Study of Remibrutinib (LOU064) Efficacy and Safety and Exploration of Its Mechanism of Action in Participants With Chronic Urticaria

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Male and female participants ≥ 18 years of age at the time of signing of theinformed consent forms.

3. CINDU patients: Confirmed diagnosis of CINDU with a duration of ≥ 4 months (definedas onset of CINDU with supporting documentation (e.g. medical record, clinicalhistory, photographs) and inadequate control with H1-AH at local label approveddoses at the time of randomization. The response to the provocation test for eachCINDU subtype is required before randomization (either during screening or prior torandomization on Day 1):

4. CINDU patients: Patients should be symptomatic for their most bothersome symptom asassessed with the USDD during baseline with a NRS score of 3 or more

5. CSU patients: Diagnosis of CSU (acc. to Zuberbier et al 2022c) not adequatelycontrolled with H1-AH at approved doses alone for at least 4 weeks prior torandomization, as defined by all of the following:

• UAS7 score (range 0-42) ≥ 16 and HSS7 (range 0-21) ≥ 8 during 7 days prior torandomization

• CSU for ≥ 6 months

6. Participants must be willing and able to attend the protocol defined test procedurethroughout the study.

Exclusion Criteria:

1. Participants who have a familial/hereditary form (e.g. familial coldautoinflammatory syndrome, familial cold urticaria) of the target CINDU that isbeing considered for the participant's inclusion in this study.

2. Diseases, other than CSU or CINDU, with urticaria or angioedema symptoms includingbut not limited to:

• urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticariapigmentosa),

• food allergies yielding urticaria symptoms when the allergen is not avoided bythe dietary habits of the participant

• hereditary or acquired angioedema.

3. CINDU patients only: To prevent any confounding effect of CSU symptoms, the CINDUstudy population will consist of participants with predominant CINDU and should nothave a significant share of CSU symptoms (that might make the assessment of CINDUsymptoms difficult) as per the investigator's judgement.

4. CSU patients only: Patients should have no relevant inducible urticaria trigger

5. Any other skin disease associated with chronic itching that might influence, in theinvestigator's opinion, the study evaluations and results (e.g., atopic dermatitis,bullous pemphigoid, dermatitis herpetiformis, senile pruritus, etc.) or skindiseases associated with only wheals and no itch e.g asymptomatic dermographism

6. Known or suspected ongoing, chronic or recurrent infectious disease including butnot limited to opportunistic infections (e.g., tuberculosis, atypicalmycobacterioses, listeriosis or aspergillosis) and/or known positivity for HumanImmunodeficiency Virus (HIV) infection.

7. Evidence of an ongoing Hepatitis C infection (defined by the detection at screeningof Hepatitis C virus antibodies (anti-HCVAb) and hepatitis C ribonucleic acid (HCV-RNA) in participants who are positive for anti-HCVAb) and/or an ongoingHepatitis B infection (defined by the detection of Hepatitis B virus surface antigen (HBsAg) and/or hepatitis B virus (HBV)-DNA at screening; participants who arepositive for anti-hepatitis B core (HBc) antibodies but who are negative forantibodies against HBsAg and HBV-DNA can be included into the study if they agree tomonitoring for HBsAg and HBV-DNA reactivation).

8. Major surgery within 8 weeks prior to screening or planned surgery for the durationof the study.

9. Evidence of clinically significant cardiovascular (such as but not limited tomyocardial infarction, unstable ischemic heart disease, NYHA Class III/IV leftventricular failure, arrhythmia and uncontrolled hypertension within 12 months priorto Screening), neurological, psychiatric, pulmonary, renal, hepatic, endocrine,metabolic, hematological disorders, gastrointestinal disease or immunodeficiencythat, in the investigator's opinion, would compromise the safety of the participant,interfere with the interpretation of the study results or otherwise precludeparticipation or protocol adherence of the participant.

10. Uncontrolled disease states, such as asthma, or inflammatory bowel disease, or anyother disease where flares are commonly treated with oral or parenteralcorticosteroids.

11. History of lymphoproliferative disease or any known malignancy or history ofmalignancy of any organ system within the past 5 years (except for basal cellcarcinoma or actinic keratosis that have been treated with no evidence of recurrencein the past 3 months, carcinoma in situ of the cervix or non-invasive malignantcolon polyps that have been removed).

12. History or presence of impaired renal function as indicated by clinicallysignificantly abnormal creatinine or BUN values, or abnormal urinary constituents (e.g. proteinuria, hematuria)

• Evidence of urinary obstruction, or difficulty in voiding at screening

• Evidence of congenital renal abnormalities with known effect on renal function

• Calculated eGFR < 60 mL/min

13. Hematology parameters at screening:

• Hemoglobin: < 10 g/dL

• Platelets: < 100,000/mm3

• Leucocytes: < 3,000/mm3

• Neutrophils:< 1,500/mm3

14. History or current hepatic disease including but not limited to acute or chronichepatitis, cirrhosis or hepatic failure or Aspartate Aminotransferase (AST)/ AlanineAminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN) orInternational Normalized Ratio (INR) of more than 1.5 at screening

15. Use of other investigational drugs s within 5 half-lives or within 30 days (forsmall molecules) prior to Screening or until the expected pharmacodynamic (PD)effect has returned to baseline (for biologics), whichever is longer; or longer ifrequired by local regulations

16. Contraindications to or hypersensitivity to remibrutinib (or its excipients or todrugs of similar chemical classes) or other substances provided to the subjects asrescue medication to control symptoms, such as antihistamines.

17. Participants taking prohibited therapies as listed in Section 6.6.2. In particularpatients with pretreatment with remibrutinib or another BTK-inhibitor within 4months prior to randomization.

18. History of live or live attenuated vaccine within 6 weeks prior to randomization orrequirement to receive these vaccinations at any time during the study drugtreatment.

19. Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100mg/d or clopidogrel up to 75 mg/d which are allowed. The use of dual anti-platelettherapy (e.g., acetylsalicylic acid + clopidogrel) is prohibited.

20. Requirement for anticoagulant medication (for example, warfarin or Novel OralAnti-Coagulants (NOAC)).

21. History of gastrointestinal bleeding, e.g., in association with use of nonsteroidalanti-inflammatory drugs (NSAID), that was clinically relevant (e.g., whereintervention was indicated or requiring hospitalization or blood transfusion)

22. Significant bleeding risk or coagulation disorders.

23. Known history or evidence of ongoing alcohol or drug abuse within the last 6 monthsbefore randomization as per source records.

24. Pregnant or nursing (breast feeding) women.

25. Women of child-bearing potential, defined as fertile, following menarche and untilbecoming post-menopausal unless they are permanent sterile or they are using highlyeffective methods of contraception during dosing for 7 days after stopping studytreatment. Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the participant). Note that periodic abstinence (e.g., calendar, ovulation,symptothermal, post-ovulation methods) and withdrawal are not acceptablemethods of contraception

• Bilateral oophorectomy with or without hysterectomy, total hysterectomy orbilateral salpingectomy at least six weeks prior to the first dose of studytreatment. In case of oophorectomy alone, only when the reproductive status ofthe woman has been confirmed by follow up hormone level assessment is sheconsidered to be not of child-bearing potential.

• Bilateral tubal occlusion, Bilateral tubal ligation (at least six weeks priorto the first dose of study treatment)

• Male partner sterilization (vasectomy) of male partner(s) of the femaleparticipant at least six months prior to screening). The vasectomized malepartner should be sole partner for that participant and received medicalassessment of the surgical success.

• Use of oral (estrogen and progesterone), injected, or implanted hormonalmethods of contraception or placement of an intrauterine device (IUD) orintrauterine system (IUS), or other forms of hormonal contraception that havecomparable efficacy (failure rate < 1%), for example hormone vaginal ring ortransdermal hormone contraception.

The decision on the contraceptive method should be reviewed at least every 3 months to evaluate the individual need and compatibility of the method chosen. In case of use of hormonal contraception, women should have been stable on the same method for a minimum of 3 months before taking study treatment. Women are considered post-menopausal if they have no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Women are considered not of child-bearing potential if they are post-menopausal or permanently sterileor have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks prior to first dose of study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child-bearing potential.

If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.