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score of 4 as a cutoff (unpublished).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:

1. 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.