Remibrutinib

The WI-NRS is a patient-reported outcome (PRO) instrument consisting of a single question that asks participants to rate the severity of their worst itch over a defined period. The score range is from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicate worse itch severity.

UAS7 is a validated patient-reported measure of chronic spontaneous urticaria disease activity over 7 days. It is calculated as the sum of the weekly Hives Severity Score (HSS7) and the weekly Itch Severity Score (ISS7) and ranges from 0 to 42. Lower scores indicate lower disease activity / better disease control, and a score of ≤6 indicates well-controlled disease. HSS7 and ISS7 are each derived from daily diary entries over the 7 days preceding the visit.

Response status is defined as tolerating an oral dose of at least 600 mg peanut protein (1044 mg cumulative tolerated dose) without dose-limiting symptoms during the double-blind placebo-controlled food challenge (DBPCFC).

Response status is defined as tolerating an oral dose of at least 1000 mg milk protein (2044 mg cumulative tolerated dose) without dose-limiting symptoms during the double-blind placebo-controlled food challenge (DBPCFC).

Response status is defined as tolerating an oral dose of at least 1000 mg egg protein (2044 mg cumulative tolerated dose) without dose-limiting symptoms during the double-blind placebo-controlled food challenge (DBPCFC).

Evaluate the safety of long-term treatment with remibrutinib in adult participants with moderate to severe Hidradenitis Suppurativa.

The EDSS is an ordinal scale used for assessing neurologic impairment in MS based on a neurological examination. It consists of scores in each of seven functional systems and an ambulation score that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). 6mCDP is defined as an increase from baseline in EDSS sustained for at least 6 months.

The UAS7 is the sum of the Weekly Hives Severity (HSS7) score and the Weekly Itch Severity (ISS7) score, and ranges from 0-42. Weekly scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 days preceding the visit.

Number of new/enlarging T2 lesions per year on MRI at month 24 (relative to baseline)

HiSCR50 is defined as at least a 50% decrease in Abscess and Inflammatory Nodule (AN) count with no increase in the number of abscesses and in the number of draining tunnels/fistulae compared to baseline.

The MG-ADL is a categorical scale that assesses MG symptoms and their effects on daily activities. MG-ADL is composed of items related to patient's assessment of functional disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. Each item is assessed on a 4-points scale where a score 0 represents normal function and a score 3 represents loss of ability to perform that function (total score 0 to 24).

Total Fric score (a scale from 0-4 where a positive response with all of the four pins is TFS = 4, while a positive response with only one pin - the largest pin is TFS = 1)

The Temptest is used to induce itch and hives in participants with cold urticaria. Critical temperature threshold (CTT), as measured by the Temptest, determines the highest temperature that induces symptoms.

Itch numerical rating scale, a scale from 0 to 10 Patients are asked to rate itching severity based on the worst level of itching in the past 24 h using an 11-point scale from 0 ("no itch") to 10 ("worst itch imaginable")

The UAS7 is the sum of the Weekly Hives Severity Score (HSS7 score) and the Weekly Itch Severity Score (ISS7 score). The possible range of the weekly UAS7 score is 0 - 42 (highest activity).

The Urticaria Activity Score (UAS) is sum of the Hive Severity Score (HSS) and the Itch Severity Score (ISS). UAS7 is sum of the HSS7 and the ISS7 scores. Possible range of weekly UAS7 score is 0 to 42. Complete UAS7 response is UAS7 = 0. Negative change from baseline indicates improvement.

Itch Severity Score (ISS) scale is 0 to 3. Score (ISS7) is derived by adding up average daily scores of 7 days preceding visit. Possible range of weekly score is therefore 0 to 21. Itch Severity Score scale: 0 - None 1 - Mild (minimal awareness, easily tolerated) 2 - Moderate (definite awareness, bothersome but tolerable) 3 - Severe (difficult to tolerate). Negative change from baseline indicates improvement.

Hives Severity Score (HSS) scale is 0 to 3. A weekly score (HSS7) is derived by adding up the average daily scores of the 7 days preceding the visit. Possible range of the weekly score is therefore 0 to 21. Hives Severity Score scale: 0 - None 1 - Mild (1-6 hives/12 hours) 2 - Moderate (7-12 hives/12 hours) 3 - Severe (\>12 hives/12 hours). Negative change from baseline indicates improvement.

A linear regression with SBP as a covariate was employed. The change in SBP from baseline to Week 4 was predicted at the median baseline level. The change from baseline in the 24-hour weighted average SBP was calculated using the time weighted average of the area under the curve (AUC) of SBP obtained over a 24-hour period as measured by ABPM. That is, the time weighted average of AUC of 24-hour SBP obtained at baseline was subtracted from corresponding time weighted average of AUC of SBP at Week 4. In the analysis, if participants took prohibited antihypertensive treatment before Week 4, their subsequent measurements were excluded. In such cases, the excluded measurements were imputed by increasing the 24-hour SBP by 3 mmHg from the baseline value at Week 4. Moreover, participants who discontinued of study treatment due to any reason prior to the Week 4 were excluded from the analysis. The Mixed Models for Repeated Measures (MMRM) approach was used.

The efficacy of remibrutinib in CSU participants with a UAS7\<16 at Week 52 in the prior core study with respect to time to first of the three events: relapse or study treatment discontinuation due to lack of efficacy or intake of strongly confounding prohibited medication up to Week 24 compared to placebo. (Epoch 1) Time to first composite event (i.e., relapse (UAS7≥16), study treatment discontinuation due to lack of efficacy or intake of strongly confounding prohibited medication) during the randomized withdrawal period (Epoch 1) Urticaria Activity Score (UAS7) describes the number of hives with 0 being No Hives and 3 is most severe. The final score is calculated by adding together daily scores which can range from 0-6 for 7 days. The resulting maximum score is then 42.

An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Treatment emergent Adverse Event (TEAEs) in this study are events that started after the first dose of study treatment and until 30 days after the last study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 30 days after the last study treatment.

ARR is the average number of confirmed MS relapses in a year

The Weekly Urticaria Activity Score (UAS7) is a simple scoring system to evaluate urticaria signs and symptoms. It is based on scoring wheals (hive severity score) and itch (itch severity score) separately on a scale of 0 (no signs/symptoms) to 3 (intense signs/symptoms) over 7 days. The final score is calculated by adding together the daily scores, which can range from 0 to 6, for 7 days. This results in a maximum total score of 42 (highest urticaria severity), and a minimum possible score of 0. This endpoint is a secondary endpoint for testing strategy Scenario 2 with Weekly Itch Severity Score (ISS7) and Weekly Hives Severity Score (HSS7) as co-primary efficacy endpoints).

The severity of the itch was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (severe). A weekly score (ISS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest itch severity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint).

The hives (wheals) severity score, defined by number of hives, was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (\> 12 hives/12 hours). A weekly score (HSS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest hives activity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint).

The Weekly Urticaria Activity Score (UAS7) is a simple scoring system to evaluate urticaria signs and symptoms. It is based on scoring wheals (hive severity score) and itch (itch severity score) separately on a scale of 0 (no signs/symptoms) to 3 (intense signs/symptoms) over 7 days. The final score is calculated by adding together the daily scores, which can range from 0 to 6, for 7 days. This results in a maximum total score of 42 (highest urticaria severity), and a minimum possible score of 0. This endpoint is a secondary endpoint for testing strategy Scenario 2 with Weekly Itch Severity Score (ISS7) and Weekly Hives Severity Score (HSS7) as co-primary efficacy endpoints).

The severity of the itch was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (severe). A weekly score (ISS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest itch severity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint).

The hives (wheals) severity score, defined by number of hives, was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (\> 12 hives/12 hours). A weekly score (HSS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest hives activity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint.

The facial inflammatory lesion count is defined as the sum of papules, pustules, and nodules present on the face. Lesions are visually counted across the full facial area (forehead, cheeks, nose, chin). A negative value indicates a reduction in lesions (clinical improvement), as lower counts reflect less inflammatory activity.

Rate of change in regional brain volumes using 7T MRI over 24 months

Prevalence of SELs identified using 7T MRI over 24 months

Change in count of PRLs identified using 7T MRI over 24 months

Change in size of PRLs identified using 7T MRI over 24 months

Change in quantitative susceptibility measures of PRLs identified using 7T MRI over 24 months

Rate of change in myelin water fraction assessed using 7T MRI over 24 months

Functional MRI changes (default mode network) assessed using 7T MRI over 24 months

Rate of change in microstructural tissue integrity assessed using 7T MRI over 24 months

Prevalence of leptomeningeal enhancement identified using 7T MRI over 24 months

Prevalence of regional neuromelanin changes identified using 7T MRI over 24 months

To investigate the efficacy of remibrutinib versus placebo for the most bothersome symptom in CINDU patients. The USDD was developed to assess daily exposure and avoidance of triggers, severity of urticaria symptoms (including NRS for pain itch and burning). On the first day of completion, the participants will be asked which symptom (itch, pain, and burning) is the most bothersome symptom of urticaria.

To investigate the impact of remibrutinib versus placebo on urticaria symptom control. The UCT is a 4-item PRO measure developed to assess disease control in patients with CU specifically CINDU and CSU. It has a 7-day recall period and participants respond with how much they were bothered by their urticaria symptoms, what is the impact on QoL, how often the treatment did not control their urticaria and their overall perception of disease control. Each question can be scored on a scale from 0 to 4 and the overall score ranges from 0 (no control) to 16 (maximum control). The cut-off value for disease control was established at 12. Participants with a score above 12 are considered controlled. A minimally important difference of 3 points was validated as reflective of a clinically relevant change of control.

Responder rate was defined as the percentage of participants tolerating a single dose of \>= 600 mg (1044 mg cumulative tolerated dose) of peanut protein without dose-limiting symptoms during the double blind placebo controlled food challenge (DBPCFC). The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive dose. Dose-limiting symptoms indicate a true allergic reaction occurring during administration of a single dose of peanut protein at the DBPCFC that should preclude the administration of any further doses in the view of the investigator. Symptoms that require administration of any rescue medication were considered dose-limiting symptoms.

An AE refers to any undesirable medical occurrence, such as an unintended sign (including abnormal laboratory findings), symptom, or disease, experienced by a participant. Serious AEs (SAEs) is defined as any AE that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or any other medically significant condition. Treatment-emergent AEs were defined as AEs that either begin on the same day or after the first dose of study medication during the treatment period in the extension study or worsen on the same day or after the first dose of study medication in the extension study and within the minimum of either 28 days post last dose or the end of the study visit. The number of participants with treatment-emergent AEs was summarized.

UAS7 score change (LS mean Change) from baseline at Week 4 estimated with a mixed-effect repeated measurement analysis of UAS7 score change from baseline (FAS) The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. A negative change score (week 4 score minus Baseline score) indicates improvement.

To evaluate the effect of remibrutinib compared with placebo.

The maximum (peak) observed concentration following multiple-dose administration

The area under the curve (AUC) from time zero to the end of the dosing interval (tau) following multiple-dose administration

Amount of unchanged drug excreted in the urine collection interval from time zero to 12 hours following multiple-dose administration

Renal clearance following multiple-dose administration

Clinically significant changes in physical examination and anamnesis, vital signs, ECG, safety laboratory will be reported under (S)AEs.