Sirolimus for Eosinophil-Associated Gastrointestinal Disorders

Eosinophil-Associated Gastrointestinal Disorders (EGID) are a group of related disorders
characterized by gastrointestinal symptoms and eosinophilic infiltration of the
gastrointestinal wall. The 2 major forms of EGID, eosinophilic esophagitis (EoE) and
eosinophilic gastroenteritis (EG), differ in regard to the site of inflammation (esophagus
vs. stomach/small bowel). Both EoE and EG are highly associated with coexisting allergic
disease, and a large fraction of EGID patients are sensitized to multiple food allergens.
Existing data strongly support the concept that EGID is a food-allergen-driven,
eosinophilic, inflammatory gut disease. Multiple lines of evidence support a major role for
Th2 cells and the cytokines they express (IL-4, IL-5, and IL-13) in EGID pathogenesis.

There are presently no drugs with a labeled indication for EGID. Most adult patients are
managed long-term with corticosteroid therapy, which raises concerns about toxicity.
Sirolimus is an immunomodulator approved for use in preventing transplant rejection. It
specifically inhibits Th2 cell proliferation in vitro, suggesting it may have activity in
EGID.

This study is a phase I open-label design intending to target a sirolimus whole blood
concentration of 6 ng/mL for a duration of 56 days. Twenty adult EGID subjects 10 with EoE
and 10 with EG with evidence of Th2-mediated IgE sensitization and peripheral blood
eosinophil counts (Bullet)800 cells/ L will be recruited to participate. Subjects will begin
sirolimus at a dose of 1.2 mg/m2/day. Blood sirolimus level will be checked at 14- to 28-day
intervals, and the dose will be serially adjusted in each subject as needed to target the 6-
ng/mL target trough concentration. Blood will be drawn at each visit to monitor drug levels
and safety labs.

- INCLUSION CRITERIA:

Individuals will be eligible for study participation if they meet all of the following
criteria:

1. Age greater than or equal to18 years and less than or equal to 65 years at the time
of Study Visit 1.

2. Presence of the following diagnostic criteria for EGID:

1. Subjects with EoE must have: 1) esophageal symptoms; 2) histologic evidence of
esophageal tissue infiltration by eosinophils with a peak greater than or equal
to25 eosinophils per high-powered field (while on greater than or equal to 2
months of twice daily proton-pump inhibitor therapy); and 3) no known etiology
for the tissue eosinophilia despite careful clinical evaluation.

2. Subjects with EG must have: 1) gastrointestinal symptoms; 2) histologic evidence
of stomach or duodenal tissue infiltration by eosinophils with a peak greater
than or equal to35 eosinophils per high-powered field; and 3) no known etiology
for the tissue eosinophilia despite careful clinical evaluation.

3. Blood AEC greater than or equal to 800 cells/microL at the screening visit. This
screening value will not be used to calculate the baseline AEC used in the principal
secondary endpoint.

4. Baseline laboratory values within the following ranges:

1. White blood cell count greater than or equal to3,300 cells/microL.

2. Absolute neutrophil count greater than or equal to1,000 cells/microL.

3. Hemoglobin greater than or equal to10 g/dL.

4. Platelet count greater than or equal to100,000 platelets/microL.

5. Three or more positive allergen-specific IgE tests (skin tests or in vitro assay) out
of this panel of 10 food and aeroallergens: milk, eggs, wheat, soy, shrimp, cod,
corn, peanut, dust mite, cat.

6. Subjects currently on medication for their EGID or for GI symptoms must be on a
stable dose for 1 month prior to screening and be willing to continue on that dose
for the duration of the study. Other medications (e.g. for hypertension, asthma, or
depression) may be adjusted by the subject s physician.

7. Willingness to have samples stored for future research and genetic testing.

8. Women of childbearing potential must have a negative serum beta-hCG.

9. Agree to practice abstinence or effective contraception as detailed below.

Contraception: The fetal risks associated with sirolimus are not known, but pre-clinical
animal data demonstrate some risk. Subjects must agree not to become pregnant or
impregnate a female, accordingly. Females of childbearing potential must have a pregnancy
test at each NIH visit. Because of the risk involved, both male and female subjects and
their partners must use 2 methods of birth control. As per the sirolimus package insert,
subjects must continue to use both methods for 3 months after stopping the study drug. Two
methods of birth control may be selected from the list included below:

- Hormonal contraception.

- Male or female condoms with or without a spermicidal.

- Diaphragm or cervical cap with a spermicidal.

- Intrauterine device.

If pregnancy is suspected or should occur, subjects must notify the study staff
immediately.

EXCLUSION CRITERIA:

Individuals will not be eligible to participate in this study if they meet any of the
following criteria:

1. Are breast feeding.

2. Are HIV positive or have any other known immunodeficiency.

3. Have used any investigational agent within 6 months of the screening visit.

4. Express the FIP1L1-PDGF-R fusion gene.

5. Have evidence of preexisting proteinuria with urine albumin-to-creatinine ratio >200
mg/g (men) or >300 mg/g (women).

6. Have serum creatinine with estimated GFR <60 mL/min/1.73 m2.

7. Have any chronic liver disease, including hepatitis B or C.

8. Use of medications that have CYP3A4 or P-glycoprotein (P-gp) inhibitor or inducer
activity.

9. Are Taking ACE inhibitor medicatons

10. Drug allergy or intolerance to allergies to sirolimus, other rapalogs, or excipients
in the preparation.

11. Have any condition that, as determined by the investigator, places the patient at
undue risk by participating in the study.