Omalizumab for Lupus

Background:

The immune system in systemic lupus erythematosus is characterized by abnormal activation of various cell types, such as T and B lymphocytes, macrophages and dendritic cells and the production of autoantibodies against nuclear antigens. Until recently most of the pathogenic autoantibodies were thought to be IgG antibodies. We have recently shown that Lyn deficient mice develop a lupus nephritis-like disease which is mediated by basophils activated by IgE autoantibodies. Moreover, SLE patients also have elevated serum self reactive IgEs, and activated basophils that express the lymph node homing molecule CD62L and the MHC Class II molecule, HLA-DR; markers that are associated with increased disease activity. Follow up studies confirmed an association of IgE anti-dsDNA antibodies with active SLE using a SLEDAI score of 4 as a cutoff (unpublished). In addition, we have also observed a strong correlation of IgE dsDNA antibodies with hypocomplementemia strongly suggesting that these autoantibodies are serologic markers of immune activation in SLE. Based on these observations we propose that depleting IgE (including IgE autoantibodies) may lead to improvement in SLE by reducing IgE-induced basophil activation.

Omalizumab is a humanized IgG1 monoclonal antibody against human IgE. It is approved by the FDA for the treatment of asthma. Omalizumab was shown to effectively deplete circulating IgE and decrease basophil action. In this study we propose to assess the safety of omalizumab in moderately active lupus patients and to assess its effect on circulating IgE autoantibodies and basophil activation. We will also collect preliminary data about its clinical efficacy.

Primary Objective:

To determine if omalizumab is tolerated in patients with Systemic Lupus Erythematosus.

Secondary Objectives:

To determine if the use of omalizumab in a subset of SLE patients with mild to moderate disease and elevated IgE autoantibody levels leads to clinical efficacy.

Study Population:

Adults 18 years or older diagnosed with SLE attending NIAMS outpatient clinic (OP-9) as well as other rheumatology outpatient clinics and private rheumatologist offices around the country with moderately active lupus (SLEDAI 2K score between 4-14).

Design:

• Active lupus: Assess study eligibility (week -2).
• If fulfills the criteria randomize at 2:1 ratio of omalizumab vs. placebo respectively within 2 weeks (week 0).
• Omalizumab loading dose (600 mg) or placebo by subcutaneous injection on day 0, followed by omalizumab (300 mg) or placebo by subcutaneous injection every 4 weeks (weeks 4, 8, 12)
• Evaluate patients at weeks 2, 4, 8, 12 and 16. Preliminary analysis of the available data will be done when the last subject completed the blinded phase (week 16).
• Open label phase: On week 16 subjects who were randomized to the placebo arm originally will receive 600 mg omalizumab by subcutaneous injection whereas those in the omalizumab arm will receive 300 mg omalizumab by subcutaneous injection in a blinded fashion. After that all subjects will receive omalizumab 300 mg by subcutaneous injection every 4 weeks, on weeks 20, 24, 28.
• Evaluate patients at weeks 18, 20, 24, 28
• Follow up phase: Subjects will have a follow up evaluation 4 and 8 weeks after the last dose (weeks 32 and 36).
• Allow one time intra-muscular injection of methylprednisolone 0.4 0.75 mg/kg for continued disease activity/flare.

Outcome Measures

Primary Endpoint:

Safety of omalizumab in patients with SLE.

Secondary Endpoints:

Reduced free IgE autoantibody levels: a statistical significant difference in the change in IgE autoantibody levels between the placebo and omalizumab groups at 16 weeks

Decreased basophil activation: a statistically significant difference in the change in the proportion of activated basophils between the placebo and omalizumab groups at 16 weeks

Reduced IgG autoantibody levels: a statistically significant difference in the change in IgG autoantibody levels between the placebo and omalizumab group at 16 weeks

Pharmacodynamics as measured by total and free IgE and FcepsilonR levels with associated PK

Clinical efficacy: the difference in clinical responders at 16 weeks.

Clinical response will be defined as an improvement in SLEDAI 2K scores of 4 or more without a worsening in PGA (physician s global assessment)

This study will provide important preliminary information about the safety and possible effect of IgE depletion in SLE patients. If omalizumab is well tolerated and shows preliminary evidence of efficacy, follow up studies testing its clinical usefulness are planned. This agent is expected to be devoid of the most common toxicities of therapies commonly used in the treatment of SLE, such as myelosuppression, amenorrhea and osteoporosis.

• INCLUSION CRITERIA:

Age at entry at least 18 years

Must give written informed consent prior to entry in the protocol. After preliminary screening visit under the Studies of the pathogenesis and natural history of systemic lupus erythematosus (SLE) protocol 94-AR-0066.

Must fulfill at least 4 of the criteria for SLE as defined by the American College of Rheumatology (Criteria published by EM Tan et al., Arthritis Rheum 25:1271, 1982, updated by MC Hochberg, Arthritis Rheum 40:1725, 1997).

Increased (>mean plus 2SD of healthy controls) autoantibody levels of any of the following IgE autoantibodies: anti-dsDNA, anti-Sm, anti-SSA.

Moderately active lupus defined by either of these (a or b) sets of criteria:

• Chronic glomerulonephritis: Subjects who meet following conditions at 8 weeks after completion of adequate induction immunosuppressive therapy:

-Subjects with lupus nephritis not achieving complete renal response

defined as A) no active urinary sediment at the time of screening AND

B) Urinary protein to creatinine ratio of <1 mg/mg or 24 hours urinary protein of less than 1 gm at the time of screening.

-Received at least 6 months of adequate induction immunosuppressive therapy (with pulse methylprednisolone, cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil or high dose daily corticosteroids),

AND all of the following as assessed at the time of screening:

• less than 30 percent increase in creatinine compared to lowest level during treatment with induction immunosuppressive therapy,
• proteinuria < 1.5 times before starting treatment with induction immunosuppressive therapy,
• < 2 plus cellular casts in the urinary sediment (on a scale of 0-4), and
• Extra-renal disease activity does not exceed 10 on the non-renal components of the SLEDAI 2K score.

(b)Patients with no active lupus nephritis and moderately active extra-renal lupus defined as a SLEDAI 2K score in the range of 4-14, inclusive.

Medications allowed at entry:

• Prednisone less than or equal to 20 mg/day
• Hydroxychloroquine up to 400 mg or 6.5 mg/kg/day (if > 400 mg)
• Methotrexate up to 25 mg once a week
• Azathioprine up to 2 mg/kg/day
• Mycophenolate mofetil up to 3 grams/day
• Cyclosporine up to 5 mg/kg/day

Exclusion criteria

Subjects will be excluded from the study if they meet any of the following criteria:

Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test at screening.

Women of childbearing potential and fertile men who are not practicing or who are unwilling to practice two forms of birth control during and for a period of 3 months after the completion of the study. Acceptable forms of birth control include abstinence, barrier methods, implantable intrauterine devices and oral, transdermal patch or injectable contraceptives.

Weight > 105 kg

Total IgE level > 700 IU/mL

Active SLE requiring aggressive immunosuppressive therapy (ie CNS vasculitis, proliferative lupus nephritis requiring induction therapy, etc)

History of stroke, MI

Use of rituximab within 6 months or any other biologic within 5 half-life of the drug at the time the first administration of study medication.

Significant impairment of major organ function (lung, heart, liver, kidney)

Therapy with cyclophosphamide, pulse methylprednisolone or IVIG within 8 weeks at the time of first administration of study medication.

Initiation or a change in the dose of an ACE-inhibitor or ARB within 2 weeks of first study treatment.

Allergy to murine or human antibodies

History of anaphylaxis

Bronchial asthma treated within 12 months

Serum creatinine > 2.0 mg/dL

Previous history of ischemic heart disease or evidence of ischemic heart disease on ECG.

Congestive heart failure (New York Heart Association Class III and IV) or cardiomyopathy as per the assessment of clinician performing history and physical examination and to be confirmed by echocardiogram when clinically indicated.

History of thrombosis or recurrent 2nd trimester spontaneous abortions (3 or more) and elevated levels of anti-cardiolipin antibodies or lupus anticoagulant

History of malignancy with the exception of basal cell or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix.

Active infection that requires the use of intravenous antibiotics and has not resolved at least 2 weeks prior to the administration of the first dose of study medication.

Active hepatitis B, hepatitis C or HIV infection

WBC <2,500/microL or Hgb <8.0 g/dL or platelets <70,000/microL.

Alkaline phosphatase, ALT and/or AST > 2.0 times upper limit of normal (ULN)

Significant concurrent medical condition that, in the opinion of the Principal Investigator, could affect the patient's ability to tolerate or complete the study.

Live vaccines within 4 weeks of first injection.

Known or suspected Helminthic infection/infestation.

History of menorrhagia, GI Bleed or other clinically significant bleeding.

Subjects currently on anticoagulants or anti-platelet agents. Any subject who was on these agents in the past within the biologic half-life of these agents will also be excluded. Daily baby aspirin (81 mg) therapy for the prevention of cardiovascular disease (CVD) will be allowed.