1. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 Tysabri® (natalizumab) Risk Minimization Action Plan (RiskMAP) Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Claudia B. Karwoski, Pharm.D., Risk Management Team Leader Office of Surveillance and Epidemiology July 31, 2007 Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Claudia B. Karwoski, Pharm.D., Risk Management Team Leader Office of Surveillance and Epidemiology July 31, 2007 Center for Drug Evaluation and Research

2. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 2 OverviewOverview TOUCH Prescribing Program –Key Elements of MS-TOUCH –Experience with TOUCH in multiple sclerosis (MS) patients –Proposed features of CD-TOUCH –Additional considerations in Crohn’s disease (CD) patients Postmarketing Safety Update TOUCH Prescribing Program –Key Elements of MS-TOUCH –Experience with TOUCH in multiple sclerosis (MS) patients –Proposed features of CD-TOUCH –Additional considerations in Crohn’s disease (CD) patients Postmarketing Safety Update

3. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 3 Reintroduction to US Market PCNS AC recommended return to market based on magnitude of efficacy –Treatment effect as monotherapy at 2 years* Progression of disability: absolute reduction in risk of 12%; relative reduction in risk of 42% Annualized relapse rate: absolute reduction of 49%; relative reduction of 67% PCNS AC also recommended a RiskMAP that includes mandatory registration and restricted distribution PCNS AC recommended return to market based on magnitude of efficacy –Treatment effect as monotherapy at 2 years* Progression of disability: absolute reduction in risk of 12%; relative reduction in risk of 42% Annualized relapse rate: absolute reduction of 49%; relative reduction of 67% PCNS AC also recommended a RiskMAP that includes mandatory registration and restricted distribution *PCNS AC FDA Briefing Document, February 9, 2006

4. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 4 TOUCH Prescribing Program Performance-linked Access System RiskMAP –Requires documentation of safe use before the patient can be treated with the product –Often requires participation of all parties involved in the prescribing, dispensing, or administration of the product –It is the rigorous of the 3 categories of RiskMAPs –Has some disadvantages but also has some evidence of effectiveness in minimizing risk Performance-linked Access System RiskMAP –Requires documentation of safe use before the patient can be treated with the product –Often requires participation of all parties involved in the prescribing, dispensing, or administration of the product –It is the rigorous of the 3 categories of RiskMAPs –Has some disadvantages but also has some evidence of effectiveness in minimizing risk

5. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 5 TOUCH Goals Risk minimization goals: –To promote informed risk-benefit decisions regarding natalizumab use –To minimize the health consequences of PML (e.g., death, disability) –To minimize the risk of PML Risk minimization goals: –To promote informed risk-benefit decisions regarding natalizumab use –To minimize the health consequences of PML (e.g., death, disability) –To minimize the risk of PML

6. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 6 TOUCH Goals Risk assessment goals: –To determine the incidence and risk factors for PML and other serious opportunistic infections (OI) with natalizumab treatment –To assess further the overall safety profile of natalizumab Risk assessment goals: –To determine the incidence and risk factors for PML and other serious opportunistic infections (OI) with natalizumab treatment –To assess further the overall safety profile of natalizumab

7. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 7 Key Elements of MS-TOUCH Mandatory enrollment of prescribers, patients, infusion sites, and afflilated central pharmacies Controlled distribution to authorized infusion sites and pharmacies Education program for health care providers and patients Safety surveillance of PML, serious OI, and deaths Program evaluation of health outcomes, process compliance, and assessment of knowledge Mandatory enrollment of prescribers, patients, infusion sites, and afflilated central pharmacies Controlled distribution to authorized infusion sites and pharmacies Education program for health care providers and patients Safety surveillance of PML, serious OI, and deaths Program evaluation of health outcomes, process compliance, and assessment of knowledge

8. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 How Does MS-TOUCH Work to Meet Its Risk Minimization Goals?

9. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 9 Challenges in Minimizing Risk of PML Risk factors for natalizumab-associated PML are not known No known effective non-invasive laboratory test to monitor for PML May not be preventable No known effective treatment Risk factors for natalizumab-associated PML are not known No known effective non-invasive laboratory test to monitor for PML May not be preventable No known effective treatment

10. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 10 MS-TOUCH Methods to Minimize the Risk of PML Program reinforces: –Appropriate patient selection –Risk communication to HCPs and patients –Close patient monitoring Program reinforces: –Appropriate patient selection –Risk communication to HCPs and patients –Close patient monitoring

11. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 11 Prescribers Role in Minimizing Risk Appropriate Patient Selection –At enrollment prescribers indicate that they acknowledge: Their patient has relapsing form of MS based upon clinical and radiological evidence Indicated as monotherapy Generally recommended for patients who have had an inadequate response to, or are unable to tolerate alternative MS therapies Appropriate Patient Selection –At enrollment prescribers indicate that they acknowledge: Their patient has relapsing form of MS based upon clinical and radiological evidence Indicated as monotherapy Generally recommended for patients who have had an inadequate response to, or are unable to tolerate alternative MS therapies

12. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 12 Prescribers Role in Minimizing Risk Every 6 months Prescriber determines whether patient is still appropriate for natalizumab treatment An interim history is collected as part of the re-authorization process Every 6 months Prescriber determines whether patient is still appropriate for natalizumab treatment An interim history is collected as part of the re-authorization process

13. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 13 Prescribers Role in Minimizing Risk MS-TOUCH recommends close monitoring –Routine evaluation of patient at 3 and 6 months after the first dose and every 6 months thereafter –More frequent evaluation if contacted by the infusion site and/or patient –For symptoms suggestive of PML Suspension of natalizumab dosing and further evaluation If clinically indicated, obtain MRI of the brain and cerebrospinal fluid for JC viral DNA MS-TOUCH recommends close monitoring –Routine evaluation of patient at 3 and 6 months after the first dose and every 6 months thereafter –More frequent evaluation if contacted by the infusion site and/or patient –For symptoms suggestive of PML Suspension of natalizumab dosing and further evaluation If clinically indicated, obtain MRI of the brain and cerebrospinal fluid for JC viral DNA

14. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 14 Infusion Site Staff Role in Minimizing Risk Before every infusion, staff determine if patient: –is authorized to receive natalizumab –has received and read the Medication Guide Before every infusion, staff determine if patient: –is authorized to receive natalizumab –has received and read the Medication Guide

15. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 15 Infusion Site Staff Role in Minimizing Risk Screening for possible symptoms indicative of PML and inappropriate use –Have you experienced any new or worsening medical problems (change in thinking, eyesight, balance, strength or other problems)? –Do you have a medical condition that can weaken the immune system? –Have you taken any medicines that weaken the immune system? –Have you taken any systemic steroids (other than for recent MS relapse)? A “ yes ” response prompts a call to the prescriber for authorization to infuse natalizumab Screening for possible symptoms indicative of PML and inappropriate use –Have you experienced any new or worsening medical problems (change in thinking, eyesight, balance, strength or other problems)? –Do you have a medical condition that can weaken the immune system? –Have you taken any medicines that weaken the immune system? –Have you taken any systemic steroids (other than for recent MS relapse)? A “ yes ” response prompts a call to the prescriber for authorization to infuse natalizumab

16. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 16 Patient’s Role in Minimizing Risk Acknowledge their awareness of risks Understand the required monitoring Report new or worsening symptoms Provide a list of all medicines and treatments to each scheduled infusion appointment Acknowledge their awareness of risks Understand the required monitoring Report new or worsening symptoms Provide a list of all medicines and treatments to each scheduled infusion appointment

17. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 Postmarketing Experience with MS-TOUCH

18. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 18 Post-Marketing Exposure 16,900 patients worldwide 13,745 US patients –~7,500 during initial marketing period –8,313 TOUCH patients infused Tysabri 6,245 treated for the first time 38,898 total infusions; median of 4 infusions/patient 2,100 exposed for 6-12 months None > 1 year of continuous use 16,900 patients worldwide 13,745 US patients –~7,500 during initial marketing period –8,313 TOUCH patients infused Tysabri 6,245 treated for the first time 38,898 total infusions; median of 4 infusions/patient 2,100 exposed for 6-12 months None > 1 year of continuous use Data derived from Biogen Idec; exposure as of May 23, 2007

19. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 19 MS-TOUCH Safety Surveillance There were no reports of PML in the postmarketing period Two reports of other serious opportunistic infections: There were no reports of PML in the postmarketing period Two reports of other serious opportunistic infections: SourceAge/ Gender Diagnosis# of infusions Outcome Foreign Spontaneous 26 Female Herpes Zoster 7Hospitalized, treated and discharged US Spontaneous 26 Male Herpes esophagitis ~6Hospitalized, treated and discharged

20. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 20 Baseline Patient Data Demographics –Gender: Women 5,925 Men 2,381 Unspecified 7 –Median age 46 years Demographics –Gender: Women 5,925 Men 2,381 Unspecified 7 –Median age 46 years

21. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 21 Baseline Patient Data Prior MS therapy –2.63% were naïve to MS therapy –Recent therapies Avonex (interferon beta 1a) 29% Copaxone (glatiramer acetate) 27% Rebif (interferon beta 1a) 18% Natalizumab 6.4%, ~25% had received natalizumab sometime in the past ~25% had received combination therapy ~12% indicate recent immunosuppressant use Prior MS therapy –2.63% were naïve to MS therapy –Recent therapies Avonex (interferon beta 1a) 29% Copaxone (glatiramer acetate) 27% Rebif (interferon beta 1a) 18% Natalizumab 6.4%, ~25% had received natalizumab sometime in the past ~25% had received combination therapy ~12% indicate recent immunosuppressant use

22. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 22 Pre-infusion Patient Checklist About 8% (3,123) of all checklists required prescriber contact and authorization –Overall good compliance, only 3 infusions occurred when authorization was not granted “Yes” responses to questions About 8% (3,123) of all checklists required prescriber contact and authorization –Overall good compliance, only 3 infusions occurred when authorization was not granted “Yes” responses to questions Changes in medical problems5.4% Concurrent immunosuppressant or immunomodulatory agents 1.5% Concurrent systemic corticosteroid2.3% Concomitant condition that may weaken the immune system 0%

23. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 23 Prescriber Reauthorization Prescriber is required to complete the Patient Status and Reauthorization Form every 6 months Percent of Patient Status and Re-authorization questionnaires completed 99.6% Percent of patient reauthorized to continue natalizumab 96.1% Concurrent immunosuppressant, immuno- modulatory agents, or chronic corticosteroids ~3% Intermittent courses of corticosteroids (allowed in TOUCH) 9.4%

24. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 24 Other RiskMAP Evaluation Components HCP (prescriber and nurse) survey –High percentages of correct responses to questions: Knowledge of the key risk management messages Actions taken to minimize the risk of PML Distribution data –Only 10 of >10,000 shipments were unauthorized (sent to patients or prescribers address) HCP (prescriber and nurse) survey –High percentages of correct responses to questions: Knowledge of the key risk management messages Actions taken to minimize the risk of PML Distribution data –Only 10 of >10,000 shipments were unauthorized (sent to patients or prescribers address)

25. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 25 Summary of MS-TOUCH Experience At this time the TOUCH program appears to be working satisfactorily in the MS population –No additional cases of PML since reintroduction –Primarily used as monotherapy –Good compliance with RiskMAP processes –Surveys indicate a high level of understanding of the risks and requirements of the RiskMAP –The postmarketing experience is relatively short At this time the TOUCH program appears to be working satisfactorily in the MS population –No additional cases of PML since reintroduction –Primarily used as monotherapy –Good compliance with RiskMAP processes –Surveys indicate a high level of understanding of the risks and requirements of the RiskMAP –The postmarketing experience is relatively short

26. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 26 Proposed CD-TOUCH Process for enrollment, reauthorization, and follow-up are the same Minor Differences: –MS patients are enrolled in MS-TOUCH, CD patients are enrolled in CD-TOUCH –Educational materials will be updated to include use in CD Process for enrollment, reauthorization, and follow-up are the same Minor Differences: –MS patients are enrolled in MS-TOUCH, CD patients are enrolled in CD-TOUCH –Educational materials will be updated to include use in CD

27. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 27 DifferencesDifferences CD-TOUCH does not emphasize monotherapy to same extent as MS-TOUCH The prescriber acknowledgement section includes the following statement for each program: CD-TOUCH does not emphasize monotherapy to same extent as MS-TOUCH The prescriber acknowledgement section includes the following statement for each program: MS-TOUCHCD-TOUCH TYSABRI is indicated as monotherapy for relapsing forms of MS TYSABRI is indicated for the treatment of moderately to severely active CD

28. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 28 DifferencesDifferences CD-TOUCH allows for concomitant use of chronic steroids. CD-TOUCH prescriber acknowledgement includes the following statement: “Patients receiving steroid therapy at the time of Tysabri initiation should undergo a steroid taper regimen once a clinical response is achieved. Steroids should be discontinued no later than 6 months after Tysabri initiation. If this is not possible, Tysabri therapy should be discontinued. Intermittent short courses of steroids are permissible to treat acute disease flares.” CD-TOUCH allows for concomitant use of chronic steroids. CD-TOUCH prescriber acknowledgement includes the following statement: “Patients receiving steroid therapy at the time of Tysabri initiation should undergo a steroid taper regimen once a clinical response is achieved. Steroids should be discontinued no later than 6 months after Tysabri initiation. If this is not possible, Tysabri therapy should be discontinued. Intermittent short courses of steroids are permissible to treat acute disease flares.”

29. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 29 DifferencesDifferences Questions 3 and 4 on the Pre-infusion Patient Checklist have minor differences –In the past month, have you taken medicines to treat cancer or MS [or CD] or any other medicines that weaken your immune system? –In the past month, other than for the treatment of a recent relapse [flare], have you taken any of the following medicines (common medicines for each disease listed)? May need further customization if concomitant therapy permitted Questions 3 and 4 on the Pre-infusion Patient Checklist have minor differences –In the past month, have you taken medicines to treat cancer or MS [or CD] or any other medicines that weaken your immune system? –In the past month, other than for the treatment of a recent relapse [flare], have you taken any of the following medicines (common medicines for each disease listed)? May need further customization if concomitant therapy permitted

30. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 30 Special Considerations in Crohn’s Disease Patients The appropriate patient and how these patients would be identified in clinical practice The best way to monitor the CD population for PML Whether concomitant immunosuppressive and immunomodulatory therapy will be permitted Whether the concurrent use of chronic steroids for 6 months is acceptable How flares of CD will be treated The appropriate patient and how these patients would be identified in clinical practice The best way to monitor the CD population for PML Whether concomitant immunosuppressive and immunomodulatory therapy will be permitted Whether the concurrent use of chronic steroids for 6 months is acceptable How flares of CD will be treated

31. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 Postmarketing Safety Update

32. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 32 Postmarketing Adverse Event Experience Sponsor’s Periodic Safety Update Report –Types and frequency of postmarketing adverse events are consistent with known safety profile –Possible higher risk of hypersensitivity with extended gap in treatment Labeling changes proposed Adverse Event Reporting System –> 1,700 reports, 65% from clinical trials –Most events appear consistent with product labeling –Proposed hypersensitivity labeling changes under review Sponsor’s Periodic Safety Update Report –Types and frequency of postmarketing adverse events are consistent with known safety profile –Possible higher risk of hypersensitivity with extended gap in treatment Labeling changes proposed Adverse Event Reporting System –> 1,700 reports, 65% from clinical trials –Most events appear consistent with product labeling –Proposed hypersensitivity labeling changes under review

33. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 33 Spontaneous Reports of Natalizumab-associated Liver Injury Adverse Event Reporting System (AERS) 28 recently identified unduplicated cases (reported 11/04 - 6/22/07) 4 cases of potentially serious hepatocellular injury; 3/4 cases in US Remaining 24 reports of mild liver abnormalities e.g. “increased liver enzymes,” “increased LFTs” No deaths or liver transplants Liver injury ‘signal’ not identified in clinical trials 28 recently identified unduplicated cases (reported 11/04 - 6/22/07) 4 cases of potentially serious hepatocellular injury; 3/4 cases in US Remaining 24 reports of mild liver abnormalities e.g. “increased liver enzymes,” “increased LFTs” No deaths or liver transplants Liver injury ‘signal’ not identified in clinical trials

34. Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 34 Cases of Serious Natalizumab-associated Liver Injury (n = 4) Liver injury occurred within 18 days after 1 st dose in 3/4 cases; after 5 doses in 1/4 cases Range of peak serum ALT: –521 u/L - 2,427 u/L* Range of peak serum total bilirubin: Normal – 15.7 mg/dL tt Diagnostic workups did not identify another obvious cause of liver injury Further evaluation of cases is in progress Liver injury occurred within 18 days after 1 st dose in 3/4 cases; after 5 doses in 1/4 cases Range of peak serum ALT: –521 u/L - 2,427 u/L* Range of peak serum total bilirubin: Normal – 15.7 mg/dL tt Diagnostic workups did not identify another obvious cause of liver injury Further evaluation of cases is in progress *upper limit of normal: 44 u/L tt upper limit of normal: 1 mg/dL