Study the Efficacy and Safety of VAY736 and CFZ533 in SLE Patients

Study Overview
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Brief Summary
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This study is designed to evaluate the safety, tolerability, pharmacokinetics and therapeutic efficacy of treatment with either VAY736 or CFZ533 in patients with SLE to enable further development of these compounds as treatment in this disease population

Detailed Description
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A placebo-controlled, patient and investigator blinded, randomized parallel cohort study to assess pharmacodynamics, pharmacokinetics, safety, tolerability and preliminary clinical efficacy of VAY736 and CFZ533 in patients with systemic lupus erythematosus (SLE)

Official Title
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A Placebo-controlled, Patient and Investigator Blinded, Randomized Parallel Cohort Study to Assess Pharmacodynamics, Pharmacokinetics, Safety, Tolerability and Preliminary Clinical Efficacy of VAY736 and CFZ533 in Patients With Systemic Lupus Erythematosus (SLE)

Conditions
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Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
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* Drug: VAY736
* Drug: VAY736 Placebo
* Drug: CFZ533
* Drug: CFZ533 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any assessment is performed Fulfill ≥4 of the 11 American College of Rheumatology 1997 classification criteria for SLE Patient diagnosed with SLE for at least 6 months prior to screening Elevated serum titers at screening of ANA (≥1:80) of a pattern consistent with an SLE diagnosis, including at a minimum either anti-double stranded DNA (anti-ds DNA) or anti-Ro (SSA) or anti-La (SSB) or anti-nuclear ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm) Currently receiving corticosteroids and/or anti-malarial and/or thalidomide treatment and/or another DMARD on a stable dose according to protocol requirements SLEDAI-2K score of ≥6 at screening BILAG 2004 score of one A score either in the mucocutaneous or in the musculoskeletal domain or one B score in either the mucocutaneous or musculoskeletal domain and at least one A or B score in a second domain at screening Weigh at least 40 kg at screening Exclusion Criteria: Cohort 2 (CFZ533/Placebo) only: Patients who are at significant risk for thromboembolic events based on the following: History of either thrombosis or 3 or more spontaneous abortions Presence of lupus anticoagulant or significantly prolonged activated partial thromboplastin time (aPTT) consistent with co-existent anti-phospholipid syndrome and without concurrent prophylactic treatment with aspirin or anticoagulants as per local standard of care All Cohorts: History of receiving prior to screening: Within 12 weeks: i.v. corticosteroids, calcineurin inhibitors or other oral DMARD Within 24 weeks: cyclophosphamide or biologics such as intravenous Ig, plasmapheresis, anti-TNF-a mAb, CTLA4-Fc Ig (abatacept) or BAFF targeting agents (e.g., belimumab) Any B-cell depleting therapies (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening, and a B-cell count <50 cells/μ at the time of screening Evidence of past exposure to tuberculosis as assessed by Quantiferon testing at screening Presence of human immunodeficiency virus (HIV) infection at screening Severe organ dysfunction or life threatening disease; ECOG performance status > 1 at screening Presence of WHO Class III-IV renal involvement with proliferative disease Presence of severe lupus kidney disease as defined by proteinuria above 6 g/day or equivalent using spot urine protein creatinine ratio, or serum creatinine greater than 2.5 mg/dL (221.05 μmol/L), or requiring immune suppressive induction or maintenance treatment exceeding protocol defined limits Active viral, bacterial or other infections at the time of screening or enrollment Receipt of live/attenuated vaccine within a 2-month period before first dosing Uncontrolled, co-existing serious disease, e.g., uncontrolled hypertension, heart failure, type I diabetes, thyroid disease within 3 months prior to first dosing, or significant, unresolved illness within 2 weeks prior to first dosing History of hypersensitivity to drugs of similar chemical class Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). Subjects who are HBsAg negative and HBcAb positive are excluded unless negative for HBV DNA. Once past screening and enrolled into study, requirements for monitoring and antiviral treatment are enacted. Subjects with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The investigational drug or placebo will be administered on top of SLE background therapy. Patients will be randomized at baseline into one of two treatment cohorts (VAY736 or CFZ533) and to either active or placebo double blind treatment within that cohort. From Week 29 onwards all patients will receive open label active treatment until week 53 in the respective cohort.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 VAY736<br>multiple doses of VAY736, s.c. | Drug: VAY736<br>* Powder for solution for injection<br>|
| Placebo Comparator: Cohort 1 VAY736 Placebo<br>multiple doses of matching placebo s.c. until week 29. Multiple doses of VAY736, s.c from week 29 until week 53. | Drug: VAY736 Placebo<br>* Solution for injection<br>|
| Experimental: Cohort 2 CFZ533<br>multiple doses of CFZ533, i.v. | Drug: CFZ533<br>* Concentrate for solution for infusion<br>|
| Placebo Comparator: Cohort 2 CFZ533 Placebo<br>multiple doses of matching placebo i.v. until week 29. Multiple doses of CFZ533, i.v. from week 29 until week 53. | Drug: CFZ533 Placebo<br>* Solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SRI-4 response status | SRI-4 response status at Week 29 (reduced steroid dose maintained between Weeks 17 and 29). Clinical efficacy will be measured using the SLE Responder Index (SRI-4), a composite endpoint that incorporates SLEDAI-2K, BILAG 2004, and a visual analog scale (VAS) of physician-rated disease activity to determine patient improvement. | 29 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PhGA VAS - overall disease activity | Changes between baseline and Week 29 in the Physicians' Global Assessment (PhGA) visual analog scale (VAS) assessing patient's overall disease activity | from Baseline to Week 29 | 
| PGA VAS - global disease activity | Changes between baseline and Week 29 in the Patient's Global Assessment (PGA) visual analog scale (VAS) assessing patient's global disease activity | from baseline to Week 29 | 
| Flare rate and time to first flare | Flare rate and time to first flare, with flare defined as one new 'A' score or two or more 'B' score using BILAG -2004 | 18 months | 
| Time to first flare | Time to first flare, with flare defined as one new 'A' score or two or more 'B' score using BILAG -2004 | 18 months | 
| PK Cohort 1 - Cmax,ss | PK Cohort 1 (VAY736): free VAY736 serum concentration (Cmax at steady state) | 18+ months | 
| PK Cohort 1 - Ctrough,ss | PK Cohort 1 (VAY736): free VAY736 serum concentration (Ctrough at steady state) | 18+ months | 
| PK Cohort 2 - Cmax,ss | PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Cmax at steady state). | 18 months | 
| PK Cohort 2 - Ctrough,ss | PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Ctrough at steady state). | 18 months | 
| PD Cohort 2 (CFZ533): total soluble CD40 | PD Cohort 2 (CFZ533): total soluble CD40 in plasma. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Lupus Erythematosus, SLE, Anti-CD40, anti-BAFF-receptor, B-cell depletion, BAFF-receptor blockade, ianalumab, VAY736, iscalimab, CFZ533