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TYSABRI Risk Management Plan

Will Maier, PhDSenior Director, Epidemiology

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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

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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

4Current TYSABRI Labeling - MSBoxed 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

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TYSABRI Risk Minimization System – MS

ControlledCentralized Distribution

RegisteredInfusion Centers

NeurologistsNeurologists

MS PatientsMS Patients

Infusion Infusion NursesNurses

Mandatory Enrollment

Form

TOUCHPrescribing

Program

6Prescriber-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

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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

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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

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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

10Risk 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

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MS Program Status Update

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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

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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)

14Excellent Compliance withTOUCH 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

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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

16Post-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

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Changes to Plan withCD Indication

18TYSABRI 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

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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

20Features 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

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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

22Risk 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

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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