Raptiva and Sirolimus in Islet Transplantation for Type 1 Diabetes

The purpose of this study is to improve the applicability of islet transplantation for
treatment of type 1 diabetes utilizing a novel immunosuppressive regimen centered on the use
of adhesion molecule blockade with an anti-LFA-1 antibody (efalizumab). The
lymphocyte-function associated antigen-1 (LFA-1) adhesion molecule is expressed on multiple
cellular populations including T cells, B cells, and NK cells and is important in
facilitating cell migration and homing. In addition, interaction of LFA-1 with its ligand
ICAM-1 on antigen presenting cells provides a powerful costimulatory signal for T cell
activation.

Animal models using anti-LFA-1 antibodies have shown impressive prolongation of vascularized
and cellular allograft survival. These potent immunosuppressive properties have also been
documented in several clinical trials with efalizumab, a humanized IgG1 monoclonal antibody
directed against LFA-1. The drug was found to be safe, well tolerated, and efficacious in
treating moderate to severe psoriasis.

More recently, a multicenter trial employing efalizumab in conjunction with prednisone,
sirolimus and cyclosporine maintenance immunosuppression in recipients of kidney allografts
showed an acceptable safety profile when used at a dose of 0.5mg/kg/week and excellent
rejection-free graft survival over the first 6 months after transplant.

This study represents the first clinical trial that applies adhesion molecule blockade with
efalizumab to prevent the immune response against pancreatic islets in the setting of type 1
diabetes mellitus, with the long-term goal of immunosuppression withdrawal.

Genentech, the manufacturer of efalizumab voluntarily withdrew the drug from the U.S. market
in April of 2009. Previously transplanted subjects have been transitioned to alternative
immunosuppressives and no new subjects will be transplanted under this protocol.

Inclusion Criteria:

1. Primary islet allotransplant

2. Type I diabetes mellitus for a minimum of 5 years

3. One of the following signs or symptoms despite intensive efforts made in close
cooperation with their diabetic care team:

- Metabolic lability/instability characterized by hypoglycemia or ketoacidosis (>2
hospital admissions in the previous year), erratic glucose profiles (MAGE>120
mg/dL), or disruption in lifestyle of danger to life, self or others

- Reduced awareness of hypoglycemia or >1 episode in the last 1.5 years of severe
hypoglycemia

- Persistently poor glucose control (as defined by HgbA1c>10% at the end of six
months of intensive management efforts with the diabetes care team)

- Progressive secondary complications as defined by (i) a new diagnosis by an
ophthalmologist of proliferative retinopathy or clinically significant macular
edema or therapy with photocoagulation during the last year; or (ii) urinary
albumin excretion rate >300 mg/day but proteinuria <3g/day; or (iii) symptomatic
autonomic neuropathy (as defined by postural hypotension in the setting of
euvolemia, gastroparesis or diarrhea attributed to diabetic neuropathy, or
neuropathic bladder as diagnosed by an urologist)

4. Age 18 to 65 years of age.

Exclusion Criteria:

1. Current use of immunosuppressive agents

2. Lymphopenia (<1000/µL) or leukopenia (<3000 total leukocytes/µL)

3. Presence of panel-reactive anti-HLA antibody >20%

4. Positive lymphocytotoxic cross-match using donor lymphocytes and serum

5. Evidence of acute EBV infection (IgM>IgG) OR negative screen for EBV by IgG
determination

6. Calculated or measured GFR < 60 ml/min/m2

7. Portal hypertension or history of significant liver disease

8. History of malignancy within 10 years (except for adequately treated basal or squamous
cell CA of the skin)

9. Active peptic ulcer disease

10. Severe unremitting diarrhea or other GI disorders potentially interfering with the
ability to absorb oral medications

11. Untreated proliferative retinopathy

12. Pregnancy or breastfeeding

13. Female subjects not post-menopausal or surgically sterile, or not using an acceptable
method of contraception

14. Active infections

15. Serologic evidence of infection with HIV, or HbsAg or HCV Ab positive

16. Major ongoing psychiatric illness

17. Ongoing substance abuse, drug or alcohol; or recent history of noncompliance

18. Any condition that in the opinion of the Principle Investigator would not allow for
safe participation in the study