NIH Substudy of AIN457 (Anti-IL-17 Monoclonal Antibody) for Treatment of Moderate to Severe Crohn's Disease

Purpose:

- Crohn's disease is an inflammatory bowel disease with major symptoms such as diarrhea
and abdominal pain when the disease is in an active stage.

- AIN457 is a protein developed by NOVARTIS that is used to stop the action of
Interleukin-17 (IL-17), a protein made by the body that contributes to many different
kinds of inflammatory diseases, including Crohn's disease. AIN457 is being developed
for the potential treatment of various inflammatory diseases like rheumatoid arthritis
and psoriasis, but has not been tested for suitability in people with Crohn's disease.

Objectives:

- The main objective of the NIH substudy is to obtain additional blood and gut biopsy
tissue for monitoring biochemical changes in immune variables in response to study drug
or placebo.

- The main objective of the main multicenter study (sponsored by NOVARTIS) is to
determine whether AIN457 is safe and effective in the treatment of Crohn's disease, and
if effective, how long the effect will remain.

Eligibility:

- Important eligibility criteria to consider for patients to be enrolled in the AIN457 trial
include:

Inclusion criteria:

- Male or female; 18-75 years old

- Diagnosis of Crohn's disease for at least 3 months prior to screening

- Moderate to severe active Crohn's disease at baseline, defined as: CDAI greater than or
equal to 220 and less than or equal to 450

- Active disease despite prior treatment with stable dose of corticosteroids for 2 weeks,
or immunosuppressant for at least 3 months (e.g. methotrexate, azathioprine).

Exclusion criteria:

- Subjects with symptoms associated with active bowel stricturing disease and
pre-stenotic dilation on radiography.

- Fistulizing disease if complicated by sepsis and/or untreated abscess.

- Subjects with multiple bowel surgeries and clinically important short bowel syndrome
defined as an inability to maintain caloric intake.

- Prior therapy with rituximab.

- Receiving corticosteroids dose equivalent to a > 40mg dose of prednisone per day.

- Subjects demonstrating clinical improvement due to other Crohn's therapy.

- Subjects with active or history of clinically significant cardiac abnormalities.

Design:

- For the NIH substudy, additional blood will be drawn and a colonoscopy will be
performed before the first infusion and after the second infusion.

- The multicenter study plans to enroll seventy-two (72) subjects with moderate to severe
active Crohn's disease that is not controlled by corticosteroids, immunosuppressant
(e.g. methotrexate or purine metabolites) or anti-inflammatory treatment (e.g. 5-ASA).
At baseline visit, if the eligibility of the subject is confirmed, the subject will be
randomized (2:1 ratio) to receive either AIN457 or placebo administered as a 2 hours
intravenous infusion. A total of two infusions will be given on day 1 and day 22
respectively.

- After infusions there will be a follow-up period of up to 18 weeks.

- Once this study is completed, an extension study will be conducted that will offer
access to AIN457. Patients who complete the current study may be eligible to enter the
extension study and receive therapy with AIN457.

- INCLUSION CRITERIA:

1. Male or female; 18-75 years old

2. All female subjects must have negative pregnancy test results at screening and
baseline. Women of childbearing potential (WoCBP) must be using simultaneously
double-barrier or two acceptable methods of contraception, (e.g., intra-uterine
device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.
Hormone replacement as either oral or implantable is acceptable as one form),
from the time of screening and for the duration of the study, through study
completion and for 4 months following study completion.

Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.

Postmenopausal females must have had no regular menstrual bleeding for at least
two (2) years prior to initial dosing. Menopause will be confirmed by a serum
FSH level of > 40 IU/L at screening. Pregnancy test will be required only at
screening.

Female subjects who report surgical sterilization must have had the procedure at
least six (6) months prior to initial dosing. Surgical sterilization procedures
should be supported with clinical documentation made available to the sponsor
and noted in the Relevant Medical History/Current Medical Conditions section of
the CRF.

If female subjects have male partners who have undergone vasectomy, the
vasectomy must have occurred more than six (6) months prior to first dosing.

3. Male subjects willing to use simultaneously two acceptable methods of
contraception (e.g. spermicidal gel plus condom) for entire duration of the
study, up to the study completion visit and at least for 6 months following the
completion of the study.

Periodic abstinence and withdrawal are not acceptable methods of contraception.

4. Diagnosis of Crohn's disease for at least 3 months prior to screening

5. Confirmation of Crohn's disease by endoscopic or imaging examination

6. Moderate to severe active Crohn's disease at baseline, defined as:

--CDAI greater than or equal to 220 and less than or equal to 450

7. Patients with active disease despite prior treatment with corticosteroids for at
least 2 weeks, or immunosuppressants for at least 3 months.

- Patients who are being treated with azathioprine, 6-MP or MTX are eligible
but must have been on a stable dose for at least 10 weeks prior to
baseline.

- Patients treated with corticosteroids are eligible but must have been on
stable doses of prednisolone not exceeding 40 mg for two weeks prior to
baseline.

- Patients who are being treated with immunosuppressants other than those
listed above, such as cyclosporine, tacrolimus and mycophenolate, are not
eligible. These subjects will be required to stop immunosuppressants prior
to baseline. These patients are eligible after observing a wash out period
as specified in Exclusion criterion #7.

8. Absence of clinically relevant abnormalities for screening laboratory test
results

9. Able to communicate well with the investigator, and to understand and comply
with the requirements of the study.

10. Understand and sign the written informed consent.

EXCLUSION CRITERIA:

Subjects meeting any of the following criteria will be excluded from entry into or
continuation in the study, unless sponsor approval is obtained:

1. Body Mass Index is greater than 34.

2. Positive Purified Protein Derivative (PPD) tuberculin skin test of greater than or
equal to 5 mm at screening or 6 months prior to screening. A positive PPD test will
be defined using the [MMWR 2000 guidance], summarized as criteria for tuberculin
positivity by risk group.

- A PPD test should not be done in subjects who had a tuberculosis vaccination in
the past. These subjects will be eligible to participate if, according to local
guidelines, latent tuberculosis can be excluded.

- For those study sites using QuantiFeron test a positive test at screening will
exclude the subject from the participation in the study.

- If the result for either PPD or QuantiFeron test is indeterminate, the subject
will be excluded.

3. Subjects with symptoms associated with active bowel stricturing disease and
pre-stenotic dilation on radiographs.

4. Fistulizing disease if complicated by sepsis and/or untreated abscess.

5. Subjects with multiple bowel surgeries and clinically important short bowel syndrome
defined as an inability to maintain caloric intake.

6. a. Concomitant treatment with anti-TNF-alpha therapy (or other biological therapy)
and systemic immunosuppressive agents such as cyclosporine, mycophenolate,
pimecrolimus, or tacrolimus, except azathioprine, its metabolite 6-MP and MTX.

The following washout period will be required for subjects to be eligible to
participate in the trial.

- Three (3) months washout prior to baseline for certolizumab

- Two (2) months washout prior to baseline for adalimumab, etanercept and
infliximab

- One (1) month washout prior to baseline for cyclosporine, mycophenolate,
pimecrolimus, tacrolimus, and any other systemic immunosuppressants not listed
under exclusion criterion # 7b

6b. Patients who are being treated with azathioprine, 6-MP or MTX are eligible
but must have been on a stable dose for at least 10 weeks prior to baseline and
throughout the whole study period.

7. Prior therapy with rituximab.

8. Receiving corticosteroid dose equivalent to a greater than 40mg dose of prednisone
per day.

9. Subjects demonstrating clinical improvement due to other Crohn's therapy.

10. Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic,
hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral,
psychiatric, or other disease which would make the subject unsuitable for the trial.

11. Subjects with active or history of clinically significant cardiac abnormalities, for
example:

- Requiring drugs with QT-prolonging properties (e.g. antiarrhythmic drugs, such
as amiodarone, sotalol, dofetilide, quinidine, procainamide, disopyramide).

- QTc greater than 450msec long QT-syndrome (own or with a family history) or with
a family history of sudden unexplained death.

- Left branch bundle block (LBBB), or subjects who have been hospitalized for
heart failure of cardiac etiology, in the previous 6 months, and subjects who
have significant and persistent left-ventricular dysfunction (LVEF less than
40%).

- History of in the preceding 3 months, significant and persistent arrhythmias
such as ventricular fibrillation or tachycardia, or atrial fibrillation or
flutter.

- Symptomatic coronary artery disease.

- Presence of severe cardiac disease (New York Heart Association Classification
greater than or equal to III) and/or abnormal ECG, considered by the
investigator to be unsafe for the study.

12. Liver disease or liver injury as indicated by abnormal liver function tests such as
SGOT (AST), SGPT (ALT), gamma-GGT, alkaline phosphatase, or serum bilirubin. The
Investigator should be guided by the following criteria:

- Any single parameter may not exceed 2 times the upper limit of normal (ULN). A
single parameter elevated up to and including 2 times the ULN should be
re-checked once more as soon as possible, and in all cases, at least prior to
enrollment/randomization, to rule out lab error.

- If the total bilirubin concentration is increased above 2 times the ULN, total
bilirubin should be differentiated into the direct and indirect reacting
bilirubin. In any case, serum bilirubin should not exceed the value of 1.6 mg/dL
(27 micromol/L).

Re-check results must be within normal limits (or returning to within normal limits)
in order for subject to qualify.

13. Total WBC count which falls outside the range of 4500-13,000/microL, or platelets
less than 100,000/microL at screening.

14. History of severe hypersensitivity to any biological agents (antibody or soluble
receptor), including serious allergic reaction (hypotension, wheezing, urticaria),
lupus-like syndrome or demyelinating disease.

15. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing or longer
if required by local regulation.

16. Administration of live vaccines within 6-month prior to dosing.

17. History of immunodeficiency diseases, including a positive HIV (ELISA and Western
blot) test result.

18. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.

19. Significant illness within the two weeks prior to dosing or any active systemic
infection or medical condition that may require treatment or therapeutic intervention
during the study.

20. Subjects with:

- History or presence of impaired renal function as indicated by clinically
significantly abnormal creatinine greater than 1.3 mg/dL or blood urea nitrogen
(BUN) greater than 30 mg/dL, or the presence of greater than +1 albumin on the
urinary dipstick.

- Presence of proteinuria, active sediments, casts or WBCs in urine.

- Evidence of urinary obstruction or difficulty in voiding at screening.

- History of renal trauma, glomerulonephritis, or subject with one kidney.

21. History of malignancy (other than basal cell carcinoma or adequately treated
carcinoma-in-situ of the cervix).

22. Unable or unwilling to undergo multiple venipunctures because of poor tolerability or
lack of easy access to veins.

23. Conditions associated with an immune-compromised condition such as recent surgical
procedure; or history of drug or alcohol abuse within the 12 months prior to dosing.
Subjects who are unable to discontinue analgesic medications containing opiates and
opioids, as well as cannabinoids for medical use.

24. Participation in any clinical investigation within four (4) weeks prior to initial
dosing or five half-lives of the investigational agent, whichever is longer, and for
any other limitation of participation based on local regulations.

NIH EXCLUSION CRITERIA:

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

2. Prothrombin Time International Normalized ration (PT INR) greater than 1.3 or Partial
Thromboplastin Time (PTT) 3 sec than control