Phase 2 Dose-finding IMU-838 for Ulcerative Colitis (CALDOSE-1)

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 in Moderate-to-severe Ulcerative Colitis

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.

Two 5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment.

Two 15 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment.

Two 22.5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment.

The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging.

The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging. Patients who have received placebo during the induction phase will be 're-randomized' to continue to receive placebo (in a blinded fashion).

Two 15 mg tablets once daily of IMU-838 or one 30 mg tablet IMU-838 once daily for up to 10 years and up to 3 years in UK sites

Composite endpoint: Proportion of patients with both, symptomatic remission and endoscopic healing at Week 10. All patients (both, Enrollment Period 1 and Enrollment Period 2 patients) who were randomized to 30 mg/day and 45 mg/day will be used for the assessment of the primary efficacy endpoint

Proportion of patients with both symptomatic remission and endoscopic healing at Week 10 (all individual IMU-838 doses will be compared with one another and to placebo)

Proportion of patients achieving symptomatic remission during the induction phase (including extended induction phase)

Proportion of patients with symptomatic response during the induction phase (including extended induction phase)

The emergence of any clinically significant findings compared to screening will be captured during the induction and maintenance phases

pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose

pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose

pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose

pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose

pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose

INCLUSION CRITERIA: Induction phase Male and female patients, aged 18 - 80 years UC diagnosed more than 3 months before Screening (Day-30) as documented in the medical chart Previous treatment failure defined as: 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 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.) 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) 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) 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 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. 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 Ability to understand and comply with study procedures and restrictions 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 Diagnosis of Crohn's disease, inflammatory bowel disease type unclassified, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine History of colectomy with ileorectal anastomosis or ileal-pouch anal anastomosis or imminent need for colectomy (i.e. colectomy is being planned) Active therapeutically uncontrollable abscess or toxic megacolon Malabsorption or short bowel syndrome History of colorectal cancer or colorectal dysplasia (with the exception of dysplasia in polyps which have been removed) Infectious disease exclusion criteria 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 Treatment for intestinal pathogens other than C. difficile within 30 days prior to first randomization 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 Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine Other medical history and concomitant disease exclusion criteria Known history of nephrolithiasis or underlying condition with a strong association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia Diagnosis or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial Renal impairment i.e. estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m² Serum uric acid levels at Screening >1.2 x ULN (for women >6.8 mg/dL, for men >8.4 mg/dL) History or clinical diagnosis of gout Known or suspected Gilbert syndrome Indirect (unconjugated) bilirubin ≥1.2 x ULN at Screening (i.e. ≥ 1.1 mg/dL) 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 Use of any investigational product within 8 weeks or 5 x the respective half-life before first randomization, whatever is longer Use of the following medications within 2 weeks before first randomization: Tofacitinib Methotrexate Mycophenolate mofetil Any calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus) Oral systemic corticosteroids >20 mg/day prednisolone equivalent including beclomethasone dipropionate (at >5 mg/day) and budesonide (multi-matrix [MMX] at >9 mg/day) Oral aminosalicylates (e.g. mesalazines) >4 g/day Use of the following medications within 4 weeks before first randomization: Use of intravenous corticosteroids Use of thiopurines including azathioprine, mercaptopurine and 6-thioguanine Use of any rectal and topical aminosalicylates and/or budesonide 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 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 Use of biologics as follows: anti-tumor necrosis factor α antibodies (infliximab, adalimumab, golimumab, including their biosimilars) within 4 weeks before first randomization vedolizumab and ustekinumab within 8 weeks before first randomization Use of the DHODH inhibitors leflunomide or teriflunomide within 6 months before first randomization Any use of natalizumab (Tysabri™) within 12 months before first randomization 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 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 Known hypersensitivity to DHODH inhibitors (teriflunomide, leflunomide) or any ingredient of the investigational product Pregnancy or breastfeeding History of drug or alcohol abuse during the past year Concurrent participation in any other clinical trial using an investigational medicinal product or medical device An employee of an investigator or sponsor or an immediate relative of an investigator Exclusion criteria for open-label treatment extension arm 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 * 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 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.

University Clinical Centre of the Republic of Srpska, Internal Medicine Clinic, Department of Gastroenterology and Hepatology

University Multiprofile Hospital for Active Treatment "Sveti Georgi" EAD, Plovdiv, Gastroenterology clinic

FSBEI HE "Military Medical Academy n.a. S.M. Kirov" under the Ministry of Defence of Russian Federation

Public Enterprise "Dnipropetrovsk regional clinical hospital named after I.I. Mechnikova", Department of Gastroenterology (Hepatology)

MNPE "Regional Clinical Hospital of Ivano-Frankivsk Regional Council", Gastroenterology Department, SHEI "Ivano-Frankivsk National Medical University", Chair of Internal Medicine #1

Municipal Non-profit Enterprise "City Clinical Hospital #2 named after prof. O.O. Shalimova", of Kharkiv City Council, Proctology Department

Municipal Non-profit Enterprise of Kharkiv Regional Council "Regional Clinical Hospital", Gastroenterology Department

Kyiv City Clinical Hospital #18, Proctology Department, National Medical University named after O.O.Bogomolets, Chair of Surgery #1

Medical Centre of Limited Liability Company "Medical Centre "Consilium Medical", clinico-consultation department

Municipal Non-profit Enterprise of Lviv Regional Council "Lviv Regional Clinical Hospital", proctology department, Danylo Galytsky Lviv National Medical University, Chair of Surgery #1

Municipal Non-profit Enterprise "Vinnytsia Regional Clinical Hospital named after M.I. Pyrogova of Vinnytsia Regional Council, Regional Specialized Clinical Gastroenterological Center,

Municipal Non-profit Enterprise "Vinnytsia City Clinical Hospital #1, Gastroenterology Department, Vinnytsia National Medical University named after M.I.Pyrogova, Chair of Propaedeutics of Internal Medicine

Municipal Institution "Zaporizhzhska Regional Clinical Hospital" of Zaporizhzha Regional Council, gastroenterology department

London North West University Healthcare NHS Trust (LNWH), St Mark's Hospital, R&D Department, Northwick Park Hospital

European Medicines Agency (EMA). Guideline on the development of new medicinal products for the treatment of Ulcerative Colitis.[Online]. 2016.

US Food and Drug Administration (FDA). Ulcerative Colitis: Clinical Trial Endpoints. Guidance for Industry.[Online]. 2016.

European Union (EU). Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data. [Online].

EU. Regulation 2016/679 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). 2016; [Online].