Global Managed Access Program Cohort for Remibrutinib in Adult Patients With Chronic Spontaneous Urticaria

Inclusion Criteria:

Patients eligible for inclusion in this Treatment Plan have to meet all of the following criteria:

1. Adult male and female subjects (≥ 18 years) who are able and willing to providewritten informed consent prior to enrolling in the cohort.

2. CSU diagnosis for ≥ 6 months (defined as onset of CSU with supportingdocumentation).

3. Diagnosis of CSU refractory to H1-AH at locally label approved doses and toomalizumab (where applicable), as assessed by the treating physician, using one ofthe following tools: UAS7, UCT or DLQI

4. Not eligible or able to enroll in a clinical trial or no relevant clinical trialsavailable

Exclusion Criteria:

Patients eligible for this Treatment Plan must not meet any of the following criteria:

1. Previous premature discontinuation from a remibrutinib clinical trial for any reason

2. History of hypersensitivity to remibrutinib or its excipients or to other BTKinhibitors

3. Participants having a clearly defined predominant or sole trigger of their chronicurticaria (chronic inducible urticaria) including urticaria factitia (symptomaticdermographism), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-,cholinergic-, or contact-urticaria

4. Other diseases with symptoms of urticaria or angioedema, including but not limitedto urticaria vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis,hereditary urticaria, or drug-induced urticaria

5. Any other skin disease associated with chronic itching that might influence in thephysician's opinion the treatment effect, e.g. atopic dermatitis, bullouspemphigoid, dermatitis herpetiformis, senile pruritus or psoriasis

6. Use of prohibited concomitant treatment

7. Known history or evidence of ongoing alcohol or drug abuse within the last 6 monthsbefore treatment start

8. History of malignancy of any organ system (other than localized basal cell carcinomaof the skin or in situ cervical cancer), treated or untreated, within the past 5years, regardless of whether there is evidence of local recurrence or metastases

9. Pregnant or nursing (lactating) women

10. Women of child-bearing potential (WoCBP), defined as all women physiologicallycapable of becoming pregnant, unless they are using highly effective methods ofcontraception during dosing and for 7 days after stopping of program treatment.Highly effective contraception methods include:

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

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy) total hysterectomy or bilateral tubal ligation at least six weeksbefore taking investigational drug. In case of oophorectomy alone, only whenthe reproductive status of the woman has been confirmed by follow up hormonelevel assessment

• Male sterilization (at least 6 months prior to screening). For femaleparticipants in the program, the vasectomized male partner should be the solepartner for that participant

• Use of oral, (estrogen and progesterone), injected or implanted hormonalmethods of contraception or other forms of hormonal contraception that havecomparable efficacy (failure rate <1%), for example hormone vaginal ring ortransdermal hormone contraception or placement of an intrauterine device (IUD)or intrauterine system (IUS) In case of use of oral contraception women shouldhave been stable on the same pill for a minimum of 3 months before takinginvestigational drug. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate,history of vasomotor symptoms). Women are considered not of child-bearing potentialif they are post-menopausal or have had surgical bilateral oophorectomy (with orwithout hysterectomy), total hysterectomy or bilateral tubal ligation at least sixweeks ago. In the case of oophorectomy alone, only when the reproductive status ofthe woman has been confirmed by follow-up hormone level assessment is she considerednot of child-bearing potential.

11. History of live attenuated vaccine within 6 weeks prior to treatment start orrequirement to receive these vaccinations at any time during treatment withremibrutinib

12. 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 Visit 1), neurological, psychiatric, pulmonary, renal, hepatic, endocrine,metabolic, hematological disorders, gastrointestinal disease or immunodeficiencythat, in the physician's opinion, would compromise the safety of the participant, orotherwise preclude adherence to the treatment plan

13. Uncontrolled disease states, such as asthma, or inflammatory bowel disease, whereflares are commonly treated with oral or parenteral corticosteroids

14. Hematology parameters before treatment start:

• Hemoglobin: < 10 g/dl

• Platelets: < 100 000/mm3

• Leucocytes: < 3 000/mm3

• Neutrophils: < 1 500/mm3

15. Significant bleeding risk or coagulation disorders

16. History of gastrointestinal bleeding, e.g. in association with use of nonsteroidalanti-inflammatory drugs (NSAID), that was clinically relevant (e.g. requiringhospitalization or blood transfusion)

17. Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100mg/d or clopidogrel. The use of dual anti-platelet therapy (e.g. acetylsalicylicacid + clopidogrel) is prohibited.

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

19. 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 before treatment start

20. History of renal disease, creatinine level above 1.5x ULN, or estimated GlomerularFiltration Rate (eGFR) <45ml/min (using the Cockcroft-Gault equation) beforetreatment start

21. Evidence of an ongoing Hepatitis C infection (e.g. defined by the detection ofhepatitis C-ribonucleic acid (HCV-RNA) at screening) and/or an ongoing Hepatitis Binfection (defined by the detection of Hepatitis B virus surface antigen (HBsAg)and/or hepatitis B virus (HBV)-DNA at screening; participants who are positive foranti-hepatits B core (HBc) antibodies but who are negative for antibodies againstHBsAg and HBV-DNA can be included into the program if they agree to monitoring forHBsAg and HBV-DNA re-activation)

22. 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. HIV antigen/antibody tests will be performedto determine HIV status if required according to local regulations.