A clinical study of tulisokibart for the treatment of ulcerative colitis (MK-7240-005)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prometheus Biosciences Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

23 Sep 2021 → 14 Aug 2025

Decision date (initial)

2024-10-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-509741-12-00

EudraCT number

2021-000091-11

WHO UTN

U1111-1309-6078

ClinicalTrials.gov

NCT04996797

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the safety and tolerability of PRA023 following 12 weeks of induction therapy
To compare the efficacy of PRA023 vs placebo for induction of clinical remission at Week 12

Secondary objectives 17

1. To compare the efficacy of PRA023 vs placebo for induction of endoscopic improvement at Week 12
2. To compare the efficacy of PRA023 vs placebo for induction of clinical response at Week 12
3. To compare the efficacy of PRA023 vs placebo in CDx positive (CDx+) subjects (Cohort 1 + Cohort 2) for induction of clinical remission at Week 12
4. To compare the efficacy of PRA023 vs placebo for induction of symptomatic remission at Week 12
5. To compare the efficacy of PRA023 vs placebo for induction of histologic remission at Week 12
6. To compare the efficacy of PRA023 vs placebo for induction of histologic-endoscopic mucosal improvement at Week 12
7. To compare the efficacy of PRA023 vs placebo in CDx+ subjects (Cohort 1 + Cohort 2) for induction of endoscopic improvement at Week 12
8. To compare the efficacy of PRA023 vs placebo in CDx+ subjects (Cohort 1 + Cohort 2) for induction of clinical response at Week 12
9. To compare the efficacy of PRA023 vs placebo in CDx+ subjects (Cohort 1 + Cohort 2) for induction of symptomatic remission at Week 12
10. To compare the efficacy of PRA023 vs placebo in CDx+ subjects (Cohort 1 + Cohort 2) for induction of histologic remission at Week 12
11. To compare the efficacy of PRA023 vs placebo in CDx+ subjects (Cohort 1 + Cohort 2) for induction of histologic-endoscopic mucosal improvement at Week 12
12. To compare the efficacy of PRA023 in CDx+ (Cohort 1 + Cohort 2) vs CDx negative (CDx-) subjects for induction of clinical remission at Week 12
13. To compare the efficacy of PRA023 vs placebo for induction of mucosal healing at Week 12
14. To compare the efficacy of PRA023 vs placebo in CDx+ subjects (Cohort 1 + Cohort 2) for induction of mucosal healing at Week 12
15. To compare the efficacy of PRA023 vs placebo for change in Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 12
16. To compare the efficacy of PRA023 vs placebo in CDx+ subjects (Cohort 1 + Cohort 2) for change in IBDQ at Week 12
17. To compare the efficacy of PRA023 vs. placebo in subjects who are CDx+ per alternative algorithm (Cohort 1 + Cohort 2) for clinical remission at Week 12

Conditions and MedDRA coding

Ulcerative Colitis

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003556-PIP01-23

Plan to share IPD

Yes

IPD plan description

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Male or female ≥ 18 years of age.
2. 2. Subjects must have had a diagnosis of UC at least 3 months before Screening (confirmed by endoscopy + histology) to be eligible for study participation. For subjects with no documented confirmation of UC diagnosis or if previous diagnosis is not deemed conclusive, UC diagnosis must be confirmed at time of screening colonoscopy. Note that mention of “chronic inflammation” or “ulcerative colitis” or equivalent on histology report is acceptable.
3. 3. Moderately to severely active UC as defined by 3-component Modified Mayo score (3 components of rectal bleeding, stool frequency, and endoscopy) of 4 to 9, inclusive, with Modified Mayo endoscopic subscore ≥ 2 and rectal bleeding subscore ≥ 1.
4. 4. Subjects must satisfy at least one of the following criteria: a) In the past, had an inadequate response to one or more of the following treatments: • Oral prednisone ≥ 40 mg/day (or equivalent) or budesonide ≥ 9 mg/day or equivalent or beclomethasone ≥ 5 mg/day for at least 2 weeks • Corticosteroid dependence as defined by failed to successfully taper to < 10 mg/day of prednisone or equivalent (i.e., had a flare of disease) within 3 months of starting therapy, or if relapse occurs within 3 months of stopping corticosteroids • Immunosuppressants (azathioprine ≥ 2 mg/kg/day or 6 mercaptopurine ≥ 1.0 mg/kg/day [or documentation of a therapeutic concentration of 6-thioguanine nucleotide]) for at least 8 weeks. Note: a lower dosage of 6-MP or AZA is acceptable if local guidelines specify a different treatment regimen (which would need be documented in the source document) • An approved anti-TNF agent at an approved labeled dose for at least 8 weeks • Vedolizumab at the approved labelled dose for at least 8 weeks • An approved JAK inhibitor (e.g., tofacitinib, upadacitinib, or filgotinib) at an approved labelled dose for at least 8 weeks • An approved anti-IL-12/23 (e.g., ustekinumab) at an approved labelled dose for at least 8 weeks • An approved sphingosine 1-phosphate receptor (S1PR) modulator (e.g., ozanimod) at an approved labelled dose for least 12 weeks OR b) Had been intolerant to one or more of the above-mentioned treatments (e.g., unable to achieve doses or treatment durations because of dose limiting side effects [e.g., leukopenia, psychosis, uncontrolled diabetes, elevated liver enzymes]). OR c) Currently receiving one or more of the following treatments: • Oral Prednisone ≥ 10 mg/day (or equivalent) for at least 3 months • Immunosuppressants [azathioprine ≥ 2 mg/kg/day or 6 mercaptopurine ≥ 1.0 mg/kg/day (or documentation of a therapeutic concentration of 6 thioguanine nucleotide)] for at least 8 weeks. Note: a lower dosage of 6-MP or AZA is acceptable if local guidelines specify a different treatment regimen (which would need be documented in the source document) Notes on subjects who have had prior biologic/biologic-like therapy(ies) (anti-TNF, JAK inhibitor, S1PR modulator, anti-IL-12/23, and/or anti-integrin): • The study will include a maximum of 70% and a minimum of approximately 50% subjects who have had prior biologic/biologic-like therapy(ies) experience. Upon reaching the maximum number of allowed biologic/biologic-like experienced subjects (70%), subjects who have had prior biologic/biologic-like experience will no longer be allowed to enter the study. Upon reaching the maximum number of allowed biologic/biologic-like naïve subjects (approximately 50%), subjects who have never been exposed to a prior biologic/biologic-like will no longer be allowed to enter the study. • Subject cannot have failed (no response, insufficient response, loss of response, and/or intolerance) > 3 classes or > 4 individual biologic/biologic-like therapies (refer to exclusion criterion #26).
5. 5. For subjects who are women of childbearing potential (WOCBP) involved in any sexual intercourse that could lead to pregnancy, the subject has used two highly effective methods of contraception for at least 4 weeks prior to Day 1 and agrees to continue to use two highly effective methods of contraception until at least 12 weeks after the last dose of study drug.
6. 6. Male subjects must use, with their female partner of childbearing potential, two highly effective methods of contraception and refrain from sperm donation from screening to 12 weeks after the last dose of study drug.
7. 7. Subject must meet drug stabilization requirements, as applicable: a) Oral corticosteroid treatment must be equivalent of ≤ 20 mg prednisone or ≤ 9 mg budesonide or beclomethasone ≤ 5 mg daily at a stable dose for at least 2 weeks prior to randomization b) Oral aminosalicylates should be at a stable dose for at least 2 weeks prior to randomization c) Azathioprine and 6-mercaptopurine should be at a stable dose for at least 4 weeks prior to randomization
8. 8. Able to provide written informed consent and understand and comply with the requirements of the study.
9. 9. For Cohort 2 only: Subjects must be CDx+.

Exclusion criteria 37

1. 1. WOCBP and men with female partners of childbearing potential who are unwilling or unable to use two highly effective methods of contraception to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of study drug.
2. 2. Women who are pregnant or breastfeeding.
3. 3. Women with a positive pregnancy test on enrollment or prior to randomization.
4. 4. Diagnosis of Crohn’s disease or indeterminate colitis.
5. 5. UC limited to the rectum (< 15 cm from anal verge).
6. 6. Current evidence of fulminant colitis, toxic megacolon, or bowel perforation.
7. 7. Current or impending need for colostomy or ileostomy.
8. 8. Previous total proctocolectomy or partial colectomy.
9. 9. Surgical bowel resection within 3 months before screening.
10. 10. Concomitant primary sclerosing cholangitis (PSC)
11. 11. Past or current evidence of definite low-grade or high-grade colonic dysplasia that has not been completely removed.
12. 12. Subjects who are scheduled or anticipate the need for surgery, aside from dermatologic procedures
13. 13. Subjects who have a history of clinically significant drug or alcohol abuse.
14. 14. Concomitant illness that in the opinion of the Investigator, is likely to require systemic glucocorticosteroid therapy during the study (e.g., moderate to severe asthma).
15. 15. Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, pulmonary, cardiac, neurological, ophthalmologic or cerebral disease. Concomitant medical conditions that in the opinion of the Investigator might place the subject at unacceptable risk for participation in this study
16. 16. Subjects with a history of cancer within the last 5 years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to enrollment. Subjects with carcinoma in situ or localized cervical cancer, treated with definitive surgical intervention, are allowed.
17. 17. Subjects at risk for tuberculosis (TB). Specifically, subjects with: a) A history of active TB b) Current clinical, radiographic or laboratory evidence of active TB c) Latent TB which was not successfully treated. Subjects with a positive TB screening test indicative of latent TB will not be eligible for the study unless active TB infection has been ruled out, and an appropriate course of intervention for latent TB has been initiated at least 2 weeks prior to randomization, and no evidence of active TB on chest x-ray during Screening.
18. 18. Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (such as chronic pyelonephritis, osteomyelitis and bronchiectasis).
19. 19. Female subjects who have had a breast cancer screening that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations.
20. 20. Subjects with any active infections (excluding fungal infections of nail beds) including, but not limited to, those that require intravenous (IV) antimicrobial treatment 4 weeks or oral antimicrobial treatment 2 weeks prior to randomization. Subjects with evidence of Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C infection detected during screening are also excluded, but subjects with successfully treated Hepatitis C with no recurrence for ≥ 1 year are allowed. Subjects with active documented or suspected COVID-19 infection within 4 weeks of randomization or asymptomatic SARS-CoV-2 test positivity within 2 weeks of randomization are excluded
21. 21. Subjects with herpes zoster reactivation or cytomegalovirus (CMV) that resolved less than 2 months prior to signing informed consent.
22. 22. Subjects who have received any live vaccines within 3 months of the anticipated first dose of study medication or who will have need of a live vaccine at any time during the study.
23. 23. Positive stool studies [e.g., by Polymerase Chain Reaction (PCR), bacterial culture, toxin, etc.] if Investigator deems this positivity reflects infection rather than colonization. Subjects who have an infection can be retested after the completion of a full course of treatment, if treatment is deemed medically indicated.
24. 24. Stool positive for Clostridium difficile (C. difficile) toxin. Subjects who are positive can be retested after the completion of a full course of treatment for C. difficile infection.
25. 25. Any of the following lab values: a) Hemoglobin (Hgb) < 8.0 g/dL (80 g/L) b) White blood cell (WBC) < 2,500/mm^3 (2.5 x 10^9/L) c) Neutrophils < 1,000/mm^3 (1 x 10^9/L) d) Platelets < 100,000/mm^3 (100 x 10^9/L) e) Serum creatinine > 2 times upper limit of normal (ULN) f) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times ULN g) Any other laboratory test results that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study
26. 26. Failed (no response, insufficient response, loss of response, and/or intolerance) > 3 classes (anti-TNF, anti-integrin, anti-IL12/23, JAK inhibitor, S1PR modulator) or > 4 individual biologic/biologic-like therapies.
27. 27. Any marketed biologic or biologic-like within 2 weeks for JAK inhibitors (e.g., tofacitinib, upadacitinib, or filgotinib, 8 weeks for anti-TNF agents, 10 weeks for S1PR modulators (e.g., ozanimod), and 12 weeks for vedolizumab and anti-IL-12/23 (e.g., ustekinumab) prior to randomization or if drug level per therapeutic dose monitoring is greater than lower limit of detection
28. 28. Any biologic immunomodulators not covered in exclusion criterion 27, used for UC or other conditions within 8 weeks or 5 half-lives, whichever is longer, prior to randomization or if drug level per therapeutic dose monitoring is greater than lower limit of detection.
29. 29. Rituximab within 1 year prior to randomization.
30. 30. Parenteral corticosteroids within 4 weeks or rectal administration of corticosteroids within 2 weeks prior to randomization.
31. 31. Rectal administration of 5-ASA within 2 weeks prior to randomization.
32. 32. Tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil (CellCept®), immunoadsorption columns (such as Prosorba columns), d-penicillamine, leflunomide, thalidomide, fish-oil preparations, probiotics, fecal transplantation, non-steroidal anti-inflammatory agents (NSAIDs), aspirin > 81 mg/day within 2 weeks prior to randomization.
33. 33. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 5 half-lives (whichever is longer) of randomization.
34. 34. Prior exposure to PRA023.
35. 35. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
36. 36. Legal or mental incapacitation, or inability to understand and comply with the requirements of the study.
37. 37. Known allergies, hypersensitivity, or intolerance to PRA023 or its excipients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The proportion of subjects reporting adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, and markedly abnormal laboratory values.
2. The proportion of subjects in the 3-component Modified Mayo Score clinical remission (as defined by endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline) at Week 12. The 3-component Modified Mayo Score ranges from 0-9 and includes rectal bleeding, stool frequency and endoscopic assessment domains.

Secondary endpoints 17

1. • The proportion of subjects with endoscopic improvement, as defined by endoscopy subscore ≤ 1 with no friability, at Week 12.
2. • The proportion of subjects in 3-component Modified Mayo Score clinical response at Week 12. The 3-component Modified Mayo Score clinical response is defined by reduction from Baseline ≥ 2 points and ≥ 30% in 3-component Modified Mayo Score, accompanied by a reduction ≥ 1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤ 1.
3. • The proportion of subjects in the 3-component Modified Mayo Score clinical remission (as defined by endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline), in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. The 3-component Modified Mayo Score ranges from 0-9 and includes rectal bleeding, stool frequency, and endoscopic assessment domains.
4. • The proportion of subjects in symptomatic remission (as defined by rectal bleeding score = 0 and stool frequency score = 0) at Week 12.
5. • The proportion of subjects with histologic remission (defined as Geboes score ≤ 3.1) at Week 12.
6. • The proportion of subjects with histologic-endoscopic mucosal improvement (defined as Geboes score ≤ 3.1 and endoscopy subscore ≤ 1 with no friability) at Week 12.
7. • The proportion of subjects with endoscopic improvement, as defined by endoscopy subscore ≤ 1 with no friability, in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12.
8. • The proportion of subjects in 3-component Modified Mayo Score clinical response in CDx+ subjects treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. The 3-component Modified Mayo Score clinical response is defined by reduction from Baseline ≥ 2 points and ≥ 30% in 3-component Modified Mayo Score, accompanied by a reduction ≥ 1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤ 1.
9. • The proportion of subjects with symptomatic remission (as defined by rectal bleeding score = 0 and stool frequency score = 0) in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12.
10. • The proportion of subjects with histologic remission, defined as Geboes score ≤ 3.1, in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12.
11. • The proportion of subjects with histologic-endoscopic mucosal improvement (defined as Geboes score ≤ 3.1 and endoscopy subscore ≤ 1 with no friability), in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12.
12. • The proportion of subjects with clinical remission (defined as endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline) in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to in CDx- subjects treated with PRA023 at Week 12.
13. • The proportion of subjects with mucosal healing (defined as Geboes score ≤ 2B.1 and endoscopy subscore of ≤ 1) at Week 12.
14. • The proportion of subjects with mucosal healing (defined as Geboes score ≤ 2B.1 and endoscopy subscore of ≤ 1), in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12.
15. • The proportion of subjects with IBDQ response, as defined by ≥ 16-point increase from Baseline at Week 12.
16. • The proportion of subjects with IBDQ response, as defined by ≥ 16-point increase from Baseline, in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12.
17. • The proportion of subjects in the 3-component Modified Mayo Score clinical remission (as defined by endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline), in CDx+ subjects treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prometheus Biosciences Inc.

Sponsor organisation

Prometheus Biosciences Inc.

Address

3050 Science Park Road

City

San Diego

Postcode

92121-1102

Country

United States

Scientific contact point

Organisation

Prometheus Biosciences Inc.

Contact name

Regulatory Affairs

Public contact point

Organisation

Prometheus Biosciences Inc.

Contact name

Regulatory Affairs

Third parties 15

Locations

4 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications