Natalizumab- Unmet Need in the Management of Crohn’s Disease Doug Wolf, M.D. Atlanta Gastroenterology Associates July 31, 2007

Natalizumab-Unmet Need for CD Approximately 1 million patients with CD in the United States 80% need surgery at some point in the course of their disease While the disease is active, quality of life is decreased. This impacts on attendance and performance at work and school. Over the past 10 years, I have been involved in the care of over 1000 patients with Crohn’s disease. I have been a Principal Investigator in many Crohn’s disease clinical trials; most of the anti-TNF protocols Served as Chairman of the Professional Education Committee of the Crohn’s and Colitis Foundation

Natalizumab-Unmet Need for CD Moderate to Severe Crohn’s Disease 250, ,000 of the Crohn’s population fit the definition at some point in their disease course Over half of these patients do not have sustained (1 year) benefit with available anti-TNF agents 125,000 to 250,000 patients have potential need for another agent, e.g. natalizumab

Natalizumab-Unmet Need for CD Commonly used medications (vary in efficacy and side effects) –Mesalamine –Corticosteroids Budesonide (Entocort) [FDA approved] Prednisone –Immunomodulators Azathioprine and 6-MP Methotrexate

Natalizumab-Unmet Need for CD Biologics in Crohn’s disease –Infliximab (Remicade)[FDA approved] Effective in Induction Effective in Maintenance Loss of response over time –Adalimumab (Humira)[FDA approved] Effective in Induction Effective in Maintenance Less loss of response over time

Minority of CD patients benefit from anti-TNF therapy Week 4 Response Week 4 Remission 1 year Response 1 Year Remission Infliximab 1 (5 mg/kg) (10 mg/kg) 81% 50% 48% 28% 36% 46% 28% 38% Adalimumab 2 (160/80 mg) (80/40 qow) 3 (80/40 qwk) 59%36% 43% 54% 36% 41% 1 NEJM 1997,Lancet 2002, 2 Gastroenterology 2006, 3 Gastroenterology 2007

Natalizumab-Unmet Need in CD Readily administered in any infusion unit Infusion is similar to that for (Infliximab) Remicade, but simpler Single vial and dose-300 mg iv Monthly dosing-easy to keep on schedule Infusion unit dosing facilitates supervision Rare infusion reactions-never had to discontinue an infusion with several hundred infusions administered; tolerability seems much better than Remicade

Natalizumab-Unmet Need in CD PML Rare complication of Natalizumab therapy Occurred only in subjects on combination therapy with immunosuppressant Analogy of risk: Hepatosplenic lymphoma & Combination therapy- infliximab/6-MP Neutropenia and death: 6-MP and AZA therapy in those with TPMT deficiency

Natalizumab-Unmet Need in CD Challenges in Monitoring 6-Mercaptopurine/Azathioprine: I have had patients develop a rare but life threatening leukopenia or pancytopenia requiring hospitalization or outpatient treatment, severe hepatotoxicity(elevated bilirubin), pancreatitis, flu-like syndrome, myalgias, and arthralgias (even with normal TPMT levels) One must be attuned to these potentialities; clinical suspicion for PML is not more difficult.

Natalizumab-Unmet Need in CD Challenges in Monitoring Infliximab/Adalimumab: I have had patients develop small bowel (SB) adenoCa, SB lymphoma, optic neuritis, multiple sclerosis (MS) while on infliximab and MS on adalimumab An Atlanta colleague had an 18 y.o. patient develop hepatosplenic lymphoma. Referral to neurologists, rheumatologists, surgeons, hematologists, oncologists, etc. One must be attuned to these potentialities; clinical suspicion for PML is not more difficult.

Natalizumab-Unmet Need in CD Challenges in Monitoring Natalizumab-Take a brief history: any new neurologic signs or symptoms? If so, refer to an experienced Neurologist. Also, monitor periodic bloodwork. Follow TOUCH Prescribing program As with other biologics, one must be attuned to any clinical potentiality: neurologic or other.

Natalizumab-Unmet Need in Crohn’s Disease On behalf of these and other patients in need of treatment alternatives, I support the application for FDA approval of natalizumab in Crohn’s disease.