A Phase 2 Study to Evaluate the Safety and Efficacy of LOU064 in Patients With Moderate to Severe Sjögren's Syndrome

ESSDAI is a validated disease outcome measure for Sjögren's Syndrome. The instrument contains 12 organ-specific domains contributing to disease activity: constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematological and biological. For each domain, features of disease activity were scored according to their severity. These scores were summed across the 12 domains in a weighted manner to provide the total score. ESSDAI total score ranges from 0 to 123 with higher values indicating more disease activity. A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSDAI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.

Time frame: Baseline, Week 24

Population: Participants in the Full Analysis Set (FAS) with a valid assessment for the outcome measure. FAS included all participants who were randomized in the study.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUC0-4h is defined as the area under the blood concentration-time curve from time zero to 4 hours post-dose, which was the last sampling time. The linear trapezoidal method was used for AUC0-4h calculation.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUC0-4h is defined as the area under the blood concentration-time curve from time zero to 4 hours post-dose, which was the last sampling time. The linear trapezoidal method was used for AUC0-4h calculation.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUCtau is defined as the area under the blood concentration-time curve calculated/extrapolated to the end of a dosing interval (tau) at steady-state. Tau was 24 hours for the qd dosing group and 12 hours for the bid dosing group. For the calculation of AUCtau, the pre-dose concentrations at Week 4 and Week 24 were duplicated as 24 hours and 12 hours concentrations for the qd and bid groups, respectively. The linear trapezoidal method was used for AUCtau calculation.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUCtau is defined as the area under the blood concentration-time curve calculated/extrapolated to the end of a dosing interval (tau) at steady-state. Tau was 24 hours for the qd dosing group and 12 hours for the bid dosing group. For the calculation of AUCtau, the pre-dose concentrations at Week 4 and Week 24 were duplicated as 24 hours and 12 hours concentrations for the qd and bid groups, respectively. The linear trapezoidal method was used for AUCtau calculation.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

ESSDAI is a validated disease outcome measure for Sjögren's Syndrome. The instrument contains 12 organ-specific domains contributing to disease activity: constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematological and biological. For each domain, features of disease activity were scored according to their severity. These scores were summed across the 12 domains in a weighted manner to provide the total score. ESSDAI total score ranges from 0 to 123 with higher values indicating more disease activity. A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSDAI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.

Time frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20

Population: Participants in the Full Analysis Set (FAS) with a valid assessment for the outcome measure. FAS included all participants who were randomized in the study.

ESSPRI is an established disease outcome measure for Sjögren's Syndrome. It consists of three domains of dryness, pain, and fatigue. The patient can assess the severity of symptoms they experience on a single 0-10 numerical scale for each of the three domains. The ESSPRI score is defined as the mean of scores from the three scales: (dryness + pain +fatigue) /3. ESSPRI total score ranges from 0 to 10 with higher values indicating more disease symptoms. A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSPRI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.

Time frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24

Population: Participants in the Full Analysis Set (FAS) with a valid assessment for the outcome measure. FAS included all participants who were randomized in the study.

EQ-5D is a standardized instrument that measures the health-related quality of life. The EQ-5D consists of a descriptive system and a visual analog scale (VAS).The EQ-5D VAS records the patient's self-rated health on a vertical visual analogue scale with 0 representing 'Worst imaginable Health State' and 100 'Best imaginable Health State'. A positive change from baseline is a favorable outcome. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in EQ-5D VAS score for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.

Time frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24

Population: Participants in the Full Analysis Set (FAS) with a valid assessment for the outcome measure. FAS included all participants who were randomized in the study.

FACIT-F v4 is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue was measured on a 5-point Likert scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). FACIT-F total score ranges from 0 to 52 with higher values indicating higher quality of life (less fatigue). A positive change from baseline is a favorable outcome. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in FACIT-F for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.

Time frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24

Population: Participants in the Full Analysis Set (FAS) with a valid assessment for the outcome measure. FAS included all participants who were randomized in the study.

The physician's global assessment scale was used for the Investigator to rate the disease activity of their patient using 100 mm visual analog scale (VAS) ranging from no disease activity (0) to maximal disease activity (100). A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in PhGA score for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.

Time frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24

Population: Participants in the Full Analysis Set (FAS) with a valid assessment for the outcome measure. FAS included all participants who were randomized in the study.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. T1/2 is defined as the time taken for the blood concentration, as well as the amount of the drug in the body, to fall by one-half.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. T1/2 is defined as the time taken for the blood concentration, as well as the amount of the drug in the body, to fall by one-half.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Cmax is defined as the maximum (peak) observed blood concentration following a dose.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Cmax is defined as the maximum (peak) observed blood concentration following a dose.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as TEAEs. TEAEs are defined as adverse events that started after the first dose of study medications or adverse events present prior to start of double-blind treatment but increased in severity. The number of participants in each category is reported in the table.

Time frame: From first dose of study treatment up 30 days after last dose (Week 29)

Population: Safety Analysis Set defined as participants who received at least one dose of the study drug.

Remibrutinib was determined in whole blood by a validated LC-MS/MS method with a LLOQ of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Tmax is defined as the time to reach maximum (peak) blood concentration following a dose.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.

Remibrutinib was determined in whole blood by a validated LC-MS/MS method with a LLOQ of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Tmax is defined as the time to reach maximum (peak) blood concentration following a dose.

Time frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4

Population: Participants in the PK Analysis Set (PKS) with a valid value for the outcome measure. PKS is defined as participants with at least one available valid PK concentration measurement, who received any study drug, and with no protocol deviations that impact PK data.