Three-arm Study to Assess Efficacy and Safety of Ianalumab (VAY736) in Patients With Active Sjogren's Syndrome

Inclusion criteria

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

- Women and men ≥ 18 years of age

- Classification of Sjögren's syndrome according to the ACR/EULAR 2016 criteria

- Time since diagnosis of Sjögren's of ≤ 7.5 years at screening

- Positive anti-Ro/SSA antibody at screening

- Patients negative for anti-Ro/SSA antibody are eligible, if they have a
positive salivary gland biopsy confirmed by central expert review

- Enrollment of anti-Ro/SSA-negative patients will be limited up to ≤10% of the
study population

- Screening ESSDAI score of ≥ 5 within the following 8 domains: constitutional,
lymphadenopathy, glandular, articular, cutaneous, renal, hematological and biologic.

- Stimulated whole salivary flow (sSF) rate of ≥ 0.05 mL/min at screening

- Ability to communicate well with the Investigator, understand and agree to comply
with the requirements of the study

- Patients taking hydroxychloroquine (≤ 400 mg/day), methotrexate (≤ 25 mg/week) or
azathioprine (≤ 150 mg/day) alone or in combination, are allowed to continue their
medication, and must have been on a stable dose for at least 30 days prior to
randomization.

- Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day
predniso(lo)ne or equivalent for at least 30 days before randomization.

- Patients taking

- disease-modifying antirheumatic drugs (DMARDs) other than specifically allowed
in inclusion criterion #9 or

- the following Traditional Chinese Medicines: Total glucoside of peony (TGP) or
Tripterium glycosides (TG) must discontinue these medications at least 30 days
prior to randomization, except for leflunomide, which has to be discontinued
for 8 weeks prior to randomization unless a cholestyramine wash-out has been
performed.

Exclusion Criteria:

- Presence of another autoimmune rheumatic disease that is active and constitutes the
principal illness

- Use of other investigational drugs within 5 half-lives of enrollment, or within 30
days or until the expected pharmacodynamic effect has returned to baseline,
whichever is longer3. Prior treatment with ianalumab

- Prior use of a B-cell depleting therapy other than ianalumab within 36 weeks prior
to randomization or as long as B-cell count is less than the lower limit of normal
or baseline value prior to receipt of previous B cell-depleting therapy (whichever
is lower)

- Prior treatment with any of the following:

1. Within 24 weeks prior to randomization: iscalimab (anti CD-40 mAb), belimumab ,
abatacept, anti-tumor necrosis factor alpha biologic agents, immunoglobulins
plasmapheresis;

2. Within 12 weeks prior to randomization: i.v. or oral cyclophosphamide,
mycophenolate mofetil, i.v. or oral cyclosporine A or any other
immunosuppressants (e.g., JAK inhibitors or other kinase inhibitors) unless
explicitly allowed by protocol

- Use of corticosteroids (predniso(lo)ne or equivalent corticosteroid) at dose >10
mg/day

- Any one of the following laboratory values at screening:

- Hemoglobin levels < 8.0 g/dL

- White blood cells (WBC) count < 2.0 x 10E3/µL

- Platelet count < 80 x 10E3/µL

- Absolute neutrophil count (ANC) < 0.8 x 10E3/µL

- Active viral, bacterial or other infections requiring systemic treatment at the time
of screening or randomization, or history of recurrent clinically significant
infection or of recurrent bacterial infections with encapsulated organisms

- History of hypersensitivity to any of the study drugs or its excipients or to drugs
of similar chemical classes (e.g., mAb of IgG1 class) or to any of the constituents
of the study drug formulation (sucrose, L-histidine hydrochloride/ L-histidine,
polysorbate 20)

- History of major organ, hematopoietic stem cell or bone marrow transplant

- Required regular use of medications known to cause dry mouth/eyes as a regular and
major side effect, and which have not been on a stable dose for at least 30 days
prior to Screening, or any anticipated change in the treatment regimen during the
course of the study.

- Use of topical ocular prescription medications (excluding artificial tears, gels,
lubricants) that have not been on a stable dose for at least 90 days prior to
randomization, or any anticipated change in the treatment regimen during the course
of the study

- Receipt of live/attenuated vaccine within a 4-week period prior to randomization

- History of primary or secondary immunodeficiency, including a positive human
immunodeficiency virus (HIV) test result

- History of malignancy of any organ system (other than localized basal cell carcinoma
of the skin or in situ cervical cancer or Sjögren's related lymphoma), treated or
untreated, within the past 5 years, regardless of whether there is evidence of local
recurrence or metastases.

- History of sarcoidosis

- Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetes
mellitus), psychiatric or additional physical condition that the Investigator feels
may jeopardize the patient in case of participation in this study

- Chronic infection with hepatitis B (HBV) or hepatitis C (HCV) virus. Positive
serology for hepatitis B surface antigen (HBsAg) excludes the subject.

- HBsAg negative subjects who are hepatitis B core antibody (HBcAb) positive are
also excluded unless all of the following criteria are met:

1. HBV DNA is negative

2. hepatitis B monitoring is implemented - in these subjects, monthly testing
of HBsAg and HBV DNA must be performed while on study treatment and at
least every 12 weeks after end of treatment for the entire duration of
safety follow-up.

3. Antiviral prophylaxis must be implemented before the first administration
of the study treatment, and continued up to 12 months after end of study
treatment. If antiviral therapy cannot be given or if the patient is not
willing to comply with the antiviral treatment requirement, the patient is
not eligible for the study.

- Hepatitis C: patients with positive hepatitis C antibody and HCV-RNA at
screening are excluded. Chronic hepatitis C patients who have completed HCV
anti-viral treatment must be HCV-RNA negative at least 12 weeks after treatment
before randomization to be eligible. Cases of spontaneous HCV clearance should
be discussed with sponsor before enrollment.

- Evidence of active tuberculosis (TB) infection is exclusionary. Patient with
previously treated TB and previously treated or newly diagnosed latent TB may be
eligible.

- Pregnant or nursing (lactating) women,

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
while on study treatment and for 6 months after stopping of investigational
medication.

- Patients with a known history of non-compliance to medication, or who were unable or
unwilling to complete PRO questionnaires, or who are unable or unwilling to use the
device for collection of PROs.

- United States (and other countries, if locally required): Sexually active males,
unless they agree to use barrier protection during intercourse with a woman of
childbearing potential, while taking study treatment. As condom use alone has a
reported failure rate exceeding 1% per year, it is recommended that female partners
of male study participants use a second method of birth control.

Although ianalumab is not teratogenic and/or genotoxic, and not transferred to semen,
male contraception is required, as requested by FDA.

Globally, for all sexually active males, contraception should be used in accordance with
locally approved prescribing information of concomitant medications administered.