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

A randomized, double-blind, placebo controlled, 2-arm multicenter phase 3 study to assess the efficacy and safety of ianalumab in patients with active Sjogren's syndrome (NEPTUNUS-1)

Two-arm study of the clinical efficacy, safety and tolerability of ianalumab (VAY736) in patients with active Sjogren's syndrome. The purpose of the study is to demonstrate the clinical efficacy, safety and tolerability of ianalumab (VAY736) administered subcutaneously (s.c.) monthly compared to placebo in patients with active Sjogren's syndrome.

Eligibility Criteria:
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 by protocol
  * 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 and 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 the 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. Patients 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.