A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis

The ACR20 response was a composite measure of clinical, laboratory, and functional assessments used to evaluate improvement in rheumatoid arthritis signs and symptoms. ACR20 responders were participants with at least 20% improvement from baseline in tender joint count (TJC) and swollen joint count (SJC), and at least 20% improvement in 3 of the 5 remaining core measures: Patient's Assessment of Arthritis Pain, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) which measures participants' perceived degree of difficulty performing daily activities, and acute phase reactant as measured by high-sensitivity C-reactive protein (hsCRP). Percentage of participants achieving ACR20 response= (number of ACR20 responders)/ (number of participants analyzed) \*100.

Time frame: Week 12

Population: All randomized participants who received atleast one dose of study drug. Non-Responder Imputation (NRI) was applied for participants who had missing data, used rescue or prohibited medication or early discontinued from study or study intervention before or at Week 12. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

CDAI is a tool for measurement of disease activity in rheumatoid arthritis that does not require laboratory component and was scored by the investigative site. It integrates TJC28 (scored 0-28 with higher scores indicating higher disease activity), SJC28 (scored 0-28 with higher scores indicating higher disease activity), Patient's Global Assessment of Disease Activity (scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity), and Physician's Global Assessment of Disease Activity(scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity).CDAI is calculated by summing values of 4 components. CDAI scores range from 0 to 76; lower scores indicated lower disease activity. Negative change from baseline indicates improvement. LS Mean was calculated using MMRM with treatment, stratification factors, baseline value, visit, treatment-by-visit interaction as fixed factors and participant as a random factor.

Time frame: Baseline, Week 12

Population: All randomized participants who received atleast one dose of study drug and had data for CDAI. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

DAS based on 28 joints consisted of composite numerical score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP = 0.56\*sqrt (TJC28) + 0.28\*sqrt (SJC28)+ 0.014\* patient's global assessment of disease activity + 0.36\*natural log(hsCRP+1) +0.96. Total scores ranged 1.0-9.4; lower scores indicated lower disease activity. A negative change from baseline indicates improvement in condition. Least Square (LS) Mean was calculated using mixed model repeated measures (MMRM) with treatment, stratification factors, baseline value, visit, treatment-by-visit interaction as fixed factors and participant as a random factor.

Time frame: Baseline, Week 12

Population: All randomized participants who received atleast one dose of study drug and had data for DAS28-hsCRP. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

HAQ-DI was a patient-reported questionnaire used in rheumatoid arthritis to assess physical function over the past week. It covered 8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities. Each activity category consists of 2 to 3 items. Each item is scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Any activity requiring assistance from another individual or the use of an assistive device adjusts to a minimum score of 2 to represent a more limited functional status. Total score was computed as the sum of domain scores and divided by the number of domains answered. The total score ranges from 0 to 3, with higher scores indicating greater physical limitations. LS Mean was calculated using MMRM with treatment, stratification factors, baseline value, visit and treatment-by-visit interaction as fixed effects and participant as a random effect.

Time frame: Baseline, Week 12

Population: All randomized participants who received atleast one dose of study drug and had data for HAQ-DI outcome. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

Minimum observed concentration of peresolimab was assessed and stratified by Treatment-Emergent Anti-Drug Antibody (TE-ADA) status (TE ADA positive and TE ADA negative). A TE ADA evaluable participant was defined as TE ADA positive if they met the following criteria: 1. Had baseline status of ADA Not Present and at least 1 postbaseline status of ADA Present with titer ≥ 2×minimum required dilution (MRD) of the ADA assay (Treatment Induced TE ADA). The MRD of peresolimab is 1:10. 2. Had baseline and postbaseline status of ADA Present, with the postbaseline titer being 2 dilutions (4-fold) greater than the baseline titer. TE-ADA negative participants were defined as those not meeting the TE ADA positive criteria.

Time frame: Baseline through Week 12

Population: All randomized participants who received atleast one dose of study drug and had TE-ADA data for this outcome. Participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups). No study participant treated with peresolimab 1000 mg Q4W had a positive TE-ADA result up to Week 12; thus, zero participants analyzed and no data were collected.

The ACR50 response was a composite measure of clinical, laboratory, and functional assessments used to evaluate improvement in rheumatoid arthritis signs and symptoms. ACR50 responders were participants with at least 50% improvement from baseline in TJC and SJC, and at least 50% improvement in 3 of the 5 remaining core measures: Patient's Assessment of Arthritis Pain, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, HAQ-DI which measures participants' perceived degree of difficulty performing daily activities, and acute phase reactant as measured by hsCRP. Percentage of participants achieving ACR50 response = (number of ACR50 responders) / (number of participants analyzed) \* 100.

Time frame: Week 12

Population: All randomized participants who received atleast one dose of study drug. NRI was applied for participants who had missing data, used rescue or prohibited medication or early discontinued from study or study intervention before or at Week 12. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

The ACR70 response was a composite measure of clinical, laboratory, and functional assessments used to evaluate improvement in rheumatoid arthritis signs and symptoms. ACR70 responders were participants with at least 70% improvement from baseline in TJC and SJC, and at least 70% improvement in 3 of the 5 remaining core measures: Patient's Assessment of Arthritis Pain, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, HAQ-DI which measures participants' perceived degree of difficulty performing daily activities, and acute phase reactant as measured by hsCRP. Percentage of participants achieving ACR70 response = (number of ACR70 responders) / (number of participants analyzed) \* 100.

Time frame: Week 12

Population: All randomized participants who received atleast one dose of study drug. NRI was applied for participants who had missing data, used rescue or prohibited medication or early discontinued from study or study intervention before or at Week 12. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

Low disease activity was defined as a CDAI score of ≤10. CDAI is a tool for measurement of disease activity in rheumatoid arthritis that does not require a laboratory component and was scored by the investigative site. It integrates TJC28 (scored 0-28 with higher scores indicating higher disease activity), SJC28 (scored 0-28 with higher scores indicating higher disease activity), Patient's Global Assessment of Disease Activity (scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity), and Physician's Global Assessment of Disease Activity (scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity). CDAI is calculated by summing the values of the 4 components. CDAI scores range from 0 to 76; lower scores indicated lower disease activity.

Time frame: Week 12

Population: All randomized participants who received atleast one dose of study drug. NRI was applied for participants who had missing data, used rescue or prohibited medication or early discontinued from study or study intervention before or at Week 12. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

Remission was defined as a CDAI score of ≤2.8. CDAI is a tool for measurement of disease activity in rheumatoid arthritis that does not require a laboratory component and was scored by the investigative site. It integrates TJC28 (scored 0-28 with higher scores indicating higher disease activity), SJC28 (scored 0-28 with higher scores indicating higher disease activity), Patient's Global Assessment of Disease Activity (scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity), and Physician's Global Assessment of Disease Activity (scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity). The CDAI is calculated by summing the values of the 4 components. CDAI scores range from 0 to 76; lower scores indicated lower disease activity.

Time frame: Week 12

Population: All randomized participants who received atleast one dose of study drug. NRI was applied for participants who had missing data, used rescue or prohibited medication or early discontinued from study or study intervention before or at Week 12. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

DAS28-hsCRP LDA was defined as DAS28-hsCRP score of ≤3.2. The Disease Activity Score (DAS) based on 28 joint counts consisted of a composite numerical score derived from the following variables: tender joint count (0 to 28), swollen joint count (0 to 28), high-sensitivity C-reactive protein (hsCRP, mg/mL), and the patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56\*square root (sqrt) (TJC28) plus (+) 0.28\*sqrt (SJC28)+ 0.014\* participant's global assessment of disease activity+ 0.36\*natural log(hsCRP+1) + 0.96. Total Scores ranged from 1.0 to 9.4, with lower scores indicating less disease activity.

Time frame: Week 12

Population: All randomized participants who received atleast one dose of study drug. NRI was applied for participants who had missing data, used rescue or prohibited medication or early discontinued from study or study intervention before or at Week 12. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).

DAS28-hsCRP remission is defined as DAS28-hsCRP \<2.6. DAS based on 28 joints consisted of composite numerical score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP=0.56\*sqrt (TJC28) + 0.28\*sqrt (SJC28) + 0.014\* patient's global assessment of disease activity + 0.36\*natural log(hsCRP+1) +0.96. Total Scores ranged from 1.0-9.4, where lower scores indicated less disease activity.

Time frame: Week 12

Population: All randomized participants who received atleast one dose of study drug. NRI was applied for participants who had missing data, used rescue or prohibited medication or early discontinued from study or study intervention before or at Week 12. As pre-specified in the SAP, participants receiving the same initial treatment were grouped together based on treatment from Week 0 to Week 12 (Placebo) and Week 0 to Week 24 (Peresolimab 1000 mg and 400 mg groups).