Trial Outcomes & Findings for PK, PD, Safety, and Efficacy of SAIT101 Versus MabThera® Versus Rituxan® in Patients With Rheumatoid Arthritis (NCT NCT02819726)

This was a global study conducted in 66 study centres. The first participant entered the study on 11 October 2016 and the date of the last participants last study visit was 07 November 2018.

Results were not available for 1 participant in each treatment arm

Pharmacokinetic endpoint: Area under the concentration-time curve from time 0 (immediately predose on Day 1) to last quantifiable concentration (AUC0-t). Geometric means by treatment (Pharmacokinetic Analysis Set).

Pharmacokinetic endpoint: Area Under the Plasma Concentration from time 0 to infinity (AUC0-∞ (infinity). Calculated by linear up/log down trapezoidal summation and extrapolated to infinity by addition of the last quantifiable concentration divided by the elimination rate constant: AUC(0-last) + C(last)/λz.

Pharmacokinetic endpoint: Area Under the Concentration verses time from time 0 to Day 15 prior to infusion (AUC0-D15) calculated by linear up/log down trapezoidal summation. Actual time/concentration on Day 15 was used for the calculation of this parameter unless the parameter was derived by interpolation.

Pharmacokinetic endpoint: Maximum Plasma Concentration (Cmax) after Day 15 infusion (Dose 2)

Pharmacokinetic endpoint: Trough concentration (Ctrough) before the second infusion on Day 15 (Dose 2). Trough (pre-dose) concentration prior to second infusion on Day 15 obtained directly from the observed concentration versus time data.

Disease Activity Score 28 C-reactive protein score (DAS28-CRP) at Week 24 (Full Analysis Set). CRP samples were collected at Baseline and Weeks 8, 16 and 24. DAS28-CRP was calculated using the following equation: \[0.56\*Square Root (SQRT) (tender 28 joint count)+0.28\*SQRT(swollen 28 joint count)+0.36\*ln(CRP+1)\]\*1.10+1.15. Total DAS28-CRP scores were calculates and range from 2.0 (minimum) to 10 (maximum). Lower scores represent a better patient outcome. Disease remission is considered achieved if the score is between 0 and \<2.6. Low disease activity corresponds to 2.6 to \<3.2. Moderate activity is between 3.2 \& ≤5.1, while high activity is above 5.1.

Pharmacokinetic endpoint: Area under the concentration time curve week 2 to week 24 (AUC(w2-24) calculated by linear up/log down trapezoidal summation.

Pharmacokinetic endpoint: Area under the concentration time curve Day 0 to Week 12 calculated by linear up/log down trapezoidal summation.

Pharmacokinetic endpoint: Maximum plasma concentration over the first dosing interval obtained directly from the observed concentration versus time data.

Time of maximum concentration postinfusion over the second dosing interval, obtained directly from the observed concentration versus time data.

Pharmacokinetic endpoint: Apparent terminal rate constant (λz) determined by linear regression of the terminal points of the log-linear concentration-time curve. Best fit method followed by visual assessment was used to identify the terminal linear phase of the concentration-time profile. A minimum of 3 data points was used for determination.

Pharmacokinetic endpoint: Systemic clearance (CL) over the first dosing period calculated as dose (first + second dose) divided by AUC(0-∞).

Pharmacokinetic endpoint: Volume of distribution (VD) over the first dosing period calculated as dose (first + second dose) divided by \[λz AUC(0-∞)\]

Pharmacokinetic endpoint: Terminal half-life determined as ln2/λz.

Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) samples taken at Baseline and Weeks 8, 16, 24, 36 and 52. DAS28-CRP was calculated using the following equation: \[0.56\*Square Root (SQRT) (tender 28 joint count)+0.28\*SQRT(swollen 28 joint count)+0.36\*ln(CRP+1)\]\*1.10+1.15. Total DAS28-CRP scores are presented and range from 2.0 (minimum) to 10 (maximum). Lower scores represent a better patient outcome. Disease remission is considered achieved if the score is between 0 and \<2.6. Low disease activity corresponds to 2.6 to \<3.2. Moderate activity is between 3.2 \& ≤5.1, while high activity is above 5.1.

American Collage of Rheumatology (ACR) 20% response criteria (ACR20) response rates were assessed at Baseline and Weeks 8, 16, 24, 36 and 52. An ACR20 response is defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[Health Assessment Questionnaire (HAQ)\], visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).

Efficacy endpoint: American Collage of Rheumatology 50% response criteria (ACR50) response rates and American Collage of Rheumatology 70% response criteria (ACR70) at weeks 8, 16, 24, 36 and 52. An ACR50 response is defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[Health Assessment Questionnaire (HAQ)\], visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). An ACR70 response is defined as both improvement of 70% in the number of tender and number of swollen joints, and a 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure \[Health Assessment Questionnaire (HAQ)\], visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).

Efficacy endpoint: Individual components of the ACR improvement criteria on Day 1 and at weeks 8, 16, 24, 36 and 52: Swollen Joint Count (SJC) and tender joint count (TJC) (the 66/68 joint count system). SJC and TJC assess the level of skeletal disease involvement. The 66/68 Joint Count evaluates 66 joints for swelling and 68 joints for tenderness.

Efficacy endpoint: Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Physicians global assessment of disease activity (assessed on 1 to 100 mm Visual Analog Scale \[VAS\]). Where 0 = no disease activity and 100 = maximum disease activity.

Participants assessment of pain (assessed on 1 to 100 mm Visual Analog Scale \[VAS\]). Participants assessment of pain (assessed on 1 to 100 mm Visual Analog Scale \[VAS\]) where 0 = no pain and 100 = severe pain.

Efficacy endpoint: Individual Components of the ACR Improvement Criteria on Day 1 and at Weeks 8, 16, 24, 36 and 52: Participants global assessment of disease activity (assessed on 1 to 100 mm visual analogue scale \[VAS\]). Patients rate how their Rheumatoid Arthritis has affected them, where 0 = very well and 100 = very poor.

the Health Assessment Questionnaire-Disability Index (HAQ-DI) contains 20 questions split into 8 categories (dressing \& grooming, arising, eating, walking, hygiene, reach, grip \& activities). Scores were: 0 = Without ANY Difficulty; 1 = With SOME Difficulty; 2 = With MUCH Difficulty; 3 = UNABLE to Do. Total scores were calculated as the summed category scores divided by the number of categories. Total HAQ-DI scores are presented which range from 0 to 3. Higher scores represent a worse outcome. Scores of 0 to 1 represent mild to moderate difficulty, 1 to 2 moderate disability, and 2 to 3 severe to very severe disability.

C-reactive protein (CRP) level (Mg/L). CRP is a marker for inflammation. a normal reading is \<3 Mg/L. Higher values indicate disease related inflammation and increased cardiovascular risk. CRP levels between 3 Mg/L and 10 Mg/L are mildly elevated. Levels between 10 Mg/L and 100 Mg/L are moderately elevated and CRP levels above 100 Mg/L are severely elevated.

Disease Activity Score 28- Erythrocyte Sedimentation Rate (DAS28-ESR) consisted of tender joint counts (TJC), swollen joint counts (SJC) \& erythrocyte sedimentation rate (ESR). The formula is: \[0.56\*SQRT(tender 28 joint count)+0.28\*SQRT(swollen 28 joint count)+0.7\*ln(ESR)\]+0.014\*patient global health assessment. Total DAS28-ESR scores are presented. Total scores range from 2 (minimum) to 10 (maximum). A lower score represents a better patient outcome. A DAS28-ESR of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.

Efficacy endpoint: number of participants with a major clinical response defined as a continuous ACR70 from Baseline (Day 1) for at least 24 weeks. ACR70 is a measure based on American College of Rheumatology criteria of at least a 70% improvement in the number of tender and swollen joints, and a 70% improvement in at least 3 of the following: the patient's global assessment of disease status; the patient's assessment of pain; the patient's assessment of function measured using the Stanford Health Assessment Questionnaire the physician's global assessment of disease status; serum C-reactive protein levels.

Number if Participants with a Clinical Remission Response (CRR) defined by the Simplified Disease Activity Index (SDAI) \<3.3 at weeks 8, 16, 24, 36 and 52 (EOS).

Efficacy endpoint: Proportion of participants with European League Against Rheumatism (EULAR) response (defined as good response, moderate response or no response) at weeks 8, 16, 24 36 and 52 (EOS). EULAR (European League Against Rheumatism) response was classified using the individual amount of change in the DAS28-CRP score. The DAS28-CRP was classified into 3 categories: low disease activity (\<= 3.2), moderate disease activity (\> 3.2 and \<= 5.1) and high disease activity (\> 5.1). Good response was defined as \>1.2 improvement in the DAS28-CRP from baseline with low disease activity.

Change from baseline (Day 1) in immunoglobulin G (IgG), Immunoglobulin M (IgM) and Immunoglobulin A (IgA) levels (mg/dL) at Week 8, 16, 24 36 and 52 (End of study)

Pharmacodynamic endpoint: proportion of participants (n) with depletion of CD19+ B-cell count up to week 24 (Pharmacodynamic analysis set).

Time needed to CD19+ B-cell depletion in Part A (calculated as the first time CD19+ B-cell count below 20/µL minus time of first dosing in days).

Duration of CD19+ B-cell depletion (only participants that returned to non-depletion at or before week 24 were included)

Number of participants with CD19+ B-cell count recover versus baseline. Incidence of B-Cell recovery was defined as either CD19+ B-cell counts retuned to baseline or the lower limit or normal of 110 cells/µL at week 24).

Area under the concentration time curve of CD19 B-cell count change at Day 15 (AUEC0-d15) and week 24 (AUEC0-w24) based on change from baseline and percent of baseline values

Pharmacodynamic endpoint: Descriptive statistics (mean \[SD\]) of the change from baseline in CD19+ B-cell count during the study period (Day 15 \[AUEC(0-d15\] and Week 24 \[AUEC(0-w24\])

Pharmacodynamic endpoint: Change from baseline (Day 1) in C-reactive protein (CRP) levels (mg/dL) at weeks 8, 16, 24, 36 and 52 (EOS)