Low Dose IL-2 for Ulcerative Colitis

Interleukin-2 (IL-2) is a T cell growth factor. IL-2 is currently licensed for the treatment
of metastatic renal cell carcinoma and metastatic melanoma, where it promotes the expansion
of anti-cancer cytotoxic T cells and natural killer (NK) cells. However at low doses
(100-times lower than those used in cancer therapy), IL-2 promotes the selective expansion of
regulatory T cells (Tregs): an immune modulating subset of CD4+ lymphocytes.

A recent phase 1 clinical trial from our collaborators at the Dana Farber Cancer Institute
showed that low-dose IL-2 selectively expands Tregs in patients with treatment-resistant
Graft vs. Host Disease (GvHD), and that low-dose IL-2 is safe in this condition. A detailed
immunological analysis of samples from this study showed that low-dose IL-2 treatment was
associated with increased Treg proliferation, increased de novo thymic generation of Tregs,
and a resolution of defects in intracellular signalling and apoptosis seen in Tregs in
chronic GvHD. A recent phase 1 study from another group showed that low-dose IL-2 is safe in
the treatment of HCV-associated vasculitis. Low-dose IL-2 has also been shown to be
well-tolerated in subjects with HIV.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Evidence from
pre-clinical models of intestinal inflammation, and also from patients with monogenetic
defects in Treg function, suggests that Tregs play a role in the prevention of inflammation
in the intestine.

The treatment (or intervention) in this study is a once-daily, subcutaneous injection of
IL-2, for a total of 8 weeks. The first 2 doses of the study drug will be administered by
research nurses at Boston Children's Hospital. Further doses will be self-administered, at
home. Training will be provided for correct self-administration.

This is a 3+3 dose escalation study of IL-2 in moderate-to-severe UC. This study design is
powered to identify the MTD of low-dose IL-2 in UC. Once the MTD is identified, a further 10
subjects will receive IL-2 at that dose. Recruitment of between 2 and 28 patients is planned.

Dose levels are based on the experience of our collaborators in GvHD. In addition to
determining the MTD, this study will determine if low-dose IL-2 is safe and well-tolerated in
patients with moderate-to-severe ulcerative colitis. A detailed immunological analysis of
samples obtained from this study will determine if low-dose IL-2 expands Tregs in vivo, in
patients with moderate-to-severe UC. Immunological changes will then be correlated with
clinical response.

The study will take place at Boston Children's Hospital. The study will involve 10 study
visits. Most of the study visits involve blood tests. A flexible sigmoidoscopy or colonoscopy
will be performed as part of the screening process. A flexible sigmoidoscopy will also be
performed on completion of therapy, to determine clinical response.

The first two subjects to receive the study drug will be admitted overnight following the
first dose. Subsequent doses will be administered on an out-patient basis. All other subjects
will receive IL-2 on an out-patient basis.

Responders (with an acceptable side-effect profile) will be allowed to continue the study
drug for at least 1 year. Compensation will be provided for participants.

Inclusion Criteria:

- Age 18-70 years.

- A diagnosis of UC made by standard clinical, radiological, endoscopic and histological
criteria.

- Moderate to severe UC with a Mayo score of 6-12.

- Failure to tolerate or failure to respond to at least one conventional therapy with
the intention of inducing or maintaining remission (examples include oral
corticosteroids, oral 5-aminosalicylates, azathioprine and/or 6-mercaptopurine, or a
tumor necrosis factor (TNF) antagonist). Corticosteroid dependency (inability to taper
oral corticosteroids without a recurrence of disease activity) is also included in
this category.

- Stable doses of concomitant medications.

- A negative pregnancy test in the 2 weeks prior to anticipated commencement of the
study drug, in female subjects of child-bearing age. Men and women of reproductive
potential must agree to use an acceptable method of birth control during treatment and
for six months after completion of treatment.

- Ability to provide informed consent.

Exclusion Criteria:

- A diagnosis of Crohn's disease or Inflammatory Bowel Disease - Unspecified (IBD-U, a
diagnostic classification formerly termed "indeterminate colitis").

- Requirement for immediate surgical, endoscopic or radiological intervention for toxic
megacolon, massive hemorrhage, perforation, sepsis, or intra-abdominal or perianal
abscess.

- Ileostomy, proctocolectomy or subtotal colectomy with ileorectal anastomosis.

- History of colorectal cancer or dysplasia.

- Positive stool test for Clostridium difficile.

- Current medically significant infection.

- Significant laboratory abnormalities, including;

1. Hb < 8.0 g/dL, WBC < 2.5 x 103/mm3, Plt < 100 x 103/mm3.

2. Creatinine ≥ 1.5x institutional upper limit of normal (ULN).

3. Total bilirubin > 2.0 mg/dL, ALT > 2x institutional ULN, GGT > 2x institutional
ULN. Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed.

4. Abnormal thyroid function tests.

- Positive serology for HIV, hepatitis B virus (HBV) or HCV.

- Positive screening test for tuberculosis (TB).

- First dose of an anti-TNF medication within 4 weeks of anticipated study commencement,
or a subsequent dose within 2 weeks of commencement; or ciclosporin or tacrolimus
within 2 weeks of anticipated study commencement.

- Received another investigational new drug (IND) within 5 half-lives of that agent
before the planned commencement of SC IL-2.

- Malignancy within the last 5 years.

- Allergy to any component of the study drug.

- Pregnant or lactating women.

- Inability to comply with the study protocol or inability to give informed consent.

- Prior exposure to IL-2.

- Uncontrolled cardiac angina or symptomatic congestive cardiac failure (NYHA Class III
or IV).