Study of Safety and Efficacy of Multiple Doses of CFZ533 in Two Distinct Populations of Patients With Sjogren's Syndrome

A 48-week, 6-arm, Randomized, Double-blind, Placebo-controlled Multicenter Trial to Assess the Safety and Efficacy of Multiple CFZ533 Doses Administered Subcutaneously in Two Distinct Populations of Patients With Sjogren's Syndrome (TWINSS)

This study was to evaluate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple doses of CFZ533 (iscalimab) in patients with Sjögren's Syndrome (SjS).

This study consisted of a 6-week screening, 2 treatment periods of 24 weeks each, and a follow-up period of 12 weeks. In Periods 1 and 2, thirteen (13) treatment administration visits were planned, including a weekly loading regimen (2 visits) at the start of each treatment period. One administration equaled to two subcutaneous (s.c.) injections.

This study included two distinct cohorts termed Cohort 1 and Cohort 2.

• Cohort 1: subjects with moderate-to-severe systemic and symptomatic disease involvement.
• Cohort 2: subjects with low systemic disease involvement but high symptom burden.

Inclusion Criteria:

Both cohorts must have met all the following criteria:

1. Signed informed consent must be obtained prior to participation in the study

2. Male or female patient >= 18 years of age

3. Classification of Sjögren's Syndrome according to ACR/EULAR 2016 criteria (Shiboski et al 2016)

4. Seropositive for anti-Ro/SSA antibodies

5. Stimulated whole salivary flow rate of >= 0.1 mL/min

6. Able to communicate well with the Investigator to understand and comply with the requirements of the study

   Inclusion criteria specific for Cohort 1:

7. Screening ESSDAI value >= 5 within the following 8 organ domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, renal, hematologic and biologic

   • Patients with involvement of one or more of the remaining 4 domains are eligible but scores of these domains will not contribute to the assessment for eligibility for Cohort 1
   • At selected sites participating in Cohort 2, patients who based on the above criterion 7, do not qualify for Cohort 1, should be further evaluated for Cohort 2

8. Screening ESSPRI score of >= 5

   Inclusion criteria specific for Cohort 2:

9. Screening ESSDAI value < 5 within 8 domains scored for inclusion criterion #7 Cohort 1

10. Screening ESSPRI fatigue subscore >= 5 or ESSPRI dryness subscore >= 5

11. Hypergammaglobulinemia defined by IgG greater than upper limit of normal (ULN) or lymphocytopenia (less than lower limit of normal (LLN)) or hypocomplementemia (low C3, or low C4 - when considered due to disease activity and not due to genetic factors)

12. Score of >= 30 on IDEEL symptom bother questionnaire at Screening

Exclusion Criteria:

1. Sjögren's Syndrome overlap syndromes where another autoimmune rheumatic disease constitutes the principal illness

2. Use of other investigational drugs within 5 half-lives of enrollment or within 30 days whichever is longer, or longer if required by local regulations

3. Prior treatment with any of the following within 6 months prior to randomization:

   • B-cell depletors (e.g. rituximab, ianalumab) unless CD19+ B cell count have returned to ≥ 50 cells/µL
   • abatacept
   • anti-tumor necrosis factor alpha monoclonal anti-body
   • intravenous/subcutaneous Ig; plasmapheresis; i.v. or oral cyclophosphamide
   • i.v. or oral cyclosporine A
   • any other immunosuppressants unless explicitly allowed in criterion #5

4. Use of steroids (predniso(lo)ne or equivalent corticosteroid) at dose > 10 mg/day

5. Use of steroids and synthetic DMARDS at inconsistent dose and within 3 months prior to randomization