Clinical Study of the Efficacy, Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of BCD-261 in Subjects With Moderate to Severe Active Crohn's Disease

A Randomized Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of BCD-261 in Subjects With Moderate to Severe Active Crohn's Disease

The aim of the study is to evaluate the efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of study drug (BCD-261) in comparison with placebo and to characterize the dose-response relationship in patients with moderate to severe active Crohn's Disease. The study will be conducted in a population of male and female subjects ≥18 years and ≤75 years with moderate to severe active Crohn's Disease and an inadequate response to prior treatment with glucocorticoids, immunosuppressants, or biologics/targeted immunosuppressants.

Subjects meeting the eligibility criteria will be randomized in 5 groups to receive one of four studied dosage regimens of BCD-261 or placebo. The study groups will differ in drug dosages of BCD-261 (low, medium, high) during the induction and maintenance periods of therapy. After the primary endpoint assessment subjects in placebo group will be switched to BCD-261 medium studied dose.

Inclusion Criteria:

1. The diagnosis of Crohn's disease involving the terminal ileum or colon (types L1-L3 according to the Montreal classification), established ≥3 months prior to signing the informed consent form and confirmed by endoscopic findings.
2. Moderate to severe active Crohn's disease, manifested by the following signs:

(1) Crohn's Disease Activity Index (CDAI) ≥220 and ≤450 points.

(2) Simple Endoscopic Score for Crohn's Disease (SES-CD) ≥6 points or ≥4 points for the disease form with isolated involvement of the ileum (according to central independent review).

3. Inadequate response to therapy according to the investigator's assessment, manifested by at least one of the following signs:

1. Persistent symptoms of disease activity despite treatment with at least one course of glucocorticoids including prednisolone at a dose of ≥40 mg/day or equivalent or budesonide ≥9 mg/day or equivalent for at least 2 weeks with oral administration (at least 1 week with intravenous administration at a dose equivalent to oral prednisolone ≥40 mg/day).
2. Steroid dependence manifested by an increase in disease activity after initial improvement, with a decrease in the dose of glucocorticoids below the dose equivalent to 10 mg of oral prednisolone per day, within 3 months from the beginning of treatment, or a relapse of the disease within 3 months after the end of glucocorticoid use.
3. Persistent symptoms of disease activity despite treatment with at least one course of immunosuppressants (azathioprine at a dose of ≥2.0 mg/kg and/or 6-mercaptopurine at a dose of ≥1.0 mg/kg and/or methotrexate at a dose of ≥15.0 mg/week) for ≥12 weeks, or in response to another treatment regimen with these drugs according to a regional standard of care.
4. Primary lack of response to therapy with TNFa inhibitors and/or anti-integrins, and/or IL-12/23 inhibitors, and/or targeted immunosuppressors (upadacitinib), defined as the persistence of symptoms of disease activity despite at least one course of induction of remission according to a treatment scheme approved by the regional standard.
5. Loss of response to therapy with TNFa inhibitors and/or anti-integrins, and/or IL-12/23 inhibitors, and/or targeted immunosuppressors (upadacitinib), defined as the appearance of symptoms of disease activity after initial improvement as a result of treatment with at least one course of induction of remission and at least one course of maintenance of remission according to a treatment scheme approved by the regional standard.
6. A history of intolerance to glucocorticoid therapy and/or immunosuppressors (azathioprine, 6-mercaptopurine, methotrexate) and/or biologic therapies (TNFα inhibitors, anti-integrins, IL-12/23 inhibitors) and/or targeted immunosuppressors (upadacitinib), as determined by the treating physician.

4. Maintaining a stable dose of concomitant medications for ≥2 weeks prior to signing the ICF and in the screening period for glucocorticoids and for ≥4 weeks prior to signing the

ICF and in the screening period for immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate).

Exclusion Criteria:

1. A history of or current at the time of signing the ICF ulcerative colitis, unspecified colitis, ischemic colitis, radiation colitis, microscopic colitis, complicated form of diverticular disease.

2. A history of primary sclerosing cholangitis.

3. Presence of active intra-abdominal or perianal abscess at the time of signing the ICF.

4. Presence of an endoscopically obstructed stricture/stenosis of the intestine at the time of signing the ICF.

5. A history of toxic megacolon, intestinal obstruction, intestinal perforation (except for those caused by injury or appendicitis).

6. A history of dysplasia in any part of the gastrointestinal tract at the time of signing the ICF.

7. Previous resections of the small intestine with a total length of resected segments >100 cm and/or resection of >2 segments of the large intestine (ascending colon (including the cecum), transverse colon, descending colon (including the sigmoid colon), rectum)3.

8. Presence of intestinal stoma or artificial rectum or the need for them.

9. Failure of ≥3 classes of biologics/targeted immunosuppressors (according to INN) with different mechanisms of action (TNFa inhibitors, anti-integrins, IL-12/23 inhibitors, upadacitinib) or ≥4 biologics/targeted immunosuppressants (according to INN), regardless of the mechanism of actio

   • Use of any of the indicated therapies within the specified time frame or need for therapy with these drugs during the study period:

     1. Use of TNFa inhibitors within 8 weeks prior to signing the ICF or during the screening period.
     2. Use of anti-integrins or IL-12/23 inhibitors within 12 weeks before signing the ICF or during the screening period.
     3. Use of Janus kinase inhibitors (upadacitinib) within 2 weeks prior to signing the ICF or during the screening period.
     4. Use of oral glucocorticoids at a dose equivalent to prednisone >20 mg/day or budesonide >9 mg/day or rectal administration of glucocorticoids at any dose within 2 weeks prior to signing the ICF or during the screening period or parenteral administration of glucocorticoids at any dose within 4 weeks prior to signing the ICF or during the screening period.
     5. Use of immunosuppressants not included in the approved therapy (tacrolimus, cyclosporine, mycophenolate mofetil, rapamycin, leflunomide, penicillamine, etc.) within 4 weeks before signing the ICF or during the screening period.
     6. Long-term regular use of non-steroidal anti-inflammatory drugs (≥3 times a week for ≥6 weeks) for 2 weeks prior to signing the ICF.
     7. Use of any other investigational drugs in other clinical trials at the time of signing the ICF or less than 8 weeks or 5 half-lives (whichever is longer) before the date of signing the ICF or during screening.