Efficacy and Safety of Belimumab in Subjects With Primary Sjögren's Syndrome

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by an increase in BAFF (BLyS) levels and a resulting B cell hyperactivity. B cells are involved in the pathogenesis of SS in both systemic and glandular features, and B cell downregulation may lead to a decrease of disease activity. Moreover, pathogenesis of SS is closed to that of Systemic lupus erythematosus, where Belimumab has been proven to be effective.

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by an increase in BAFF (BLyS) levels and a resulting B cell hyperactivity. B cells are involved in the pathogenesis of SS in both systemic and glandular features, and B cell downregulation may lead to a decrease of disease activity. Moreover, pathogenesis of SS is closed to that of Systemic lupus erythematosus, where Belimumab has been proven to be effective.

This phase II open-label study has 2 mains objectives:

* To evaluate the proof of concept of efficacy of belimumab in subjects with SS
* To evaluate the safety and tolerability of belimumab in subjects with SS Belimumab will be administered (10mg/kg on D0 D14 D28 and every 28 days for 24 weeks, with extension to 48 weeks if responders) to all patients

Eligibility Criteria:
Inclusion Criteria:

* Have a diagnosis of primary SS according to the updated American European Consensus Group Criteria. In addition, patients must be always positive for anti-SSA or anti-SSB antibodies
* Have the presence, at screening, of Systemic involvement (polysynovitis, skin, renal, lung, CNS involvement, peripheral neuropathy, vasculitis, autoimmune cytopenia, defined in Annex 1) or persistent (up to 2 months) parotid, submandibular or lachrymal gland swelling of more than 2 cm OR

Objective sicca (positive oral and/or ocular tests reported in the American European Consensus Group Criteria) with at least one among the following biological features of serum B lymphocyte activation :

increased IgG levels increased free light chain levels of immunoglobulins (according to central laboratory ranges) increased serum beta2-microglobulin levels decreased C4 levels (C4 levels inferior to central laboratory ranges) monoclonal gammapathy cryoglobulinemia OR

* SS of more recent onset, i.e., less than 5 years of duration of symptoms, associated with:

  * oral or ocular dryness
  * fatigue
  * musculoskeletal pain (i.e, 3 criteria for response as reported at page (ix-x), characterized by VAS score more than 50/100 in all the 3 fields.

Exclusion Criteria:

1. Any BLyS-targeted (BLyS-receptor fusion protein \[BR3\], TACI Fc, or belimumab) at any time.
2. Any of the following within 364 days of Day 0:

   * B-cell targeted therapy (eg, rituximab, other anti-CD20 agents, anti-CD22 \[epratuzumab\], anti-CD52 \[alemtuzumab\]
   * A biologic investigational agent other than B cell targeted therapy (eg, abetimus sodium, anti CD40L antibody \[BG9588/ IDEC 131\]).

4- Intravenous or oral cyclophosphamide within 180 days of Day 0.

5- Any of the following within 90 days of Day 0:

* Anti-TNF therapy
* Interleukin-1 receptor antagonist
* Abatacept
* Interleukin-6 receptor antagonist
* Intravenous immunoglobulin
* Prednisone \> 100 mg/day
* Plasmapheresis.

  9- Very severe SS disease.

  10- Major organ or hematopoietic stem cell/marrow transplant.

  11- Unstable or uncontrolled acute or chronic diseases not due to SS

  13- History of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.

  14- Required management of acute or chronic infections, as follows:
* Currently on any suppressive therapy for a chronic infection
* Hospitalization for treatment of infection within 60 days of Day 0.
* Use of parenteral (IV or IM) antibiotics

  16- Historically or at screening positive test for HIV antibody, hepatitis C virus antibodies, or, hepatitis B surface antigen (HbsAg) (with or without positive serum HBV DNA), or antiHBcAg positivity (without anti-HbsAg positivity).

  17- Grade 3 or greater laboratory abnormality based on the protocol toxicity scale except for the following that are allowed:
* Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.
* Stable Grade 3/4 proteinuria (≤ 6 g/24 hour equivalent by spot urine protein to creatinine ratio allowed). (mentioned earlier in Exclusion #8)
* Stable Grade 3 neutropenia or stable Grade 3 white blood cell count.