Considering the efficacy results of the induction phase (allowed use of corticosteroids as concomitant medication) in the study population and since IMU-838 did not show superiority over placebo, the OLE was prematurely closed by the sponsor.

This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding study to evaluate the efficacy and safety of IMU-838 for induction and maintenance therapy with an option for open-label treatment extension in moderate-to-severe ulcerative colitis (CALDOSE-1).

The investigational medicinal product (IMP) IMU-838 (vidofludimus calcium) is a new compound that selectively inhibits the human enzyme dihydroorotate dehydrogenase (DHODH). Dihydroorotate dehydrogenase plays a major role in the de-novo pyrimidine synthesis and is specifically expressed at high levels in proliferating or activated lymphocytes. Resting lymphocytes satisfy their pyrimidine requirements through a DHODH-independent salvage pathway. Thus, IMU-838-mediated DHODH inhibition selectively affects activated, rapidly proliferating lymphocytes. The metabolic stress secondary to DHODH inhibition leads to a reduction of pro-inflammatory cytokine release including interleukin (IL)-17 (IL-17A and IL-17F) and interferon gamma (IFNγ), and to an increased apoptosis in activated lymphocytes.

This is a phase 2, multicenter, randomized, double-blind, and placebo-controlled trial in patients with moderate-to-severe UC with an option for open-label treatment extension. The study comprises a blinded induction phase to establish the optimal dose of IMU-838 to induce response and remission, a blinded maintenance phase to evaluate the potential of IMU-838 to maintain remission until Week 50, and an open-label treatment extension arm for all patients who discontinue the blinded phase as scheduled or prematurely, subject to certain restrictions. A subset of patients will undergo a pharmacokinetic (PK) period at the start of the open-label period to establish a full single-dose PK profile.

INCLUSION CRITERIA:

Induction phase

1. Male and female patients, aged 18 - 80 years

2. UC diagnosed more than 3 months before Screening (Day-30) as documented in the medical chart

3. Previous treatment failure defined as:

   1. Patient had an inadequate response with, lost response to, or was intolerant to approved or experimental immunomodulators (azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate, or tofacitinib) or biologics (no more than 2 treatment failures with biologic drugs i.e. anti-tumor necrosis factor α antibodies [infliximab, adalimumab, golimumab and their biosimilars], vedolizumab, or certain experimental antibodies [ustekinumab]); or
   2. Patient had an inadequate response to, was intolerant to, or is corticosteroid dependent (corticosteroid-dependent patients are defined as i) unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids, without recurrent active disease, or ii) who have a relapse within 3 months of stopping steroids.)

4. Active disease defined as

   a. Mayo stool frequency score of ≥2 at Screening Visit 1 b. Mayo rectal bleeding score of ≥1 at Screening Visit 1 c. modified Mayo endoscopy subscore of ≥2 at the screening flexible sigmoidoscopy (endoscopy assessed by an independent central reader blinded to screening center and patient information)

5. Endoscopic appearance typical for UC and extending >15 cm from the anal verge as confirmed by an independent central reader (blinded to screening center and patient information)

6. Laboratory values: Neutrophil count >1500 cells/µL, platelet count ≥100 000 /mm3, serum creatinine <1.5 x upper limit of normal (ULN), total bilirubin, alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) <1.5 x ULN

7. Female patients must:

   a. Be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening) or post-menopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or

   b. If of child-bearing potential, must have a negative pregnancy test at Screening (blood test) and before the first study drug administration (Day 0 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method 2 months before Screening, during treatment with IMU-838, and at least 3 months after the last dose of study therapy

   Highly effective forms of birth control are those with a failure rate less than 1% per year and include:

   - oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraceptives associated with inhibition of ovulation

   • oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation
   • intrauterine device or intrauterine hormone-releasing system
   • bilateral tubal occlusion
   • vasectomized partner (i.e. the patient's male partner has undergone effective surgical sterilization before the female patient entered the clinical trial and he is the sole sexual partner of the female patient during the clinical trial)
   • sexual abstinence (acceptable only if it is the patient's usual form of birth control/lifestyle choice) 8. Male patients must agree not to father a child or to donate sperm starting at Screening and throughout the clinical trial and for 3 months after the last dose of study medication.

8. Male patients must also either

   - abstain from sexual intercourse with a female partner (acceptable only if it is the patient's usual form of birth control/lifestyle choice), or

   - use adequate barrier contraception during treatment with IMU-383 and for at least 3 months after the last dose of study medication

   For Poland and the UK the following additional requirement apply:

   • if male patients have a female partner of childbearing potential, the partner should use a highly effective contraceptive method as outlined in inclusion criterion 7

   And additionally, for Poland only:

   • if male patients have a pregnant partner, they must use condoms while taking study medication to avoid exposure of the fetus to study medication

9. Ability to understand and comply with study procedures and restrictions

10. The patient is legally competent, has been informed of the nature, the scope and the relevance of the study, voluntarily agrees to participation and the study's provisions and has duly signed the informed consent form

Maintenance phase

1. Symptomatic remission achieved at Week 10 or Week 22 of the induction phase

Open-label treatment extension arm

1. Patient is in the induction phase, had received at least 6 weeks of blinded study treatment and completed the sigmoidoscopy (incl. biopsy) regularly scheduled at Week 10/End of Induction, and has neither reached symptomatic remission nor symptomatic response

OR

Patient is in the extended induction phase, had completed all Week 10 assessments, and has not reached symptomatic remission during or at the end of the extended induction phase, Or Patient is in the maintenance phase and discontinues from the maintenance phase due to symptomatic UC relapse or other reasons with a flexible sigmoidoscopy performed at discontinuation (if the previous sigmoidoscopy had been performed more than 4 weeks before discontinuation)

OR

Patient has completed the maintenance phase as scheduled (including all Week 50 assessments)

EXCLUSION CRITERIA:

Gastrointestinal exclusion criteria

1. Diagnosis of Crohn's disease, inflammatory bowel disease type unclassified, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis

2. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine

3. History of colectomy with ileorectal anastomosis or ileal-pouch anal anastomosis or imminent need for colectomy (i.e. colectomy is being planned)

4. Active therapeutically uncontrollable abscess or toxic megacolon

5. Malabsorption or short bowel syndrome

6. History of colorectal cancer or colorectal dysplasia (with the exception of dysplasia in polyps which have been removed)

   Infectious disease exclusion criteria

7. Clostridium difficile (C. difficile) infection

   • Evidence of, or treatment for C. difficile infection within 30 days before first randomization
   • Positive C. difficile toxin B stool assay during the screening period

8. Treatment for intestinal pathogens other than C. difficile within 30 days prior to first randomization

9. Other chronic systemic infections

   • History of chronic systemic infections including but not limited to tuberculosis, human immunodeficiency virus (HIV), hepatitis B or C, within 6 months before Screening
   • Positive interferon-gamma release assay (IGRAs) for Mycobacterium tuberculosis at Screening
   • Positive HBsAg (hepatitis B virus surface antigen), HBcAb (hepatitis B core antibody), positive hepatitis C virus and/or HIV-antigen-antibody (HIV-Ag/Ab) test at Screening

10. Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine

    Other medical history and concomitant disease exclusion criteria

11. Known history of nephrolithiasis or underlying condition with a strong association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia

12. Diagnosis or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial

13. Renal impairment i.e. estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m²

14. Serum uric acid levels at Screening >1.2 x ULN (for women >6.8 mg/dL, for men >8.4 mg/dL)

15. History or clinical diagnosis of gout

16. Known or suspected Gilbert syndrome

17. Indirect (unconjugated) bilirubin ≥1.2 x ULN at Screening (i.e. ≥ 1.1 mg/dL)

18. Concurrent malignancy or prior malignancy within the previous 10 years except for the following: adequately-treated non-melanoma skin cancer and adequately-treated cervical cancer

    Therapy exclusion criteria

19. Use of any investigational product within 8 weeks or 5 x the respective half-life before first randomization, whatever is longer

20. Use of the following medications within 2 weeks before first randomization:

    1. Tofacitinib
    2. Methotrexate
    3. Mycophenolate mofetil
    4. Any calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus)
    5. Oral systemic corticosteroids >20 mg/day prednisolone equivalent including beclomethasone dipropionate (at >5 mg/day) and budesonide (multi-matrix [MMX] at >9 mg/day)
    6. Oral aminosalicylates (e.g. mesalazines) >4 g/day

21. Use of the following medications within 4 weeks before first randomization:

    1. Use of intravenous corticosteroids
    2. Use of thiopurines including azathioprine, mercaptopurine and 6-thioguanine
    3. Use of any rectal and topical aminosalicylates and/or budesonide

22. Use of oral systemic corticosteroids ≤20 mg/day prednisolone equivalent including beclomethasone dipropionate (at ≤5 mg/day) and budesonide (MMX at ≤9 mg/day) unless they have been used for at least 4 weeks before first randomization and at a stable dose for at least 2 weeks before first randomization

23. Oral aminosalicylates (e.g. mesalazines) ≤4 g/day unless they have been used for at least 6 weeks and with a stable dose for at least 3 weeks before first randomization

24. Use of biologics as follows:

    1. anti-tumor necrosis factor α antibodies (infliximab, adalimumab, golimumab, including their biosimilars) within 4 weeks before first randomization
    2. vedolizumab and ustekinumab within 8 weeks before first randomization

25. Use of the DHODH inhibitors leflunomide or teriflunomide within 6 months before first randomization

26. Any use of natalizumab (Tysabri™) within 12 months before first randomization

27. Use of the following concomitant medications is prohibited at Screening and throughout the duration of the trial:

    • any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid
    • treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib
    • any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs
    • Rosuvastatin at doses ˃10 mg/day

    General exclusion criteria

28. History of, or current serious, severe, or unstable (acute or progressive) physical or mental illness, or any medical condition, including laboratory anomalies or renal or hepatic impairment, that may require treatment or would put the patient in jeopardy if he/she was to participate in the study

29. Known hypersensitivity to DHODH inhibitors (teriflunomide, leflunomide) or any ingredient of the investigational product

30. Pregnancy or breastfeeding

31. History of drug or alcohol abuse during the past year

32. Concurrent participation in any other clinical trial using an investigational medicinal product or medical device

33. An employee of an investigator or sponsor or an immediate relative of an investigator

Exclusion criteria for open-label treatment extension arm

1. Any ongoing, clinically significant treatment-emergent (started during the IMU-838 treatment in the blinded treatment arms) adverse event (AE) or laboratory abnormality (including blood chemistry and urinalysis) as assessed by the investigator *

2. Significant treatment or study non-compliance during induction and/or maintenance phase (as assessed by the investigator), and/or inability or unwillingness to follow instructions by study personnel as assessed by the investigator

3. Significant protocol deviations during induction and/or maintenance phase that are assessed by the investigator to negatively affect further patient cooperation in this study

   • If treatment-emergent AEs are the reason for exclusion from the open-label extension arm, the eligibility can be re-assessed up to 30 days following the last treatment in the blinded treatment arms.