Abatacept in Juvenile Dermatomyositis

JDM is a chronic systemic autoimmune disease with a predominance of muscle and skin
inflammation of unknown etiology and varying prognosis. Children with JDM unresponsive to
corticosteroids or other immunosuppressive medications face poor clinical and functional
outcome and suffer various sequelae of the disease. Abatacept is a fully human soluble
recombinant protein consisting of the cytotoxic T cell Lymphocyte Antigen-4 (CTLA4) fused
with Fc region of human IgG1 that has been modified to prevent complement fixation and
antibody-dependent cellular cytotoxicity. Abatacept binds specifically to the CD80 (B7-1) and
CD86 (B7-2) molecules, those expressed on antigen-presenting cells (APCs). Upon engagement of
CTLA4 to CD80 or CD86, the resultant inhibition of signal transduction inhibits T cell
activation.. The rationale for use of Abatacept in the therapy of JDM includes the expression
of CTLA4, CD28, CD86, and CD40 on inflammatory cells of muscle biopsies of patients with DM,
as well as CTLA4 and CD28 on muscle cells.

A patient's participation in this study will last approximately 24 weeks with possible
extension to 48 weeks. At screening, participants will have a physical exam, muscle strength
assessment, blood and urine collection, and chest x-ray; they will also be asked to complete
several questionnaires. All participants will receive each week subcutaneous injection of
Abatacept. Each injection will be given on an outpatient basis.

There will be a total of 6 study visits. All participants will visit the outpatient clinic at
selected time points for muscle strength testing, a physical exam, disease activity
measurements, blood and urine collection, and muscle MRI; they will also be asked to complete
several questionnaires. During the study, participants will be monitored closely for
improvement or worsening of their disease and for serious drug related side effects.

Eligibility Ages Eligible for Study: ≥ 7 years and older Genders Eligible for Study: Both
Race/Ethnic Backgrounds Eligibility for Study: No restrictions

Inclusion Criteria:

1. Adults with definite or probable JDM and pediatric patients 7 years of age and older
with definite or probable JDM.

2. Body weight of at least 25 kg (or at least 55 lbs) and age ≥ 7 years of age.

3. Patients must reside within the United States or Canada.

4. Refractory myositis, as defined by the intolerance to or an inadequate response to
corticosteroids plus an adequate regimen of at least one other immunosuppressive
agent, including azathioprine, methotrexate, IVIG, mycophenolate mofetil,
cyclophosphamide, tacrolimus or cyclosporine A, or a biologic therapy. The definition
of intolerance is: side effects that require discontinuation of the medication or an
underlying condition that precludes the further use of the medication.

5. At least moderately active disease as documented by:

- MD global VAS with a minimum value of 2.5 cm on a 10 cm scale AND

- At least 2 other abnormal core set measures listed below:

6. Therapy with prednisone or another glucocorticoid is required, unless there is
documented intolerance in the medical record or a medical condition that
contraindicates further use of prednisone. The prednisone dose must be stable for at
least 4 weeks prior to the screening visit.

7. Background therapy with at least 1 non-corticosteroid immunosuppressive agent is
required at a stable dose for at least 6 weeks prior to the screening visit unless
there is documentation that the patient is intolerant, which is defined as side
effects that require discontinuation of the medication(s) or an underlying condition
that precludes the further use of the IS medication.

8. If an immunosuppressive agent was discontinued prior to the screening visit then there
must be a:

- 4 week washout for prednisone or methotrexate

- 8 week washout for any other IS agent

- For discontinuation of biologic therapies, a washout of 5 terminal half lives

9. If on hydroxychloroquine or colchicine, the dose should be stable for 6 weeks prior to
Visit 1.

10. If on statin or fibric acid derivative agents, the dose should be stable for 6 weeks
prior to Visit 1.

11. Ability of patient or parent to complete self-report questionnaires.

12. Men and women of reproductive potential must agree to use a reliable method of birth
control during the 24 week duration of the trial described in the reproductive risks
section of this protocol (section 4.3). They must also agree to use a reliable method
of birth control for 100 days after the last dose of study drug is administered.

13. Patients must agree to forgo immunization with a live vaccine during the course of the
study or within 3 months after discontinuation.

14. Patients must have a letter from the referring rheumatologist or specialist
supervising the care of the JDM, agreeing to the patient's participation in the study
and to continuing to provide care for the patient, including emergency care during the
trial.

Core Set Measures:

- An MMT-8 score that is no greater than 125/150

- Patient/Parent Global VAS with a minimum value of 2.0 cm on a 10cm scale

- CHAQ/HAQ disability index with a minimum value of 0.25

- Elevation of at least one of the muscle enzymes [which includes creatine kinase (CK),
aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate
aminotransferase (AST)] at a minimum level of 1.3 x the upper limit of normal.

- Global extra-muscular disease activity score with a minimum value of 2.0 cm on a 10 cm
VAS scale

Exclusion Criteria:

1. Drug-induced myositis (myositis in patients taking medications known to induce
myositis-like syndromes, including, but not limited to, statin agents, fibric acid
derivatives, and colchicine).

2. Juvenile polymyositis; inclusion body myositis; cancer-associated myositis, defined as
the diagnosis of myositis within 2 years of the diagnosis of cancer except basal or
squamous cell skin cancer or carcinoma in situ of the cervix if at least 5 years since
excision

3. Myositis in overlap with another connective tissue disease (CTD) that precludes the
accurate assessment of a treatment response (for example, difficulty in assessing
muscle strength in a scleroderma patient with associated myositis)

4. History of receiving a live vaccine 4 weeks prior to initiation of study treatment

5. Joint disease, severe calcinosis, or other musculoskeletal condition, which precludes
the ability to quantitate muscle strength.

6. Wheelchair bound patients.

7. Known hypersensitivity to abatacept or prior receipt of abatacept

8. Concomitant illness that would prevent adequate patient assessment or in the
investigators opinion pose an added risk for study participants:

9. Recurrent or chronic infections, including HIV, tuberculosis, hepatitis B and C, or TB
infection, including contact with a household contact with active tuberculosis (TB)
and who did not receive appropriate and documented prophylaxis for TB. (a documented
negative Hepatitis B surface antigen and Hepatitis C antibody completed at the
screening visit or within 6 weeks prior to screening visit is required)

10. Have had symptomatic herpes zoster or herpes simplex infection (not including simple
oral HSV lesions) within 12 weeks prior to entry or during screening period

11. Have a history of disseminated/complicated herpes zoster (for example,
multi-dermatomal involvement, ophthalmic zoster, central nervous system (CNS)
involvement, post-herpetic neuralgia)

12. Known liver disease (i.e. cirrhosis or other conditions compromising the synthetic
function of the liver)

13. Disorders that would preclude accurate assessment of neuromuscular function

14. Cardiomyopathy or arrhythmias that in the investigators opinion poses an additional
risk for study participants

15. New York Heart Association Classification III or IV for congestive heart failure

16. Psychiatric illness that precludes compliance or neuromuscular assessment

17. Serum creatinine > 2.0mg/dl

18. Pregnant females or nursing mothers

19. Life threatening illness that would interfere with the patient's ability to complete
the study.

20. Known or suspected history of drug or alcohol abuse within the past 6 months as
determined by the medical record or patient interview

21. Anticipated poor compliance

22. Participation in another clinical experimental therapeutic study within 30 days of
screening visit.

23. Any history or evidence of severe illness or any other condition that would make the
patient, in the opinion of the investigator unsuitable for the study.

24. Low total WBC <2.000, platelets < 100,000/mm3; hemoglobin <10 gm/dl

25. History of recurrent infection including active skin infections with calcinosis

26. Subjects with a history of cancer in the last 5 years

27. Subjects who have at any time received treatment with any investigational drug within
28 days (or less than 5 terminal half-lives of elimination) of the day 1 dose of study
drug, including waiting until CD19 returns to a detectable level and IgG level is
within normal limits (normal serum levels of IgG per reference lab: 7-9 years ≥572
mg/dl, 10-11 yrs ≥698 mg/dl, 12-13 yrs ≥759 mg/dl, 14-15 yrs ≥716 mg/dl,16-19 yrs ≥549
mg/dl, >19 yrs ≥700 mg/dl) for those patients who have received rituximab

28. Concomitant treatment with anti-TNF therapies, rituximab or anakinra or other biologic
therapies.

29. Initiation of colchicine and hydroxychloroquine as new drugs during study
participation is not allowed.

30. Initiation of statins or fibric acid derivatives during study participation is not
allowed.

31. Initiation of an exercise program within 4 weeks of the screening visit. Only a
stretching program may be initiated during the study (See section 5.4 Other
Restrictions)

32. Prisoners or subjects who are involuntarily incarcerated.

33. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness.