Phase 2 Dose-finding IMU-838 for Ulcerative Colitis

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 symptoms defined as a Mayo stool frequency score of ≥2 and a 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:

1. 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

2. 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

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. calculated creatinine clearance ≤60 mL/min

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

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

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

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.