients include the Clinical Activity (Rachmilewitz) Index, the Mayo Score, and the Modified Mayo Score.

The clinical activity (Rahamelvich) index takes into account seven variables: number of stools, blood in the stool, researcher's global assessment of symptom status, abdominal pain or cramps, temperature due to colitis, extraintestinal symptoms, and laboratory findings. It is. This is further explained in D'Haens (ibid.) and Rachmilewitz D., BMJ 1989; 298: 82-86, incorporated herein by reference in its entirety. Determination of the clinical activity (Rahamelvich) index produces a patient score ranging from 0 to 29 points (higher scores imply more severe disease).

Clinical remission is considered a clinical activity (Rahamelvich) index score of 4 points or less. Response, as determined by the clinical activity (Rahamelvich) index, means that the patient scores lower after treatment than before treatment.

The Mayo score is an index that takes into account four items: defecation frequency, rectal bleeding, lower GI endoscopy results, and physician's global assessment (PGA). This is further explained in D'Haens (ibid.) and Schroeder KW et al, N Engl J Med 1987; 317:1625-1629, incorporated herein by reference in its entirety. Determination of the Mayo score yields a score ranging from 0 to 12 points (higher scores imply more severe disease). In addition to the four specific items, the patient's functional assessment is also measured, which is not meant to be included in the 12-point index calculation, but is included in the general well-being (well- being) should be used as a measure of

Mayo scoring for each of the four items is determined as shown in the table below.

^bEach patient serves as his or her own control to establish the degree of abnormality in bowel frequency.
^c Daily bleeding score represents bleeding on the most severe day.
^d Physician's overall evaluation certifies three other criteria, the patient's daily record of abdominal discomfort and general sense of well-being, physical findings, and other observations such as the patient's performance status.

Remission according to the Mayo score is determined by: (1) defecation frequency (normal bowel movements), (2) rectal bleeding (no rectal bleeding), (3) patient's functional assessment score (generally good), and (4) endoscopy. It may be defined as complete resolution of microscopic findings (normal) and a PGA score of 0. Response, as determined by the Mayo score, is typically determined by improvement in the PGA score (minimum 1 point reduction from baseline) and at least one other clinical assessment (bowel frequency, rectal bleeding, patient functional assessment, improvement in endoscopic findings) and no deterioration in other clinical evaluations.

Alternatively, clinical remission may be defined as a Mayo score of 0 and clinical improvement (response) as a decrease from baseline in the Mayo score of 3 or more points.

Alternatively, clinical remission is a Mayo score of 0 and clinical improvement (response) is a decrease in Mayo score of 3 or more points from baseline (or 2 or more points if Mayo score baseline is 3 or less). decrease).

Alternatively, remission as determined by the Mayo score may be defined as requiring a subscore of 0 for both sigmoidoscopy and rectal bleeding, and a score of 0 or 1 for bowel frequency and PGA. Response can be defined as a decrease in Mayo score of 3 or more points from baseline; clinical response can be defined as a decrease in Mayo score of 2 or more points from baseline (also known as partial Mayo score). (no endoscopic subscore), endoscopic response may be defined as a decrease in endoscopic subscore of 1 or more points from baseline.

Alternatively, clinical remission can be defined as a sum of Mayo scores of 2 points or less and no individual subscores of more than 1 point, and clinical response is defined as a sum of Mayo scores of 3 or more points from baseline. and a reduction of 30% or more and a reduction in the rectal bleeding subscore of 1 point or more or an absolute value of the rectal bleeding subscore of 0 or 1, and mucosal healing may be defined as an absolute value of the endoscopic subscore of 0 or 1. obtain.

In one embodiment, the patient with active ulcerative colitis has a Mayo score greater than 2. Patients in remission from ulcerative colitis typically have a Mayo score of 2 or less.

The modified Mayo score is related to the Mayo score defined above. The modified Mayo score differs from the Mayo score in that colonoscopy/sigmoidoscopy scoring does not take into account frailty as much. Therefore, the score table for the modified Mayo score is as follows:

^bEach patient serves as his or her own control to establish the degree of abnormality in bowel frequency.
^c Daily bleeding score represents bleeding on the most severe day.
^d Physician's overall evaluation certifies three other criteria, the patient's daily record of abdominal discomfort and general sense of well-being, physical findings, and other observations such as the patient's performance status.

The modified Mayo score remission and response values are as described above for the Mayo score. The modified Mayo score is typically found in the FDA's draft guidance document Ulcerative Colitis: Clinical Trials for Industry, found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM515143.pdf The clinical trials will be evaluated according to the Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry.

Alternatively, the modified Mayo score may differ from the Mayo score in that colonoscopy/sigmoidoscopy scoring takes less account of frailty and in that the physician's global assessment is less conclusive. be. Therefore, the scoring table for the modified Mayo score would also look like this:

^bEach patient serves as his or her own control to establish the degree of abnormality in bowel frequency.
^c Daily bleeding score represents bleeding on the most severe day.

The remission and response values for this alternative modified Mayo score are typically as described above for the Mayo score. Alternatively, remission is defined as i) 0 rectal bleeding, ii) 0 or 1 bowel movements (at least 1 point decrease from baseline at week 0), and iii) endoscopy score 0 or 1 (excluding frailty). ) may be defined according to this alternative modified Mayo score.

Induction of remission of UC may be according to the criteria set out in S. P. L. Travis, Aliment Pharmacol Ther 2011; 34: 113-124 (incorporated herein by reference in its entirety), i.e. rectal bleeding, urgency, Complete cessation of increased defecation frequency, preferably ascertained by endoscopic mucosal healing, may be followed.

Alternatively, the induction of response or remission is 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, herein incorporated by reference in its entirety.

Response or induction of remission in Crohn's disease patients may be determined according to one or more standard disease indicators. Typical indicators include the Crohn's Disease Activity Index (CDAI). CDAI is based on 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: S1542-3565(15)00787-00789. doi: 10.1016/j.cgh.2015.06.001; and Ungar et al “Advances in the development of new biologics in inflammatory bowel disease”, Annals of Gastroenterology (2016) 29, 243-248. Alternative indicators for evaluating patients with Crohn's disease include the Harvey-Bradshaw index and the Inflammatory Bowel Disease Questionnaire.

CDAI includes: frequency of liquid or loose stools; abdominal pain; general well-being; presence of complications (presence of joint pain (arthralgia) or overt arthritis; inflammation of the iris or uveitis; erythema nodosum, gangrenous presence of pyoderma, or aphthous ulcers; anal fissures, fistulas, or abscesses; other fistulas; fever in the previous week); use of Lomotil or opiates for diarrhea; presence of an abdominal mass; hematocrit; and percent deviation from standard weight. It is a composite score that takes into account a number of symptoms associated with Crohn's disease, such as: Clinical remission with CDAI is typically indicated by a score of less than 150.

Typically, subjects are in clinical remission at week 6 after initiation of oligonucleotide treatment at week 0. Clinical remission can be any of the definitions of clinical remission set forth herein. Typically, subjects are in clinical remission at week 6 after initiation of oligonucleotide treatment at week 0, with clinical remission defined as 3-component Mayo scores: i) Defined by rectal bleeding 0, ii) defecation frequency 0 or 1 (at least 1 point decrease from baseline, week 0), and iii) endoscopy score 0 or 1.

Typically, subjects will show endoscopic improvement at week 6 after starting oligonucleotide treatment at week 0. Typically, subjects are in symptomatic remission at week 6 after initiation of oligonucleotide treatment at week 0. Symptomatic remission is typically defined as a hematochezia score of 0 and a stool frequency score of 0 or 1 according to the Mayo scoring system.

Subjects treated in accordance with the present invention are typically resistant to, poorly responsive to, or intolerant of anti-inflammatory therapy, and/or at least one immunomodulatory agent, a TNF-α inhibitor, Demonstrates or previously demonstrated inadequate response, loss of response, or intolerance to anti-integrin, JAK inhibitors or IL-12/IL-23 inhibitors. Subjects treated according to the invention are typically resistant or poorly responsive to or intolerant of anti-inflammatory therapy. Subjects treated according to the present invention typically are resistant to, poorly responsive to, or intolerant of at least one immunomodulatory drug. Subjects treated according to the present invention are typically resistant or poorly responsive to or intolerant of at least one TNF-α inhibitor.

Accordingly, subjects typically receive anti-inflammatory therapy, preferably anti-inflammatory therapy for UC, and/or immunomodulatory drugs, TNF-α inhibitors or anti-integrin therapy, preferably such therapy for UC. have previously taken or are currently taking.

Anti-inflammatory therapies for UC are discussed herein and typically include oral corticosteroids and glucocorticosteroids (GCS), sulfasalazine and 5-ASA. Accordingly, subjects treated according to the present invention are typically resistant or poorly responsive to or intolerant to GCS, sulfasalazine and/or 5-ASA. Typically, subjects treated in accordance with the present invention are typically resistant or poorly responsive to or intolerant to oral corticosteroids.

Immunomodulators, TNF-α inhibitors, and anti-integrins are discussed herein and typically include azathioprine, 6-mercaptopurine, and the TNF-α inhibitor infliximab and its biosimilars and derivatives; Biologics include golimumab and its biosimilars and derivatives, adalimumab and its biosimilars and derivatives, and the anti-integrin vedolizumab and its biosimilars and derivatives. Accordingly, subjects treated in accordance with the present invention typically include azathioprine, 6-mercaptopurine, infliximab and biosimilars and derivatives thereof, golimumab and biosimilars and derivatives thereof, adalimumab and biosimilars and derivatives thereof. , and resistance or inadequate response or intolerance to the anti-integrin vedolizumab and its biosimilars and derivatives. Typically, subjects treated according to the invention are resistant to or poorly responsive to or intolerant of azathioprine and/or 6-mercaptopurine. Typically, subjects treated in accordance with the present invention are resistant to, have a poor response to, or are intolerant to infliximab and/or adalimumab. Subjects treated according to the invention may be resistant or poorly responsive to or intolerant of JAK inhibitors (eg, tofacitinib). Subjects treated according to the invention may be resistant or poorly responsive to or intolerant of IL-12/IL-23 inhibitors (eg, ustekinumab).

Diseases that are resistant or poorly responsive to therapy typically include active disease despite a history of at least one course of therapy (e.g., anti-inflammatory or immunomodulatory therapy) in the context of the present invention. It is a disease in which signs and symptoms persist. Typically, in the context of treatment for UC, signs and symptoms of active disease persist despite a history of two or more courses of anti-inflammatory or immunomodulatory therapy. Typical courses of treatment with anti-inflammatory or immunomodulatory therapies for UC are well understood by those skilled in the art and typically include treatments sufficient in dosage and frequency sufficient to induce remission in a typical patient. with the administration of

Intolerance to a therapy, such as an anti-inflammatory therapy or an immunomodulatory therapy, in the context of the present invention means that the therapy causes unacceptable side effects in the subject, such as side effects that typically lead to discontinuation of the therapy. means.

Typically, the subject has previously received or is currently receiving aminosalicylic acid (5-ASA), preferably 5-ASA therapy for UC.

Typically, the subject has previously received or is currently receiving oral glucocorticosteroids (GCS), preferably oral GCS therapy for UC.

Typically, the subject has previously received or is currently receiving budesonide, eg, oral MMX budesonide therapy.

Typically, the subject has previously received or is currently receiving a 5-aminosalicylic acid and/or salazopyrine compound.

Typically, the subject has previously received or is currently receiving azathioprine and/or 6-mercaptopurine.

Typically, subjects who are resistant or have inadequate response or intolerance to anti-inflammatory therapy will receive rectal, oral, and/or parenteral GCS treatment (including no GCS treatment due to previous side effects). showing or previously showing an inadequate response or loss of response (i.e., resistance) or intolerance to.

Typically, subjects who are resistant or have an inadequate response to or intolerance to anti-inflammatory therapy will have an inadequate response (e.g., steroid resistance), or steroid dependence, or no response to GCS treatment. loss of, or have a history or current condition of intolerance. Steroids/GCS are typically administered to subjects during treatment of ulcerative colitis.

Steroid resistance typically means a lack of meaningful clinical response, i.e., oral administration over a period of 30 days, or intravenous (IV) administration over a period of 7 to 10 days, for example, 40 to 40 days daily. Refers to subjects who persistently exhibit signs and symptoms of active ulcerative colitis despite a history of at least one course of steroid therapy, such as an induction regimen containing a dose equivalent to 60 mg of prednisone.

Steroid dependence typically refers to the inability to reduce the steroid dose below the equivalent of prednisolone 10 mg/d within 3 months of starting steroids without recurrent active ulcerative colitis. patients or patients who relapse within 3 months of stopping steroids.

Intolerance of GCS treatment typically refers to side effects that the subject cannot tolerate after GCS treatment, such as, but not limited to, Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, or infection. It means that you have experienced.

Typically, subjects who are resistant or have an inadequate response to or intolerance to an immunomodulatory drug will have an inadequate response or loss of response (i.e., resistance) to the immunomodulatory drug; Shows or has previously shown an intolerance. For example, a subject who has resistance or inadequate response to or intolerance to a TNF-α inhibitor may have an inadequate response or loss of response (i.e., resistance) to a TNF-α inhibitor; or exhibit or have previously exhibited an intolerance.

Insufficient response or loss of response to an immunomodulatory drug is typically associated with at least one immunomodulatory drug, such as oral azathioprine (1.5 mg/kg or more) or oral 6-mercaptopurine (0.75 mg/kg or more). ) refers to the persistence of signs and symptoms of active ulcerative colitis despite previous treatment on an 8-week regimen.

Intolerance to immunomodulatory drugs typically means that the subject has nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, lymphopenia, thiopurine methyltransferase (TPMT) gene mutations, or experienced an infection or other side effects after taking an immunomodulatory drug.

Insufficient response or loss of response to a TNF-α inhibitor is defined as infliximab (5 mg/kg (IV), 2 doses at least 2 weeks apart) or its biosimilar or derivative; golimumab (200/100 mg (SC) , 2 doses at least 2 weeks apart) or a biosimilar or derivative thereof; or a 4-week induction regimen of adalimumab (160/80 mg (SC), 2 doses at least 2 weeks apart) or a biosimilar or derivative thereof; Persistence of signs and symptoms of active ulcerative colitis despite previous treatment with at least one TNF-α inhibitor, such as (or recommended dose according to current labeling) or prior clinical benefit Recurrence of symptoms during subsequent maintenance administration.

Intolerance to a TNF-α inhibitor refers to infusion-related reactions, demyelination, congestive heart failure, infection or other side effects after receiving a TNF-α inhibitor.

Inadequate response or loss of response to an anti-integrin includes, for example, at least a 10-week regimen of vedolizumab 300 mg (IV) or its biosimilars or derivatives, or prior treatment with an anti-integrin as recommended in current labeling. It refers to the persistence of signs and symptoms of active ulcerative colitis despite treatment, or the recurrence of symptoms during maintenance treatment following previous clinical benefit.

Typically, the subject has been diagnosed with left-sided ulcerative colitis, ie, distal colitis, including rectosigmoiditis. For example, the subject may have been diagnosed with moderate to severe left-sided ulcerative colitis.

Typically, the subject is elective for colectomy.

The term "colectomy" as used herein refers to surgical removal of any extent of the large intestine (colon). As used herein, colectomy includes right hemicolectomy, left hemicolectomy, extended hemicolectomy, transverse colectomy, sigmoidectomy, rectosigmoidectomy, and Hartmann procedure. , "double barrel" or Mikulicz colostomy, total colectomy (also called the Lane procedure), total proctocolectomy, and subtotal colectomy. As used herein, the phrase "elective for colectomy" refers to a subject who may elect to undergo a non-emergency colectomy procedure based on the evaluation of a physician and surgeon. Elective candidates for colectomy may be patients refractory to available treatments (for ulcerative colitis) or intolerant of available treatments (for ulcerative colitis). , but not limited to. This is different from an emergency colectomy, which is an acute intervention for a person with an acute illness or injury who requires immediate medical attention. This phrase also includes those selected for colectomy.

The term "oligonucleotide" as used herein 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 or cDNA, plasmids, vectors, or bacterial DNA, but are preferably produced by synthetic methods. The nucleoside residues can be linked to each other by any of a number of known internucleoside linkages. Such internucleoside linkages include, but are not limited to, naturally occurring internucleoside phosphodiester linkages, or phosphorothioates, phosphorodithioates, alkylphosphonates, alkylphosphonothioates, phosphotriesters, phosphoramidates, siloxanes, carbonates, carbalkoxy Modified internucleoside linkages include, but are not limited to, acetamidate, carbamate, morpholino, borano, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate and sulfone internucleoside linkages. The term "oligonucleotide" also encompasses polynucleosides having one or more stereospecific internucleoside linkages (eg, (Rp)- or (Sp)-phosphorothioate, alkylphosphonate, or phosphotriester linkages). As used herein, the terms "oligonucleotide" and "dinucleotide" are meant to include polynucleosides and dinucleosides having any such internucleoside linkage, whether or not the linkage includes a phosphate group. clearly intended. In certain preferred embodiments, these internucleoside linkages may be phosphodiester, phosphorothioate, or phosphorodithioate linkages, or combinations thereof.

The term "oligonucleotide" also includes polynucleosides having additional substituents such as, but not limited to, protein groups, lipophilic groups, intercalating agents, diamines, folic acid, cholesterol and adamantane. The term "oligonucleotide" includes, but is not limited to, peptide nucleic acids (PNA), peptide nucleic acids with phosphate groups (PHONA), locked nucleic acids (LNA), morpholino backbone oligonucleotides, and backbones containing alkyl or amino linkers. Any other nucleobases including polymers such as oligonucleotides having sections are included. Alkyl linkers may be branched or unbranched, substituted or unsubstituted, and chirally pure or racemic.

Oligonucleotides of the invention can include naturally occurring nucleosides, modified nucleosides, or mixtures thereof. The term "modified nucleoside" as used herein is a nucleoside that includes a modified heterocyclic base, a modified sugar moiety, or a combination thereof. In some embodiments, the modified nucleoside is a non-natural pyrimidine or purine nucleoside, as described herein. In some embodiments, the modified nucleoside is a 2'-substituted ribonucleoside, an arabinonucleoside, or a 2'-deoxy-2'-substituted arabinoside.

As used herein, the term "hybrid oligonucleotide" is an oligonucleotide having more than one type of nucleoside.

As used herein, the term "oligonucleotide" includes hybrid and chimeric oligonucleotides. A "chimeric oligonucleotide" is an oligonucleotide that has more than one type of internucleoside linkage within its sequence structure. A preferred example of such a chimeric oligonucleotide is a chimeric oligonucleotide containing a phosphorothioate, phosphodiester or phosphorodithioate region and a nonionic linkage such as an alkylphosphonate or alkylphosphonothioate linkage (US5635377 and US5366878).

As used herein, the term "oligonucleotide" also includes circularized variants and cyclic oligonucleotides.

Preferably, the oligonucleotide comprises at least one naturally occurring phosphodiester, or one modified phosphorothioate, or phosphorodithioate internucleoside linkage, but preferably, but not limited to, methylphosphonate, methylphosphonothioate, Phosphotriesters, phosphothiotriesters, phosphorothioates, phosphorodithioates, triester prodrugs, sulfones, sulfonamides, sulfamates, formacetals, N-methylhydroxylamine, 2'OMe (oxymethyl at the 2' position) groups), carbonates, carbamates, morpholinos, boranophosphonates, phosphoramidates, etc., especially primary amino-phosphoramidates, N3 phosphoramidates and N5 phosphoramidates. , and stereospecific bonds (eg, (Rp)- or (Sp)-phosphorothioate, alkylphosphonate, or phosphotriester bonds) are also envisioned.

The sugar moiety of the nucleoside can be a non-naturally occurring sugar moiety. As used herein, "naturally occurring sugar moieties" are sugar moieties that naturally occur as part of nucleic acids, such as, for example, ribose and 2'-deoxyribose, and "non-naturally occurring sugar moieties" are , any sugar that does not occur naturally as part of a nucleic acid but can be used in the backbone of 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 natural forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid targets, and increased stability in the presence of nucleases. Oligonucleotides are typically comprised of more than 10 up to 100 or more deoxyribonucleotides or ribonucleotides, preferably between about 8 and about 40, and most preferably between about 8 and about 20. The exact size depends on many factors, which in turn depend on the ultimate function or use of the oligonucleotide. Oligonucleotides may be produced by any method such as chemical synthesis, DNA replication, reverse transcription, or a combination thereof.

Oligonucleotides for use in the present invention have the sequence
Contains 5'-GGAACAGTTCGTCCATGGC-3' (SEQ ID NO: 2). Typically, at least one CG dinucleotide is unmethylated.

Typically, at least one nucleotide of the oligonucleotide has a backbone modification. Typically, at least one nucleotide of the oligonucleotide has a phosphate backbone modification. Backbone modifications are typically phosphorothioate or phosphorodithioate modifications.

The phosphorothioate bond is present in the sequence, e.g.
It can be indicated by an asterisk (*) in 5'-G ^* G ^* A ^* ACAGTTCGTCCAT ^* G ^* G ^* C-3' (SEQ ID NO: 1), where the CG dinucleotide is unmethylated.

Preferably, said oligonucleotide has the sequence
5'-G ^* G ^* A ^* ACAGTTCGTCCAT ^* G ^* G ^* C-3' (SEQ ID NO: 1), where the CG dinucleotide is unmethylated. Therefore, preferably said oligonucleotide is cobitolimod.

Accordingly, the present invention preferably provides cobitolimod for use in the treatment of active ulcerative colitis as defined herein in a human subject, wherein Individual doses as defined herein are administered to a subject on at least two separate occasions, said separate occasions being three weeks apart.

In the therapy of the invention, individual doses of 400 mg to 600 mg of said oligonucleotide, preferably cobitolimod, are administered. Typically, the same dosage of oligonucleotide is administered in each individual dose/administration, although different dosages may also be used.

Typically, individual doses of more than 350 mg of said oligonucleotide, preferably cobitolimod, are administered. For example, typically an individual dose of more than 350 mg, eg 351 to 650 mg, of said oligonucleotide, preferably covitolimod, is administered.

Typically, said oligonucleotide, preferably covitolimod, will be in an amount of 425 mg to 575 mg, preferably 450 mg to 550 mg, more preferably 460 to 540, even more preferably 470 to 530, even more preferably 480 to 520, even more preferably Each dose/administration is administered from 490 to 510, even more preferably from 495 to 505, even more preferably from 499 to 501 mg.

Preferably, about 500 mg of said oligonucleotide, preferably covitolimod, is administered. Accordingly, about 500 mg of said oligonucleotide, preferably cobitolimod, is administered on each of at least two occasions.

In the context of active agent dosage, "about" as used herein means +/-10%, typically +/-5%, preferably +/-1%.

More preferably, 500 mg of said oligonucleotide is administered, preferably covitolimod.

In the therapy of the invention, individual doses (as specified herein) of said oligonucleotide are administered to a patient on at least two separate occasions, said separate occasions being three weeks apart. This means that patients will not receive additional oligonucleotides between specific doses/administrations that are three weeks apart. In a 3 week long window between specific doses/administrations that are 3 weeks apart, the patient will not receive an oligonucleotide as defined herein, but one or more oligonucleotides for the treatment of ulcerative colitis. may receive additional therapeutic agents.

If the dose of the oligonucleotide is administered to the patient on more than two occasions, then typically each occasion is three weeks after the previous occasion. Typically, doses of said oligonucleotide (in amounts specified herein) will be administered to the patient on eg 2, 3, 4, 5, 6, 7, 8, 9 or 10 separate occasions. administered, each occasion 3 weeks after the previous occasion. Typically, doses of the oligonucleotide are administered to the patient until the patient is in remission as defined above. In some embodiments, individual doses are administered to a subject on only two separate occasions, with the separate occasions being three weeks apart.

It should be understood that reference to administration on at least two separate occasions refers to a single treatment regimen for inducing remission, where said separate occasions are three weeks apart. Therefore, following a course of treatment according to the invention, further treatment with oligonucleotides is not excluded in the future, for example after relapse to an active disease state after remission.

In the context where a patient receives only two doses, the first dose is delivered on day 0 and the second dose is delivered three weeks later. In the context of a patient receiving three doses, the first dose is delivered on day 0, the second dose is delivered three weeks later, and the third dose is delivered an additional three weeks later, i.e. on day 0. It will be delivered 6 weeks after.

As used herein, the term "3 weeks apart" means, in certain embodiments, administration of doses exactly 21 days apart, i.e., the first dose is administered on day 0; A further dose is administered on day 21. However, it will be understood that slight variations from this are still within the scope of the invention. Such small deformations may be unavoidable, for example due to patient illness or unavailability of drugs. Thus, as used herein, "3 weeks apart" means 14 to 28 days apart, typically 18 to 24 days apart, or 19 to 23 days apart. or administrations 20-22 days apart.

Thus, in certain embodiments, the present invention provides oligonucleotides 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 said oligonucleotide in an amount as defined herein are administered to a patient on at least two separate occasions, such as on two separate occasions, said separate occasions lasting 18 to 24 days. 19-23 days apart, or 20-22 days apart.

As explained in more detail below, agents for use in the present invention may be used as monotherapy treatment for an indication or together with other agent(s) as adjunctive therapy for an indication. May be administered. In the case of adjunctive (or "add-on") therapy, the agents used in the invention may be administered simultaneously, separately, or sequentially with the other agent(s), e.g., in fixed-dose combinations or separately. may be administered at a dose of

As used herein, the term "add-on" refers to the administration of the oligonucleotide in addition to a current therapy or drug regimen without interrupting the current therapy or drug regimen.

Thus, oligonucleotides may be administered as monotherapy or in combination with one or more additional therapeutic agents for the treatment of ulcerative colitis. Typically, the oligonucleotide is used as a monotherapy or in combination with one or more agents selected from anti-inflammatory agents, immunomodulatory agents, anti-TNF therapeutic agents, or other suitable agents for treating ulcerative colitis. It may also be administered in combination with additional therapeutic agents for the treatment of ulcerative colitis.

Examples of such drugs suitable for use in combination with said oligonucleotides include GCS or derivatives; prednisolone, decortin, anti-TNF or derivatives; infliximab and biosimilars and derivatives thereof, adalimumab and biosimilars and derivatives thereof; golimumab and its biosimilars and derivatives, anti-integrin or derivatives; vedolizumab and its biosimilars and derivatives, natural IFN-β, thiopurines or derivatives; azathioprine, 6-mercaptopurine, 5-ASA, sulfasalazine, methotrexate, cyclosporine, and These include, but are not limited to, their equivalents.

Typically, the subject receiving said oligonucleotide will receive one or more other oligonucleotides selected from GCS, decortin, 5-ASA, azathioprine, 6-mercaptopurine, sulfasalazine, methotrexate, prednisolone and equivalents or derivatives thereof. He also received medication.

Preferably, the subject receiving said oligonucleotide also receives one or more other drugs selected from GCS, 5-ASA, azathioprine, 6-mercaptopurine, sulfasalazine and methotrexate.

More preferably, the subject receiving said oligonucleotide also receives one or more other drugs selected from oral GCS, oral 5-ASA, oral MMX budesonide, azathioprine, 6-mercaptopurine, and oral methotrexate.

In some embodiments, the subject receiving the oligonucleotide also receives one or more steroid drugs, such as corticosteroids and glucocorticosteroids.

For purposes of the present invention, the terms "in combination with" and "add-on" refer to the process of treating the same disease in the same patient, including simultaneous administration of the oligonucleotide and one or more additional therapeutic agents, and several This includes administration in any order, such as separated in time by up to a month.

Typically, the oligonucleotide is administered locally, such as topically to a mucosa.

Typically, the oligonucleotide is administered intracolonically. Intracolonic administration typically occurs rectally. Therefore, preferably said oligonucleotide is administered rectally. Intracolonic administration is typically performed using an enema or catheter. Intracolonic administration may include administration by rectal enema. Intracolonic administration may be performed locally during a colonoscopy, for example, with the aid of a spray catheter or other suitable medical device inserted through a colonoscopic biopsy channel.

Preferably, the oligonucleotide is administered intracolonically by rectal enema. Rectal enemas are typically suitable for self-administration by the subject. In this manner, the oligonucleotide may be administered without the need for a trip to a clinic or hospital, allowing for administration of the oligonucleotide in the subject's home without the presence of a medical professional. Furthermore, this avoids the use of more complex and expensive equipment such as spray catheter devices during endoscopy.

Preferably, the oligonucleotide is self-administered rectally by the subject. For example, the oligonucleotide may be self-administered by the subject via rectal enema. Topical administration is therefore typically via an enema suitable for self-administration by the subject.

Preferably, the subject has not undergone colon cleansing prior to said administration. Therefore, for any subject described herein or for any amount of oligonucleotide described herein, the subject typically has not undergone a colonic irrigation prior to said administration.

As used herein, reference to a subject who has not undergone a "colon lavage" refers to a subject who has not undergone colon cleansing in order to reduce the amount of fecal material in the oligonucleotide-treated colon. Intended to define subjects who have not undergone cleaning. Thus, typically, the subject will receive 1 hour prior to treatment with oligonucleotides, typically 4 hours prior to treatment with oligonucleotides, preferably 8 hours prior to treatment with oligonucleotides, and more preferably 8 hours prior to treatment with oligonucleotides. Colonic irrigation is not performed 12 hours prior to treatment, more preferably 24 hours prior to oligonucleotide treatment, and most preferably 48 hours prior to oligonucleotide treatment.

Typically, the colon cleansing can be performed by any method known in the art, such as by administering a laxative.

Typically, the subject has luminal fecal material. Typically, the subject has fecal material covering or in close proximity to the colonic epithelial cells that are treated with the oligonucleotide. The subject may have fecal material in the lumen that is not in direct contact with the colonic epithelial cells that are treated with the oligonucleotide. The subject may be exposed to fecal material in the lumen that coats or is in close proximity to the colonic epithelial cells to be treated with the oligonucleotide, and in the lumen that is not in direct contact with the colonic epithelial cells to be treated with the oligonucleotide. It may also contain fecal matter. More preferably, the amount of fecal material is the normal amount expected in a patient who has not undergone colon cleansing.

Preferably, said local administration is carried out via an enema, which is suitable for self-administration by the patient. Typically, enemas have an elongated tip configured to allow insertion into the rectum. Typically, the tip is 4 to 15 cm long, typically 4 to 10 cm long, preferably 5 to 6 cm long. Typically, therefore, covitolimod is administered via a method that involves inserting only the tip of an elongated enema, 4 to 15 cm long, preferably 4 to 10 cm long, into the rectum.

The oligonucleotide may be delivered to the upper part of the descending colon or to the transverse region of the colon; however, other regions are possible if suitable. Local administration to other areas of the gastrointestinal tract is also possible.

In yet another embodiment of this aspect, said oligonucleotide is administered by any suitable route of administration, including, but not limited to, inhalation, intranasal, parenteral, oral, intradermal, subcutaneous, vaginal and rectal administration. Can be done. Additionally, in certain embodiments, systemic administration of the oligonucleotides may be used.

The oligonucleotide may be administered in the form of a pharmaceutical composition comprising an oligonucleotide as defined herein together with one or more pharmaceutically acceptable carriers. As used herein, the term "carrier" refers to any excipient, diluent, filler, salt, buffer, water, stabilizer, solubilizer, lipid, or for use in a pharmaceutical formulation. Other materials known in the art are included. It will be understood that the characteristics of the carrier will depend on the route of administration for the particular application.

As used herein, the term "pharmaceutically acceptable" refers to materials that do not interfere with the effectiveness of the immunomodulatory oligonucleotide and are compatible with biological systems such as cells, cell cultures, tissues, organs, or living organisms. . Preferably, the biological system is an organism such as a vertebrate.

Typically, the composition is a solution of the oligonucleotide in a liquid carrier.

Typically the carrier is water, preferably sterile water. Thus, typically the composition comprises an oligonucleotide as defined herein and water.

Preferably, the carrier is water and the oligonucleotide (in the form of a composition) is administered intracolonally, eg, as a rectal enema.

The concentration of oligonucleotide in a pharmaceutical composition will vary depending on several factors, including the dosage of oligonucleotide administered. Typical concentrations of oligonucleotides in compositions that are solutions are from 1 mg/ml to 20 mg/ml, preferably from 5 to 15 mg/ml, preferably from 8 mg/ml to 12 mg/ml, more preferably about 10 mg/ml. be.

Preferably, the invention provides cobitolimod for use in the treatment of ulcerative colitis, as defined herein, in a human subject, comprising an individual dose of cobitolimod of about 500 mg. Covitolimod is provided to the patient on only two separate occasions, with the separate occasions being three weeks apart.

Alternatively, the present invention provides cobitolimod for use in the treatment of ulcerative colitis, as defined herein, in a human subject, as defined herein, wherein an individual dose of cobitolimod of about 500 mg is administered. Covitolimod is administered to the patient on two or more separate occasions, three weeks apart, until the patient is in remission, typically as determined by an index 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, comprising: about 500 mg of cobitolimod individually. of covitolimod is administered to the patient on only two separate occasions, said separate occasions being three weeks apart, and the cobitolimod is administered in the form of a pharmaceutical composition comprising cobitolimod and water.

For example, the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, wherein an individual dose of cobitolimod of about 500 mg. is administered to the patient on two or more separate occasions, three weeks apart, to provide covitolimod administered intracolonally or rectally. Preferably, the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, comprising an individual dose of about 500 mg of cobitolimod. The doses are administered to the patient on two or more separate occasions, three weeks apart, providing covitolimod to be self-administered rectally by the subject. For example, the present invention provides cobitolimod for use in the treatment of chronic active ulcerative colitis, as defined herein, in a human subject, comprising: an individual dose of about 500 mg of cobitolimod; The dose will be administered to the patient on two or more separate occasions, three weeks apart, providing covitolimod to be self-administered by the subject via rectal enema.

More preferably, the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, comprising: about 500 mg of cobitolimod individually. of covitolimod administered intracolonally or rectally to the patient on only two separate occasions, the separate occasions being three weeks apart. For example, the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, wherein an individual dose of cobitolimod of about 500 mg. is administered to the patient on only two separate occasions, said separate occasions three weeks apart, providing covitolimod to be self-administered rectally by the subject. For example, the present invention provides cobitolimod for use in the treatment of chronic active ulcerative colitis, as defined herein, in a human subject, comprising: an individual dose of about 500 mg of cobitolimod; The dose is administered to the patient on only two separate occasions, three weeks apart, providing covitolimod to be self-administered by the subject via rectal enema.

More preferably, the present invention provides cobitolimod for use in the treatment of active ulcerative colitis, as defined herein, in a human subject, comprising: about 500 mg of cobitolimod individually. is administered to the patient on only two separate occasions, said separate occasions being three weeks apart, providing covitolimod administered intracolonally or rectally in the form of a pharmaceutical composition comprising covitolimod and water.

Even more preferably, the invention provides covitolimod for use in the treatment of chronic active ulcerative colitis, as defined herein, in a human subject, comprising: about 500 mg of cobitolimod. to the patient on only two separate occasions, said separate occasions being three weeks apart, providing covitolimod administered intracolonally or rectally in the form of a pharmaceutical composition comprising covitolimod and water. do.

The present invention also provides an oligonucleotide as defined herein for use in the treatment of an inflammatory bowel disease as defined herein in a human subject as defined herein. and an acceptable carrier as described above, wherein individual administrations of said composition are administered to a subject on at least two separate occasions three weeks apart, and each administration of said composition Pharmaceutical compositions are provided that deliver an amount of an oligonucleotide as defined herein.

Preferred characteristics of the oligonucleotide for use as defined above are also preferred characteristics of the composition for use.

The present invention relates to oligonucleotides as defined herein or oligonucleotides as defined herein in the manufacture of a medicament for use in the treatment of inflammatory bowel disease as defined herein in a human subject as defined herein. the use of a pharmaceutical composition as defined in the present invention, wherein the individual administrations of said oligonucleotide or composition are administered to a patient on at least two separate occasions, said separate occasions being three weeks apart; Also provided are uses where each administration of oligonucleotide or composition delivers an amount of oligonucleotide as defined herein.

Preferred features of the oligonucleotide for the use defined above are also preferred features of the use of the oligonucleotide or composition.

The present invention also provides for the administration of an oligonucleotide as defined herein or a composition as defined herein to a human subject as defined herein. A method of treating inflammatory bowel disease as defined, wherein individual administrations of said oligonucleotide or composition are administered to a patient on at least two separate occasions, said separate occasions being three weeks apart. , oligonucleotide or composition, each administration of which delivers an amount of oligonucleotide as defined herein.

The invention also provides a method of treating an inflammatory bowel disease, as defined herein, in a human subject, the method comprising:
(a) selecting a patient as defined herein; and (b) administering to said patient an oligonucleotide as defined herein or a composition as defined herein; Each administration of the composition is administered to the patient on at least two separate occasions, each separate occasion 3 weeks apart, and each administration of the oligonucleotide or composition is administered to the patient on at least two separate occasions, and each administration of the oligonucleotide or composition is administered to the patient on at least two separate occasions, each administration of the oligonucleotide or composition as defined herein. to deliver the amount of

Preferred features of the oligonucleotide for use as defined above are also preferred features of the claimed method.

Maintenance Therapy The present invention also provides an oligonucleotide for use in preventing recurrence of active ulcerative colitis in a patient, the oligonucleotide comprising the sequence 5'-GGAACAGTTCGTCCATGGC-3' (SEQ ID NO: 2). The oligonucleotide may be any oligonucleotide of SEQ ID NO: 2 described herein. Preferably, said oligonucleotide is cobitolimod.

Thus, the oligonucleotide may be for use as maintenance therapy. In the context of this aspect of the invention, references to preventing recurrence of active ulcerative colitis refer to preventing recurrence of the active phase of the disease, i.e. keeping the patient in remission and providing maintenance therapy. is intended to refer to. The present invention therefore relates to the use of an oligonucleotide as defined herein for preventing recurrence of or flare-up of the active phase of ulcerative colitis. The oligonucleotides described herein above can be used as maintenance therapy to prevent recurrence or flare-up of symptoms associated with active ulcerative colitis and/or to improve the condition of a patient.

The patient may be any patient or subject described herein. For example, the patient may be suffering from any type of ulcerative colitis described herein. Typically, the subject has been diagnosed with left-sided ulcerative colitis, ie, distal colitis, including rectosigmoiditis.

Typically, the patient has previously received treatment for active ulcerative colitis, e.g., even though the patient has previously received one or more therapeutic agents for the treatment of active ulcerative colitis. good. The one or more therapeutic agents may include the oligonucleotide of SEQ ID NO: 2 described herein. Accordingly, a patient has received an oligonucleotide as described herein, wherein individual doses of 400 mg to 600 mg of said oligonucleotide are administered to the subject on at least two separate occasions; The separate occasions are 3 weeks apart to bring the patient into remission (ie, to treat active ulcerative colitis). The one or more therapeutic agents may include any other therapeutic agents used to treat ulcerative colitis, as described herein.

Typically, individual doses of the oligonucleotide are administered to the patient periodically between those individual doses. The intervals between individual doses may be from 1 week to 12 months, for example, the intervals between individual doses may be 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 6 month or 12 months. Preferably, the interval between individual doses is 3 weeks.

Individual doses are from 10 mg to 600 mg of said oligonucleotide. For example, an individual dose may be 150 mg to 350 mg of said oligonucleotide. For example, an individual dose may be about 250 mg of said oligonucleotide. The individual dose may be 350 to 600 mg of said oligonucleotide, preferably 400 to 600 mg of said oligonucleotide. For example, individual doses may be 425 mg to 575 mg, 450 mg to 550 mg, 460 to 540, 470 to 530, 480 to 520, preferably 490 to 510, more preferably 495 to 505, even more preferably 499 to It may be 501 mg. Typically, an individual dose will be about 500 mg of said oligonucleotide.

Repeated administration of the oligonucleotide over a longer period of time may be necessary to maintain the patient in remission. The above dosing regimen, ie, administering individual doses of the oligonucleotide to the patient at regular intervals, is continued over a period of time to provide continuous maintenance therapy. Considering that ulcerative colitis is a chronic condition that cannot be cured, this means that, in practice, patients are generally treated for long periods of time, typically at least 6 months, preferably at least 1 or 2 years, e.g. means following the plan described herein for 5 or 10 years. In fact, some patients may need to be administered the regimens described herein for as long as necessary (eg, as determined by a physician) or indefinitely. Thus, a patient may be administered individual doses periodically for at least 6 months, preferably for at least 1 or 2 years, more preferably for at least 5 or 10 years, or indefinitely.

The patient may receive multiple doses of said oligonucleotide on a regular basis, where the individual doses of said oligonucleotide are between 150 and 350 m, and the intervals between those individual doses are 1 week, 2 weeks, 3 weeks. Or 4 weeks. Accordingly, in a preferred embodiment of the invention, the patient receives multiple doses of said oligonucleotide on a regular basis, each dose of said oligonucleotide being about 250 mg, and the interval between the individual doses being 3 weeks. These plans typically last for at least 6 months, preferably at least 1 or 2 years, such as at least 5 or 10 years, or indefinitely.

The patient may receive multiple doses of said oligonucleotide on a regular basis, where the individual doses of said oligonucleotide are between 400 and 600 mg, and the intervals between those individual doses are 1 week, 2 weeks, 3 weeks. or 4 weeks, but 3 weeks is preferred. In another preferred embodiment of the invention, the patient receives multiple doses of said oligonucleotide on a regular basis, each dose of said oligonucleotide being about 500 mg, and the interval between the individual doses being 3 weeks. These plans typically last for at least 6 months, preferably at least 1 or 2 years, such as at least 5 or 10 years, or indefinitely.

In the above dosing regimen, individual doses (in amounts as defined herein) of said oligonucleotide are administered to a patient on multiple occasions spaced over a specified number of weeks. This means that the patient will not receive additional oligonucleotides during certain doses/administrations separated by a certain period of time.

The oligonucleotide may be for use as a monotherapy. Alternatively, the patient may receive one or more additional therapeutic agents to prevent recurrence of active ulcerative colitis. The additional therapeutic agent can be any therapeutic agent described herein used to treat ulcerative colitis. For example, a patient may receive one or more additional anti-inflammatory agents to prevent recurrence of active ulcerative colitis. Therefore, oligonucleotides can be used as anti-inflammatory agents, immunomodulators, anti-integrin therapeutics, TNF-α inhibitors, immunosuppressants, JAK inhibitors or other drugs suitable for the treatment of ulcerative colitis or ulcerative colitis. may be administered in combination with one or more additional therapeutic agents for the prevention of recurrence of active ulcerative colitis selected from other agents suitable for the treatment of ulcerative colitis. Examples of such agents suitable for use in combination with the oligonucleotides include, but are not limited to, aminosalicylic acid (5-ASA [also known as mesalamine], sulfasalazine, olsalazine and balsalazide), GCS (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 ), natural IFN-β, decortin, tofacitinib (XELJANZ®), etrolizumab, ozanimod, SHP647, filgotinib, mirikizumab, apremilast (OTEZLA®), estrasimod, AJM300, upadacitinib, risankizumab, BI655130, Includes PF-06700841, PF-06651600 and IMU-83 and their equivalents.

For purposes of the present invention, the terms "in combination with" and "add-on" refer to the process of treating the same disease in the same patient, including simultaneous administration of the oligonucleotide and one or more additional therapeutic agents, and several This includes administration in any order, such as separated in time by up to a month.

Oligonucleotides may be administered via any route of administration described herein. Typically, the oligonucleotide is administered locally, such as by topical administration to a mucosa. Typically, the oligonucleotide is administered intracolonically. Intracolonic administration typically occurs rectally. Intracolonic administration is typically performed using an enema or catheter. Intracolonic administration preferably includes administration by enema (ie, by rectal enema). Typically, oligonucleotides administered by rectal enema, preferably oligonucleotides, are self-administered by rectal enema.

Preferably, for this aspect of the invention, the subject has not undergone colon cleansing prior to said administration.

The following non-limiting examples illustrate the invention.

Reference example 1: Clinical trial results showing optimal dosing frequency In a randomized, double-blind, placebo-controlled study, 131 patients with moderately to severely active ulcerative colitis were evaluated at baseline and at 4 weeks. Patients were randomized to receive two single doses of covitolimod/Kappaproct (30 mg) or placebo administered topically during GI endoscopy.

Patients in the treatment and placebo groups were assessed for weekly peak blood volume in stool (none, small amount, large amount), weekly number of bowel movements (less than 18, 18-35, 36-60, 61 or more). , and the number of daily defecation (less than 1, 1 to 1.99 times, 2 to 2.99 times, 3 to 3.99 times, 4 to 4.99 times, 5 to 5.99 times, 6 to 6 .99 times, 7 to 7.99 times, 8 times or more) were monitored for 12 weeks using an electronic diary (e-diary).

The results were aggregated and the treatment delta between the treatment group and the placebo group was calculated. These results show that there is a particularly high therapeutic difference 3 weeks after the first dose.

The results for the treatment and placebo groups are shown in the figure below.

Figure 1 shows the weekly percentage of treatment and placebo groups reporting bloody stools = zero (maximum of 7-day patient-reported results).

Figure 2 shows the weekly percentage of treatment and placebo groups reporting less than 18 bowel movements per week (7-day total patient-reported results).

Figure 3 shows the weekly percentage of treatment and placebo groups reporting less than 35 bowel movements per week (7-day total patient-reported results).

Figure 4 shows the weekly percentage of treatment and placebo groups reporting fewer than 3 bowel movements per day (7-day daily average of patient-reported results).

Figure 5 shows the weekly percentage of treatment and placebo groups reporting fewer than 4 bowel movements per day (7-day daily average of patient-reported results).

Figure 6 shows the weekly percentage of treatment and placebo groups reporting fewer than 5 bowel movements per day (average of daily 7-day patient-reported results).

The treatment differences for the various clinical outcomes evaluated in this study are shown in the table below.

Reference Example 2 - Clinical Trial Study A randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of topical cobitolimod in patients with moderately to severely active ulcerative colitis according to established methods.

Methods: Men and women will be selected for the study according to standard inclusion criteria in the field, including:

1. Male or female aged 18 years or older 2. Confirmed diagnosis of UC, at least 3 months after diagnosis 3. Modified Mayo Score (excluding frailty in grade 1 of the endoscopy subscore) 6 to 12, assessed by central interpretation of endoscopy performed at Screening Visit 1b (Days -7 to -10 - Screening Visit) Moderately to severely active left-sided UC (disease does not extend beyond the splenic flexure >15 cm from the anal verge, as determined by endoscopic subscore 2 or higher, and no other individual subscores lower than 1). spread over a range)
4. Current oral 5-ASA/SP use or history of oral 5-ASA/SP use5. Current GCS use or history of GCS dependence, resistance, or intolerance, including discontinuation of GCS treatment due to early side effects (only one of the GCS criteria needs to be met; European Crohn's and Colitis Organization (ECCO) )See definition in guidelines)
6. Inadequate response, loss of response, or presentation of intolerance to at least one of the following drugs:
● Immunomodulatory drugs, e.g., cyclosporine, methotrexate, AZA/6-MP, tacrolimus o At least one 8-week regimen of, e.g., oral AZA (1.5 mg/kg or more) or 6-MP (0.75 mg/kg or more) or signs and symptoms of persistent active disease despite previous treatment with low doses or thiopurine methyltransferase (TPMT) deficiency prompted by intolerance, or o For example, prior treatment with at least one immunomodulatory drug intolerance (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, lymphopenia, TPMT gene mutations, infections)
● TNF-α inhibitor and/or anti-integrin:
○For example:
■ Infliximab 5 mg/kg (intravenous (IV)) or ■ Golimumab 200/100 mg (subcutaneous (SC)) or ■ Adalimumab 160/80 mg (SC) or ■ Vedolizumab 300 mg (IV)
signs and symptoms of persistently active disease despite previous treatment with at least one induction regimen at two doses at least two weeks apart (or the dose recommended according to current labeling); or o intolerance. History (including but not limited to infusion-related reactions, demyelination, congestive heart failure, infections)
Recurrence of symptoms during maintenance medication with any of the above agents following previous clinical benefit (secondary failure) [discontinuation is not eligible despite clinical benefit]
7. Allowed administration of therapeutic doses of the following UC drugs during the study:
a) Oral GCS therapy (prednisone 20 mg or less or equivalent/day) if dose is stable for 2 weeks (day -14) before Visit 1a b) Oral MMX budesonide therapy (9 mg/day) at least 8 days before Visit 1a c) Oral 5-ASA/SP compound started at least 8 weeks before Visit 1a, provided the dose has been stable for 2 weeks before Visit 1a and started at least 8 weeks before Visit 1a d) AZA/6- MP, provided the dose has been stable for 8 weeks before Visit 1b and started at least 3 months before Visit 1a8. Ability to understand treatment, willingness to comply with all study requirements, and ability to provide informed consent

Patients may be excluded from the study according to exclusion criteria known in the field, including:

1. Suspected differential diagnosis: Crohn's colitis, ischemic colitis, radiation colitis, indeterminate colitis, infectious colitis, diverticular disease, associated colitis, microscopic colitis, giant pseudopolyposis or nontransmissible colitis. Sexual stenosis 2. Acute fulminant UC and/or signs of systemic toxicity3. UC limited to the rectum (disease extending less than 15 cm from the anal verge)
4. History of malignancy excluding:
- Treated (cured) basal cell or squamous carcinoma in situ - Treated (cured) cervical intraepithelial neoplasia or carcinoma in situ without evidence of recurrence within 5 years before Screening Visit 1a.5. 6. History or presence of clinically significant disorders that, in the investigator's opinion, affect the patient's likelihood of complying with the protocol and protocol procedures, or confound study results, or compromise patient safety.6. Concomitant treatment with cyclosporine, methotrexate, tacrolimus, TNF-α inhibitors, anti-integrin or similar immunosuppressants and immunomodulators at enrollment. 7. Previous treatment with such drug must have been discontinued at least 8 weeks before Visit 1a or have unmeasurable serum concentration levels. Treatment with rectal GCS, 5-ASA/SP or tacrolimus within 2 weeks before Visit 1b8. Long-term treatment with antibiotics or nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks of Visit 1a (one short-term treatment regimen for occasional use of antibiotics and NSAIDs is allowed)
9. Severe active infection 10. Gastrointestinal infections such as a positive Clostridium difficile stool test 11. 12. Currently receiving parenteral nutrition or blood transfusion. 13. Women who are breastfeeding or who have a positive serum pregnancy test during the screening period. Women of childbearing potential who do not use reliable methods of contraception during the study period (reliable methods include barrier protection, hormonal contraception, intrauterine devices, or abstinence)
14. 15. Concurrent participation in another clinical study with the investigational therapy or prior use of the investigational therapy within 5 half-lives and at least 30 days of the last treatment of the experimental product prior to enrollment. Previous exposure to cobitolimod

Patients selected for the trial will be randomized to a treatment sequence containing covitolimod or placebo according to the study arm set out below. Cobitolimod or placebo was administered locally to the colon via a rectal enema suitable for self-administration. Unlike the COLLECT study, no special steps were taken to ensure that the colon was clean prior to enema administration.

Research arm:
- two covitolimod 31 mg doses at weeks 0 and 3 (placebo at weeks 1 and 2);
- two cobitolimod 125 mg doses at weeks 0 and 3 (placebo at weeks 1 and 2);
- two 250 mg doses of covitolimod at weeks 0 and 3 (placebo at weeks 1 and 2);
- 4 doses of covitolimod 125 mg at weeks 0, 1, 2, and 3.

The primary endpoints were set as follows:
- The following three criteria are met: i) 0 rectal bleeding, ii) stool frequency 0 or 1 (at least 1 point decrease from baseline), iii) endoscopy score 0 or 1 (excluding frailty) Proportion of patients showing clinical remission at week 6, as defined by the modified Mayo subscore.

Secondary endpoints are as follows:
Percentage of patients who induced symptomatic remission at week 4 or 6 as defined by Mayo subscore i) 0 rectal bleeding, ii) bowel movements 0 or 1 (at least 1 point decrease from baseline) 4 or Proportion of patients without rectal bleeding as defined by a Mayo subscore of 0 rectal bleeding at week 6; Mayo subscore defecation as defined by a Mayo subscore of 0 or 1 bowel movements at week 4 or 6 (at least 1 point decrease from baseline) Proportion of patients with normal or improved endoscopic remission at week 6 as defined by a modified Mayo endoscopic subscore of 0 or 1 Clinical remission at week 6 or 3 and 30 points from baseline Proportion of patients with a clinical response defined as a reduction of % or more; Proportion of patients with histologic remission as defined by the Nancy Histological Index score at week 6; Nancy Histologic Index score at week 6 Proportion of patients with histological response defined by - Proportion of patients with decreased defecation urgency score - Mean fecal calprotectin at weeks 1, 2, 3 and 6 compared to week 0 Amount of change/Average change in each subdomain of the Inflammatory Bowel Disease Questionnaire (IBDQ) at week 6 compared to week 0

result

Conclusions In patients with moderate to severe ulcerative colitis, treatment with cobitolimod 250 mg in two doses 3 weeks apart results in a higher rate of clinical remission at week 6 compared to placebo. reach. Additionally, the proportion of patients in remission at week 6 for patients receiving two doses of covitolimod 250 mg was higher than the proportion of patients in remission for the other dosing regimens (2 x 31 mg, 2 x 125 mg, and 4 x 125 mg). Ta. Notably, the proportion of patients in remission who received two doses of cobitolimod 250 mg was higher than the proportion of patients in remission who received four doses of cobitolimod 125 mg. This is a surprising result in demonstrating that administering the same total amount of active ingredient at higher doses and less frequently provides improved clinical results.

The results also surprisingly demonstrated that clinical efficacy can be obtained without removing fecal material from the colon and/or colonic epithelial cells. Furthermore, clinical efficacy can be achieved by administration from an enema device suitable for self-administration.

Example 1
In addition to the 2x250mg dose, this study will also evaluate the 2x500mg dose. Covitolimod is administered rectally via a prefilled enema that places the drug in intimate contact with many of the desired target cells.

Potential Risks and Benefits Covitolimod is being studied in patients with refractory UC when administered rectally. The therapeutic target group is patients with chronic active left-sided UC who have not had a satisfactory response to previous treatment with conventional drugs. Results of clinical studies showed that cobitolimod was able to induce remission in these patients.

Nonclinical safety studies in rodents and cynomolgus monkeys show that cobitolimod is well tolerated and no evidence of systemic or local toxicity was found. Safety evaluations of five placebo-controlled trials with covitolimod have shown no significant toxicity. Covitolimod is easy to administer and compliance has been reported to be excellent. Overall, covitolimod was well tolerated.

Comprehensive data on covitolimod, and extensive clinical experience with similar oligonucleotides, therefore support a positive benefit-risk assessment when administered according to the proposed protocol for patients with moderately to severely active left-sided UC. support. More detailed information about the known and expected benefits and risks of covitolimod, as well as reasonably expected adverse events, can be found in the researcher's brochure.

Study Objectives Primary Objective Induction Study To assess the efficacy of cobitolimod treatment compared to placebo in inducing clinical remission in participants with moderately to severely active left-sided ulcerative colitis (UC).

Secondary objective lead-in study - To explore the most effective and clinically relevant dose and safety balance of cobitolimod 250 mg and cobitolimod 500 mg versus placebo - To assess the safety and tolerability of cobitolimod - To assess clinical symptoms and To assess the effectiveness of cobitolimod treatment in endoscopic improvement; To assess the effectiveness of cobitolimod treatment compared to placebo in other endpoints; To assess health-related quality of life (QOL) and health economics.

Induction Study The induction study will target participants with moderately to severely active left-sided UC who do not respond adequately to or cannot tolerate conventional or biologic treatments. The study consists of two parts (1a and 1b), the purpose of the first part is to explore the clinically relevant and most effective dose between covitolimod 250mg and 500mg and placebo.

After a sufficient number of participants (~150) have been randomized and eligible data for the primary endpoint is available, an interim analysis will be conducted to assess the "winning" dose. After determining which dose is most effective, the winning dose will be used to randomize the remaining participants. Participants who received the "losing" dose will be included in the overall safety assessment.

In the initial induction study, 450 eligible participants will be randomly assigned in a 1:1:1 ratio to receive a rectal dose of either cobitolimod 250 mg or 500 mg or a placebo. Patients with active left-sided UC who are at least 18 years of age, triad Mayo score 5-9, endoscopic subscore ≥2, and no other individual subscore <1 are eligible for enrollment.

Randomization in the two induction studies will be stratified by the following participant categories: concomitant glucocorticosteroid (GCS) treatment (with/without) and biologics (infliximab, adalimumab, Previous treatment (with or without golimumab, vedolizumab, ustekinumab) and a JAK inhibitor (tofacitinib).

The study treatment will be administered rectally using an enema.

There will be two screening visits in the implementation study. At the first screening visit 1a, obtain written informed consent before performing any other study procedures. Participants will be assigned a participant identification number and the registration process will begin. At the second screening visit 1b, a complete colonoscopy will be performed. Induction study visits will be conducted on day -14, days -5-7, and weeks 0, 3, and 6. If participants continue to self-administer post-induction studies, they will self-administer the study drug in the clinic under the supervision of study staff to ensure participants are properly administering the study drug.

All UC-specific medical treatments, including GCS, 5-ASA, and AZA/6-MP, must be maintained at stable doses until the end of the induction study (week 6).

Research Evaluation Criteria Mayo's subscores, such as blood in stool and frequency of defecation, are derived using electronic diary data.

Implementation Studies 1 and 2 - Primary Efficacy Endpoints Implementation Studies 1 and 2
Proportion of participants with clinical remission at week 6 (three-component Mayo score, i) rectal bleeding 0, ii) bowel movements 0 or 1 (at least 1 point decrease from baseline (week 0)), and iii) defined by endoscopic score 0 or 1)

Main secondary endpoints Introduction studies 1 and 2
・Percentage of participants showing endoscopic improvement at week 6 ・Percentage of participants showing symptomatic remission at week 6

Secondary endpoint introduction 1 and 2
・Percentage of participants showing clinical response at week 6 ・Percentage of participants showing histological improvement at week 6 ・Participants showing normal bowel movements or a decrease of 1 point or more from baseline at week 6・Proportion of participants without rectal bleeding at week 6 ・Proportion of participants showing combined endoscopic and histological improvement at week 6 ・Comparison with baseline (week 0)・Percentage of participants showing improvement in urgency at 6 weeks ・Inflammatory Bowel Disease Questionnaire (IBDQ) at 6 weeks compared to baseline (week 0) Average change in total score - Average change in ln-converted fecal calprotectin at week 6 compared to baseline (week 0)

Exploratory endpoint introduction 1 and 2
・Percentage of participants with fecal calprotectin levels below 250 mg/kg at 6 weeks ・Percentage of participants with CRP below 5 mg/L at 6 weeks ・Endoscopic screening at 6 weeks Proportion of participants who showed remission - Proportion of participants who showed histological response at 6 weeks - Proportion of participants who showed histological response at week 6
・Proportion of participants who showed a combination of endoscopic and histological remission at 6 weeks ・Participants who showed clinical remission at 6 weeks based on the 4-component Mayo score percentage of people
・Proportion of participants who demonstrated a clinical response at week 6 based on the four-factor Mayo score ・Proportion of participants whose total Inflammatory Bowel Disease Questionnaire (IBDQ) score exceeded the threshold of 170 at week 6 Proportion of participants whose Inflammatory Bowel Disease Questionnaire (IBDQ) total score at week 6 increased by more than 16 points compared to baseline (week 0) - Symptomatic remission at weeks 2 and 4 Percentage of participants who showed ・IBDQ subscore ・EQ-5D-5L
・Average change in ln-converted CRP value at week 6 compared to baseline (week 0)

Safety, adverse event (AE) incidence, serious adverse event (SAE) incidence, vital signs, physical examination, laboratory findings

Study Population All relevant medical and non-medical conditions should be considered when determining whether a particular participant is suitable to participate in this study. Participant eligibility should be reviewed and documented by an appropriately qualified member of the researcher's research team prior to participation in the study. Endoscopic eligibility and PRO2 criteria eligibility will be centrally approved and communicated to investigators before final randomization takes place. If a participant does not meet the inclusion/exclusion criteria, the participant may be considered for re-screening at a later date if eligible.

Inclusion criteria introduction studies 1 and 2
Participants must meet all of the following inclusion criteria to be randomized in the study:
1. Male or female aged 18 years or older 2. Definitive diagnosis of UC, minimum time from diagnosis at least 3 months before visit 1a 3.3-factor Mayo score 5 to 9 (endoscopy subscore 2 or higher assessed by central interpretation of endoscopy (S moderately to severely active left-sided UC (disease is defined as 15 cm or more from the anal verge, splenic curvature, )
4. Has failed or is not tolerated by at least one of the following treatments:
a. Oral corticosteroid drugs b. Azathioprine or 6-mercaptopurine (6-MP)
c. Anti-TNF therapy: infliximab or adalimumab5. You will be allowed to receive therapeutic doses of the following UC drugs during the study:
a. Oral GCS therapy (less than 20 mg prednisone or equivalent/day) if dose is stable for 2 weeks before Visit 1b.b. Oral MMX budesonide therapy (9 mg/day), initiated at least 8 weeks before Visit 1b c. Oral 5-ASA/SP compound, provided the dose has been stable for 2 weeks prior to Visit 1a and started at least 8 weeks prior to Visit 1b d. AZA/6-MP, provided the dose has been stable for 8 weeks before Visit 1b and started at least 3 months before Visit 1b6. Ability to understand treatment, willingness to comply with all study requirements, and ability to provide informed consent

Exclusion Criteria Participants who exhibit any of the following should not be randomized in the study:
1. Suspected differential diagnosis such as Crohn's enteritis, ischemic colitis, radiation colitis, indeterminate colitis, infectious colitis, diverticular disease, associated colitis, microscopic colitis, giant pseudopolyposis or non-passing stricture 2 ．． Acute fulminant UC, signs of toxic megacolon and/or systemic toxicity3. UC limited to the rectum (disease extending less than 15 cm from the anal verge)
4. Ineffective treatment with more than three advanced treatments (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab or tofacitinib) in two different classes of drugs (anti-TNF, anti-integrin, anti-IL12/23 or JAK inhibitors) Yes 5. 6. Have had surgery for UC treatment. History of malignancy excluding:
- Treated (cured) basal cell or squamous intraepithelial carcinoma - Treated (cured) for more than 5 years since last treatment 7. History or presence of clinically significant disorders that, in the investigator's opinion, affect the participant's likelihood of complying with the protocol and protocol procedures or that would confound the study results or compromise patient safety. 8. Concomitant treatment with cyclosporine, methotrexate, tacrolimus, modern/targeted therapies (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib) or similar immunosuppressive and immunomodulatory agents at enrollment.
Previous treatment with such agents must have been discontinued at least 12 weeks prior to Visit 1b or have unmeasurable serum concentration levels.
Treatment with rectal GCS, 5-ASA/SP or tacrolimus within 2 weeks before Visit 1b9. Long-term treatment with antibiotics or nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks before Visit 1b (occasional use of antibiotics and NSAIDs and one short-term treatment regimen for low-dose NSAIDs as prophylactic therapy are not allowed) )
10. Severe active infection (history of latent or active tuberculosis, documented history of past or current tuberculosis, participants living with or having frequent close contact with active tuberculosis patients, or prior to randomization) Those who have had a positive tuberculosis test in accordance with current regulations during a 12-week period (including chronic human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection)
11. Gastrointestinal infections such as a positive Clostridium difficile stool test 12. 13. Women who are breastfeeding or who have a positive serum pregnancy test during the screening period. Women of childbearing potential who do not use highly effective (less than 1% failure rate) contraceptive methods during the study period.
14. 15. Concurrent participation in another clinical study with the investigational therapy or prior use of the investigational therapy within 5 half-lives and at least 30 days of the last treatment of the experimental product prior to enrollment. Previous exposure to cobitolimod

Randomization and Stratification Participants in Implementation Study 1 will initially be randomized to one of three treatment arms in a 1:1:1 ratio. After interim analysis and selection of a "winning" dose, randomization will occur in a 1:1 ratio. Randomization will be stratified by the following factors: concomitant GCS therapy (with/without) and by “modern”/targeted therapies (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab) and JAK inhibitors (tofacitinib). Previous treatment (yes/no). A computer-generated randomization schedule will be used to assign participants to treatment order. Treatment assignments are obtained through an interactive voice response system (IVRS). Information regarding treatment assignments will be kept securely.

Concomitant Medications All medications prescribed to participants and taken during the study must be recorded on the eCRF. Any changes must be reported to the eCRF.

The following concomitant UC drugs are allowed:
- Oral GCS therapy (≤20 mg prednisone or equivalent/day), if dose is stable for 2 weeks before Visit 1b and needs to remain stable until the primary endpoint (week 6) - Oral MMX budesonide Therapy (9 mg/day) should be started at least 8 weeks before Screening Visit 1b and remain stable until the primary endpoint (Week 6). If the participant is in remission, tapering should begin after the 6th week visit, see recommended tapering scheme below.
- Oral 5-ASA and/or SP compounds, provided the dose is stable for 2 weeks before Visit 1b and started at least 8 weeks before Visit 1b. Stable dose until end of study (Week 54).
- AZA/6-MP, provided the dose is stable for 8 weeks before Visit 1b and started at least 3 months before Visit 1a. Stable dose until end of study (Week 54).

Prohibited drugsDuring the study period, the following concomitant drugs are prohibited:
- Cyclosporine, methotrexate, tacrolimus or similar immunosuppressants/immunomodulators.
- Biologics such as infliximab, adalimumab, golimumab, vedolizumab and ustekinumab
・JAK inhibitor ・Anti-IL23
Prior treatment with these agents must have been discontinued at least 8 weeks before Visit 1b or serum concentration levels must be unmeasurable.

Example 2 - Dextran Sodium Sulfate (DSS) Induced Colitis Mouse Model Materials and Methods
Mice : Balb/c mice were obtained from Charles River Laboratories, Research Models and Services (Sulzfeld, Germany). Eight-week-old female Balb/c mice were used in the experiments and housed in individually ventilated cages according to the Animal Welfare Act. Water and food were provided ad libitum.

DSS-induced colitis : 2% or 3% (w/v) dextran sodium sulfate (DSS) is administered in the drinking water of 8-week-old female Balb/c mice for 10 days. An additional control group of completely untreated mice was also part of the experimental setup. Monitor food intake and weight.

Rectal administration of cobitolimod : 1000 μg, 2000 μg or 4000 μg of cobitolimod per mouse was administered rectally twice (on days 4 and 8). A dose of 1000 μg in mice is approximately equivalent to a dose of 250 mg in humans (see Guidance for Industry - Estimating the Maximum Safe Starting Dose for Early Clinical Trials of Therapeutics in Adult Healthy Volunteers). Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Health Volunteers, July 2005, US Department of Health and Human Services Food and Drug Administration Center. for Drug Evaluation and Research). The results observed in this mouse model can be considered predictive of the effects observed in humans receiving individual doses of covitolimod of 250 mg, 500 mg and 1000 mg on two separate occasions 3 weeks apart. .

Vehicle without cobitolimod was applied rectally to a control group of mice (placebo). To ensure comparable experimental conditions, mice from different treatment groups were randomly mixed per cage before starting the experiment.

Details for each study arm are provided below:
Vehicle/DSS 2%
Vehicle/DSS 3%
Cobitolimod A /DSS 2%
Cobitolimod A /DSS 3%
Cobitolimod B/DSS 2%
Cobitolimod B/DSS 3%
Cobitolimod C /DSS 2%
Cobitolimod C /DSS 3%
Covitolimod C/ Dose without DSS A= 1000 μg (equivalent to 250 mg human)
Dose B= 2000 μg (equivalent to 500 mg human)
Dose C= 4000 μg (equivalent to 1000 mg human)

Evaluation of DSS-induced colitis: The following parameters are monitored during the experiment:
1) Disease Activity Index (DAI) score/global score = total score of weight loss, stool consistency and bloody stool, (days 0, 2, 4, 6, 7, 8, 9 and 10) (disease activity The index (DAI) is the sum score of weight loss compared to initial weight, stool consistency, and visible blood in the stool (maximum score per mouse is 12)
2) Clinical behavior scoring (days 0, 2, 4, 6, 7, 8, 9 and 10)
3) Body temperature measurement (twice)

Claims (25)

An oligonucleotide for use in the treatment of inflammatory bowel disease in a human subject, comprising the sequence 5'-GGAACAGTTCGTCCATGGC-3' (SEQ ID NO: 2), comprising at least an individual dose of 400 mg to 600 mg of said oligonucleotide. An oligonucleotide administered to a subject on two separate occasions, said separate occasions three weeks apart. Oligonucleotide for use according to claim 1, wherein said inflammatory bowel disease is ulcerative colitis. Oligonucleotide for use according to claim 2, wherein the ulcerative colitis is active ulcerative colitis. Oligonucleotide for use according to claim 2 or 3, wherein the ulcerative colitis is chronic active ulcerative colitis. The use according to any of the preceding claims, wherein the subject is resistant to, poorly responsive to, or intolerant of anti-inflammatory therapy, and optionally said subject is elective for colectomy. Oligonucleotides for. Oligonucleotide for use according to any of the preceding claims, wherein at least one CG dinucleotide is unmethylated. Oligonucleotide for use according to any of the preceding claims, wherein at least one nucleotide in the oligonucleotide comprises a backbone modification. 8. Oligonucleotide for use according to claim 7, wherein the backbone modification is a phosphate backbone modification represented by a phosphorothioate or phosphorodithioate modification. Oligonucleotide for use according to any of claims 7 and 8, wherein the backbone modification is located at the 5'- and/or 3'-end of the oligonucleotide. Oligonucleotide for use according to any of the preceding claims, wherein said oligonucleotide has the sequence 5'-GGAACAGTTCGTCCATGGC-3' (SEQ ID NO: 2) and the CG dinucleotide is unmethylated. Any of the preceding claims, wherein the oligonucleotide has the sequence 5'-G ^* G ^* A ^* ACAGTTCGTCCAT ^* G ^* G ^* C-3' (SEQ ID NO: 1), and the CG dinucleotide is unmethylated. Oligonucleotides for use as described in. Oligonucleotide for use according to any of the preceding claims, wherein said oligonucleotide is cobitolimod. Oligonucleotide for use according to any of the preceding claims, wherein individual doses of 490 mg to 510 mg of said oligonucleotide are administered. Oligonucleotide for use according to any of the preceding claims, wherein individual doses of about 500 mg of said oligonucleotide are administered. An oligonucleotide for use according to any of the preceding claims, wherein the individual doses of the oligonucleotide are administered to a subject on only two separate occasions, three weeks apart. 15. An oligonucleotide for use according to any of claims 1 to 14, wherein individual doses of said oligonucleotide are administered to a subject on two or more separate occasions three weeks apart until the subject is in remission. nucleotide. Oligonucleotide for use according to any of the preceding claims, wherein the subject receives one or more additional therapeutic agents for the treatment of inflammatory bowel disease, typically ulcerative colitis. Oligonucleotide for use according to any of the preceding claims, wherein said oligonucleotide is administered topically to the mucosa. Oligonucleotide for use according to any of the preceding claims, wherein said oligonucleotide is administered rectally. Oligonucleotide for use according to any of the preceding claims, wherein the subject has not undergone colon cleansing prior to said administration. Oligonucleotide for use according to any one of claims 18 to 20, wherein said local administration is carried out via an enema suitable for self-administration by a subject. Oligonucleotide for use according to any of the preceding claims, wherein the subject has not undergone colonic irrigation 48 hours before treatment with the oligonucleotide, preferably 24 hours before treatment with the oligonucleotide. An oligonucleotide for use according to any of the preceding claims, wherein the oligonucleotide is cobitolimod and individual doses of about 500 mg of cobitolimod are administered to a subject on only two separate occasions three weeks apart. nucleotide. A human subject as defined in any of claims 1, 5, 17, 20 and 22 comprising an oligonucleotide as defined in any of claims 1 and 6-12 together with one or more pharmaceutically acceptable carriers. A pharmaceutical composition for use in the treatment of inflammatory bowel disease as defined in any of claims 1 to 4 in a subject, comprising administering individual administrations of said composition to a subject on at least two separate occasions. 24. A composition, wherein the separate occasions are three weeks apart, each administration of the composition delivering an amount of oligonucleotide as defined in any of claims 1, 13, 14 and 23. A method of treating inflammatory bowel disease as defined in any of claims 1 to 4 in a human subject as defined in any of claims 1, 5, 17, 20 and 22, comprising: -12 or a composition as defined in claim 24 to said subject, wherein said individual administrations of said oligonucleotide or composition are administered to said patient on at least two separate occasions. , wherein said separate occasions are three weeks apart, and each administration of oligonucleotide or composition delivers an amount of oligonucleotide as defined in any of claims 1, 13, 14 and 23.