Alemtuzumab to Treat Sporadic Inclusion Body Myositis

Sporadic Inclusion-Body Myositis (s-IBM) is the most common muscle disease in patients above the age of 50 years. It is an inflammatory myopathy mediated by sensitized, cytotoxic CD8+ T cells that clonally expand in situ and invade MHC-I-expressing muscle fibers. The antigen recognized by the T cells is unknown. The disease is progressive, resists the currently available immunotherapies and leads to wheelchair confinement. Applying therapeutic strategies with agents that deplete T cells clones and investigating the antigenic specificity of the endomysial T cells is expected to enhance our understanding of the cause of s-IBM and lead to clinical improvement. The present study is designed to: a) test in a pilot study the safety, T cell depletion of the endomysial T cells and clinical efficacy of the monoclonal antibody Alemtuzumab in 20 patients with s-IBM followed for 12 months by serial quantitative assessment of muscle strength; b) explore the spectrum of the antigens recognized by the T cells extracted from the muscle biopsy specimens by searching for immune dominant peptides using positional scanning synthetic combinational peptide libraries, before and after therapy; and c) determine the reciprocal relationship between clinical response and endomysial inflammatory mediators before and after treatment. It is anticipated that the study may lead to identification of putative antigens that trigger the disease, clarify the significance of the inflammation and amyloid deposits in muscle fiber injury and provide a novel therapy for s-IBM patients.

• Only patients who are currently enrolled in protocol 02-N-0121 Study of Immune Dysregulation in Patients with Sporadic Inclusion Body Myositis (s-IBM) will be considered for enrollment in protocol 04-N-0133.

Inclusion criteria

Patients with confirmed diagnosis of s-IBM willing to undergo therapy with Alemtuzumab.

Willingness and legal ability to give and sign informed study consent.

Willingness to travel to the Clinical Center for planned studies and treatment as required by protocol.

Men and women of reproductive potential must agree to use an acceptable method of birth control during and for six months after completion of treatment.

Availability of tissue for testing. This will include muscle and peripheral blood lymphocytes isolated through routine lymphocytapheresis or phlebotomy.

Exclusion criteria

Immunosuppressive drug therapy at the time of or 6 months prior to enrollment. Specifically, candidates may not be taking Prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, anti-lymphocyte agents, cyclophosphamide methotrexate, or other agents whose concomitant use may enhance the toxicity of Alemtuzumab.

Any medical or personal difficulties that precludes serial follow-up visits.

Any active malignancy.

Significant coagulopathy or requirement for anticoagulation therapy that would contraindicate protocol.

Platelet count less than 100,000/mm(3).

Hemoglobin less than 9.0 mg/dl.

Any known immunodeficiency syndrome included HIV infection.

Any history of cardiac insufficiency, major vascular disease, or unstable coronary artery disease.

Any history of systemic or pulmonary edema.

Any history of previous treatment with monoclonal antibodies or sensitivity to the study drug (Alemtuzumab), pre-medication regimen, or prophylactic agents.

History of chronic hypotension (SBP less than 100 mmHg).

Any medical condition that would likely increase the risk of side effects of the study drug or confound the interpretation of the data including active infections.

Pregnancy and active nursing (breast feeding).

History of uncontrolled thyroid disease or a history of autoimmune thyroiditis.