Tysabri

1
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

Center for Drug Evaluation and Research
2
Overview

• TOUCH Prescribing Program
• Key Elements of MS-TOUCH
• Experience with TOUCH in multiple sclerosis (MS)
  patients
• Proposed features of CD-TOUCH
• Additional considerations in Crohns disease (CD)
  patients
• Postmarketing Safety Update

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 FDA Briefing Document, February 9, 2006
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

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

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

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

8
How Does MS-TOUCH Work to Meet Its Risk
Minimization Goals?
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

10
MS-TOUCH Methods to Minimizethe Risk of PML

• Program reinforces
• Appropriate patient selection
• Risk communication to HCPs and patients
• Close patient monitoring

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

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

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

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

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

16
Patients 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

17
Postmarketing Experience with MS-TOUCH
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 gt 1 year of continuous use

Data derived from Biogen Idec exposure as of May
23, 2007
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MS-TOUCH Safety Surveillance

• There were no reports of PML in the postmarketing
  period
• Two reports of other serious opportunistic
  infections

Source Age/ Gender Diagnosis of infusions Outcome
Foreign Spontaneous 26 Female Herpes Zoster 7 Hospitalized, treated and discharged
US Spontaneous 26 Male Herpes esophagitis 6 Hospitalized, treated and discharged
20
Baseline Patient Data

• Demographics
• Gender
• Women 5,925
• Men 2,381
• Unspecified 7
• Median age 46 years

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

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

Changes in medical problems 5.4
Concurrent immunosuppressant or immunomodulatory agents 1.5
Concurrent systemic corticosteroid 2.3
Concomitant condition that may weaken the immune system 0
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
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 gt10,000 shipments were unauthorized
  (sent to patients or prescribers address)

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

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

27
Differences

• CD-TOUCH does not emphasize monotherapy to same
  extent as MS-TOUCH
• The prescriber acknowledgement section includes
  the following statement for each program

MS-TOUCH CD-TOUCH
TYSABRI is indicated as monotherapy for relapsing forms of MS TYSABRI is indicated for the treatment of moderately to severely active CD
28
Differences

• 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
Differences

• 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
Special Considerations in Crohns 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

31
Postmarketing Safety Update
32
Postmarketing Adverse Event Experience

• Sponsors 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
• gt 1,700 reports, 65 from clinical trials
• Most events appear consistent with product
  labeling
• Proposed hypersensitivity labeling changes under
  review

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

34
Cases of Serious Natalizumab-associated Liver
Injury (n 4)

• Liver injury occurred within 18 days after 1st
  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/dLtt
• 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