1 TYSABRI Risk Management Plan Will Maier, PhD Senior Director, Epidemiology

2 TYSABRI Risk Management Plan  Risk management plan for MS –TOUCH Prescribing Program (TYSABRI Outreach; Unified Commitment to Health)  Status update on MS risk management plan  Changes to risk management plan with addition of CD indication

3 TYSABRI Risk Management Goals  Goals and activities developed in collaboration with FDA  Risk minimization –Promote informed benefit-risk decisions –Minimize the risk of PML –Potentially minimize death and disability due to PML  Risk assessment –Determine the incidence and risk factors for PML, serious opportunistic Infections –Assess long-term safety in clinical practice

4 Current TYSABRI Labeling - MS Boxed Warning  TYSABRI increases risk of PML  PML may occur with TYSABRI monotherapy  Healthcare professionals should be alert to any signs or symptoms that may be suggestive of PML –Dosing should be suspended immediately at the first signs or symptoms suggestive of PML –Evaluation should include brain MRI and CSF for JCV DNA  Warning against –Use in patients who are immunocompromised –Concurrent use with immunosuppressants or immunomodulators

5 TYSABRI Risk Minimization System – MS Controlled Centralized Distribution Registered Infusion Centers Neurologists MS Patients InfusionNurses Mandatory Enrollment Form TOUCH Prescribing Program

6 Prescriber-Patient Acknowledgement on Enrollment Form  Records informed benefit-risk decision before start of therapy  Physician signs –Is aware of PML risk –Has discussed risks and benefits with patient –Patient appropriate for TYSABRI  Patient signs –Has read Medication Guide –Has discussed risks and benefits with physician –Will report new or worsening symptoms to their physician

7 Prescriber Requirements  Must report any PML, serious opportunistic infection, or death to the Sponsor  Must complete a Patient Reauthorization Questionnaire on every patient every 6 months and submit to the Sponsor –Vital status, PML, and other serious opportunistic infections –Any concurrent immunomodulatory or immunosuppressant medications –Reauthorization of TYSABRI dosing for next 6 months  Must complete Discontinuation Questionnaire within 6 months of patient’s last dose and submit to the Sponsor  Sponsor screens and follows-up with prescriber if issues seen

8 Infusion Center Requirements  Infusion center must be trained prior to registration  TYSABRI use only in registered infusion centers  Dosing only to patients enrolled in TOUCH Prescribing Program  Prior to each dose for each patient – infusion nurse must –Provide Medication Guide –Complete Pre-infusion Patient Checklist

9 Pre-Infusion Patient Checklist  Administered by infusion nurse  Screen for new or worsening symptoms  Screen for use of immunomodulatory or immunosuppressive medications - reinforces use as monotherapy  If either reported - dosing withheld, physician contacted immediately  Real-time submission of Pre-Infusion Patient Checklists to Sponsor

10 Risk Assessment – TOUCH Prescribing Program Patient Registry Purpose To determine incidence of, and risk factors for, PML and other serious opportunistic infections in patients receiving TYSABRI  Safety follow-up of all patients receiving TYSABRI  Physicians report any PML, serious opportunistic infection, or death to the Sponsor for further analysis and follow-up  Follow-up of patient deaths through National Death Index and collection of death certificates  Provides safety surveillance and tracking of all patients, far exceeding routine pharmacovigilance

11 MS Program Status Update

12 Evaluation of Risk Management Plan  Monitor success of risk management plan  Includes analysis of safety and compliance data  Share data with FDA every 3 months  If needed, rapid implementation –Labeling changes –New risk minimization tools

13 Worldwide TYSABRI Exposure – MS  ~11,500 patients on TYSABRI therapy worldwide in commercial use between June 2006 and May 2007 –US: 11,015 patients enrolled in TOUCH 8313 patients dosed (median of 4 doses) 1750 physicians have enrolled patients 1750 infusion sites trained and authorized –Europe: ~3200 patients dosed to date  1000 patients on TYSABRI in clinical trials  21,000 patients – all exposure (all clinical trials, both post-marketing periods)

14 Excellent Compliance with TOUCH Program – MS  Patients and prescribers informed about risk –99.9% of patients enrolled at time of infusion  Prescribed as monotherapy, according to label –96.8% patients with no concurrent immunomodulatory or immunosuppressant therapies  Drug being shipped to registered infusion centers –99.9% of 10,126 drug shipments shipped to registered infusion centers  Facilitates clinical vigilance and use in appropriate patients –99.9% of 38,898 Pre-infusion Patient Checklists received 8% of infusions delayed due to patient responses ~0.5% of infusions not given following physician contact Note: TYSABRI metrics as of 23 May 2007

15 High Level of Awareness – MS  High awareness of PML risk –99% of prescribers know of increased risk of PML  Key components of TOUCH well understood –100% of nurses know TYSABRI should be administered only to enrolled patients –99% of nurses know to contact prescriber if patient reports new or worsening medical problems –98% of prescribers know to report PML Note: TYSABRI metrics as of 23 May 2007

16 Post-Marketing Safety Profile Consistent with Clinical Trials - MS  No new confirmed cases of PML  Two serious opportunistic infections (Herpes)  Increased rate of hypersensitivity in patients who have experienced a gap in TYSABRI therapy –Labeling change being implemented based on data from TOUCH Prescribing Program

17 Changes to Plan with CD Indication

18 TYSABRI RiskMAP Key Changes for CD  Label –Discontinue TYSABRI therapy if no response within 3 months –Eliminate corticosteroid use within 6 months of starting TYSABRI or stop TYSABRI therapy  Training/Communication plan –CD-specific training of infusion sites –Education of patients and gastroenterologists of risk, and features, of PML  Additional observational cohort study in CD

19 Monitoring for PML in CD Setting  CD patients generally have normal neurological function  PML symptoms consist of –Cognitive or behavioral changes –Visual dysfunction –Unilateral motor weakness  Symptoms will be readily apparent to CD patients and caregivers –Clearly unrelated to underlying disease –Prompt early contact for evaluation and early referral to neurologist

20 Features of CD Related to Risk Management  Expect TYSABRI to be prescribed by gastroenterologists who specialize in IBD  Gastroenterologists administer immunosuppressive therapies - familiar with serious complications, including CNS demyelination –Routinely refer to specialty physicians for further evaluation –No expectation to serve role as PML diagnostician  CD patients show willingness to weigh treatment benefits and risks  Regular contact with healthcare professionals at monthly infusions

21 Risk Minimization – CD Indication  All major features remain the same –Mandatory registration of all prescribers and patients –Controlled, centralized distribution –Use only in registered infusion centers –Real-time submission of monthly pre-infusion patient checklist –Mandatory physician re-authorization of dosing every 6 months  TOUCH forms adapted for CD

22 Risk Assessment – TYSABRI Observational Cohort Study (CD) Purpose Evaluation of TYSABRI long-term safety in clinical practice setting  Sub-set of patients from CD-TOUCH Patient Registry –Voluntary observational cohort study  Collects all serious adverse events  Assess risk of serious infections and malignancies  Investigate potential signals of unanticipated adverse events  4000 CD patients followed for 5 years  Powered to detect rare events with rate of 0.2 per 1000 person-years

23 Summary  Successful risk management plan in place for MS  Same goals and methods for MS and CD  Ongoing assessment of PML risk and overall safety  Evaluation plan to monitor success of risk management activities  Ensure appropriate use of TYSABRI in CD patients