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 apositive salivary gland biopsy confirmed by central expert review

• Enrollment of anti-Ro/SSA-negative patients will be limited up to ≤10% of thestudy 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 complywith the requirements of the study

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

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

• Patients taking

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

• the following Traditional Chinese Medicines: Total glucoside of peony (TGP) orTripterium glycosides (TG) must discontinue these medications at least 30 daysprior to randomization, except for leflunomide, which has to be discontinuedfor 8 weeks prior to randomization unless a cholestyramine wash-out has beenperformed.

Exclusion Criteria:

• Presence of another autoimmune rheumatic disease that is active and constitutes theprincipal illness

• Use of other investigational drugs within 5 half-lives of enrollment, or within 30days 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 priorto randomization or as long as B-cell count is less than the lower limit of normalor baseline value prior to receipt of previous B cell-depleting therapy (whicheveris 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, immunoglobulinsplasmapheresis;

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

• Use of corticosteroids (predniso(lo)ne or equivalent corticosteroid) at dose >10mg/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 timeof screening or randomization, or history of recurrent clinically significantinfection or of recurrent bacterial infections with encapsulated organisms

• History of hypersensitivity to any of the study drugs or its excipients or to drugsof similar chemical classes (e.g., mAb of IgG1 class) or to any of the constituentsof 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 andmajor side effect, and which have not been on a stable dose for at least 30 daysprior to Screening, or any anticipated change in the treatment regimen during thecourse 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 torandomization, or any anticipated change in the treatment regimen during the courseof the study

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

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

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

• History of sarcoidosis

• Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetesmellitus), psychiatric or additional physical condition that the Investigator feelsmay jeopardize the patient in case of participation in this study

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

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

1. HBV DNA is negative
2. hepatitis B monitoring is implemented - in these subjects, monthly testingof HBsAg and HBV DNA must be performed while on study treatment and atleast every 12 weeks after end of treatment for the entire duration ofsafety follow-up.
3. Antiviral prophylaxis must be implemented before the first administrationof the study treatment, and continued up to 12 months after end of studytreatment. If antiviral therapy cannot be given or if the patient is notwilling to comply with the antiviral treatment requirement, the patient isnot eligible for the study.

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

• Evidence of active tuberculosis (TB) infection is exclusionary. Patient withpreviously treated TB and previously treated or newly diagnosed latent TB may beeligible.

• Pregnant or nursing (lactating) women,

• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionwhile on study treatment and for 6 months after stopping of investigationalmedication.

• Patients with a known history of non-compliance to medication, or who were unable orunwilling to complete PRO questionnaires, or who are unable or unwilling to use thedevice 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 ofchildbearing potential, while taking study treatment. As condom use alone has areported failure rate exceeding 1% per year, it is recommended that female partnersof 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.