Nutzen und Risiko von Tysabri September 2011

Patienten unter Tysabri* Weltweite Anwendungsdaten nach Zulassung zwischen 23. November 2004 und 30. Juni 2011 Gesamtexposition 88,100 ≥12 Monate ≥18 Monate ≥24 Monate 165.500 Patientenjahre Natalizumabexposition ≥30 Monate ≥36 Monate ≥42 Monate Patienten *Post-marketing data includes patients exposed since 23 November 2004. This excludes a total of 4,700 patients exposed in clinical trials; 2,100 exposed for >12 months; 1,900 exposed for >18 months; 1,600 exposed for >24 months; 1,300 were exposed >30 months; 1,000 were exposed >36 months; and 700 were exposed >42 months. Exposure are estimates and may not fully reflect treatment interruptions that are used in certain patients.

PML-Inzidenz-Schätzungen nach Behandlungsdauer Inzidenz je 1000 Patienten * Yousry TA, et al. N Engl J Med. 2006;354:924-933 Inzidenz berechnet auf Basis der Natalizumab-Exposition bis einschließlich 31. August 2011 und 159 bestätigter Fälle bis einschließlich 01. September 2011 3

PML-Inzidenz-Schätzungen nach Behandlungszeitraum Inzidenz je 1000 Patienten * Yousry TA, et al. N Engl J Med. 2006;354:924-933 Inzidenz berechnet auf Basis der Natalizumab-Exposition bis einschließlich 31. August 2011 und 159 bestätigter Fälle bis einschließlich 01. September 2011 4

Geographische Verteilung Von den bis 01. August 2011 berichteten 159 Fällen waren: 60 aus den USA 91 aus der EU 8 aus anderen Ländern 29 Patienten sind verstorben (18%) Biogen Idec Data on file.

PML-Risiko Dauer der Natalizumabbehandlung bis PML-Diagnose: 1 Jahr bis > 4 Jahre Mittlere Dauer  2 Jahre Risiko über alle Patienten: 1.73 pro 1000 Patienten (95% CI; Bereich: 1.47 bis 2.02 pro 1000 Patienten) PML-Inzidenz steigt mit Dauer der Tysabribehandlung und bei Pat. die vor Tysabri mit Immunsuppressiva behandelt worden waren Die mittlere Behandlungsdauer mit Tysabri liegt weltweit bei ca. 2 Jahren Biogen Idec Data on file.

Vorherige Immunsuppressiva-Behandlung erhöht PML-Risiko Verglichen mit der Gesamtpopulation der mit Natalizumab behandelten Patienten haben Patienten mit vorheriger IS-Therapie ein ca 3-4 fach höheres PML-Risiko Patienten ohne vorherige IS-Therapie ein ca 50% niedrigeres PML-Risiko Kein Zusammenhang mit: Art der Immunsuppressiva Dauer der vorherigen Behandlung mit Immunsuppressiva oder Intervall zwischen letzter IS- und erster Tysabri-Gabe Basierend auf 39 von 102 Patienten mit PML bis 04. März 2011.

Vorherige Immunsuppressiva-Behandlung erhöht PML-Risiko IS-Vorbehandlung? Nein Ja Natalizumab- Therapie (Monate) Natalizumab- Therapie (Monate) Data beyond 4 years of treatment are limited. Based on natalizumab exposure data as of February 28, 2011; PML incidence data based on 102 confirmed PML cases as of March 4, 2011; prior IS data in overall natalizumab-treated patients based on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of November 23, 2010; and prior IS data in PML patients as of March 4, 2011 (with 102 confirmed PML cases of which only 88 had known prior IS status available and had natalizumab exposure between 1 and 48 doses). 1-24 0.19/1000 95% CI: 0.10, 0.33 25–48 1.37/1000 95% CI: 0.97, 1.9 1–24 0.66/1000 95% CI: 0.32, 1.2 25–48 4.3/1000 95% CI: 2.9, 6.2 1. Sandrock, et al. Presented at: ENS; May 28-31, 2011; Lisbon, Portugal. O212. 2. Sandrock, et al. Presented at: CMSC; June 1-4, 2011; Montreal, Quebec, Canada. S92

Wichtigste Erkenntnisse 42% der Tysabri-Patienten mit PML zuvor irgendwann mit Immunsuppressiva behandelt* Am häufigsten Mitoxantron, auch Azathioprin und Methotrexat (manchmal Mehrfach-medikation) Anwendungsdauer zwischen 4 Monaten und 5 Jahren Zeitraum zwischen letzter Gabe von Immunsuppressiva bis Behandlungsbeginn mit Tysabri war 2,5 Monate bis 5 Jahre Gesamtpopulation der Patienten mit vorheriger immunsuppressiver Behandlung in TYGRIS: ca. 14% in den USA und 24% in der EU/andere Geographische Unterschiede in der Verschreibung *Basierend auf 39 von 102 Patienten mit PML bis 04. März 2011.

Art der Immunsuppression läßt keine Schlüsse zu Einige Patienten haben mehrere Immunsuppressiva erhalten Vorher gegebene Immunsuppressiva: Mitoxantron (n=23) Azathioprin (n=5) Methotrexat (n=5) Cyclophosphamid (n=8) Mycophenolat (n=4) Nicht näher spezifiziert (n=3) Cladribin (n=1) Rituximab (n=1) Corticosteroide zählen nicht dazu *Basierend auf 39 von 102 Patienten mit PML bis 04. März 2011.

% PML-Fälle mit Symptom PML Symptome PML-Symptom % PML-Fälle mit Symptom Kognitiv/Verhalten 49% Motorisch (z. B.: Hemiparese) 37% Sprache (Dysarthrie, Aphasie, …) 31% Visuell (z. B. Hemianopsie) 26% Cerebellär (z. B. Ataxie) 17% Anfall ( fokal, generalisiert) Sensorisch (z. B. : Parästhesie) 3% Neurologische Defizite entwickelten sich über einige Wochern Individuelle PML-Fälle oft mit mehreren Symptomen Based on the first 35 PML cases. Biogen Idec Data on file.

MS/PML Lesion Differentiation by MRI Characteristic MS lesions PML lesions Location Periventricular perpendicular to ventricles (Dawson’s fingers), deep white matter, isolated U fibers, cerebellum and spinal cord Subcortical WM in parietal, occipital or frontal lobes. May involve precentral or postcentral gyrus ( motor / sensory cortex) or insular region. Follows WM tracks. Can cross the corpus callosum to contralateral hemisphere (butterfly pattern) or extend through internal capsule Rarely brainstem or cerebellar WM. No spinal cord involvement Appearance Well defined borders Infiltrating, ill-defined, confluent WM lesions which can be multifocal. Mass effect Large lesions can have mass effect Rare even in large lesions FLAIR Flair = T2 Flair more sensitive for detection of PML lesions in subcortical location T1W pre-contrast Isotense or mildly hypointense to Grey matter Isointense with progressive hypointensity T1 post contrast Homogeneous or ring-enhancement- resolves in 1-2 months Patchy, punctate or linear Nancy Richert Personal Communication.

Clinical Status of PML Cases Follow-up Time From PML Diagnosis (months) Survivors at Follow-up Time with Karnofsky** reported, n Functional Status of Survivors Mild Disability, n (%) Moderate Disability, n (%) Severe Disability, n (%) ≥ 6 47 6 (13%) 22 (47%) 19 (40%)* ≥ 9 18 3 (17%) 9 (50%) 6 (33%) Majority of patients with severe disability at ≥ 6 months from diagnosis (17/19, 89%) had Karnofsky scores of 40 which is at the interface between moderate and severe disability Karnofsky scores pre-PML/pre-TYSABRI were reported for very few patients (n=7); the average change in Karnofsky score attributable to PML for these 7 patients was 26. The Karnofsky Performance Scale is a validated functional outcome measure used to assess clinical outcomes across many disease states. Karnofsky scores range from 0 (death) to 100 (no functional impairment) and each score is associated with a unique functional status description. These patients may have been more likely to have reached a stable clinical state. Evaluation of disability after an acute event is best accomplished once the patient has reached a stable clinical state. In other neurological conditions, such as stroke, patients usually show greatest improvement within the first weeks to months, and neurological deficits generally stabilize beyond 3 to 6 months after the acute event (Kelley RE, Borazanci AP. Neurol Res. 2009;31:832-840.) *Karnofsky scores were available for 56 of the survivors. Of those 56 survivors with Karnofsky scores, 47 patients had at least 6 months of follow-up from diagnosis and 18 patients had at least 9 months of follow-up from diagnosis Based on outcomes from the 109* survivors out of the first 133 PML cases as of June 1, 2011 Vermersch et al. Presented at: EFNS; Sep 10-13, 2011; Budapest, Hungary.

Karnofsky Performance Scale Mild Able to carry on normal activity and to work; no special care needed 100 Normal no complaints; no evidence of disease 90 Able to carry on normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of disease Moderate Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed. 70 Cares for self; unable to carry on normal activity or to do active work 60 Requires occasional assistance, but is able to care for most of his personal needs 50 Requires considerable assistance and frequent medical care Severe Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly 40 Disabled; requires special care and assistance 30 Severely disabled; hospital admission is indicated although death not imminent 20 Very sick; hospital admission necessary; active supportive treatment necessary 10 Moribund; fatal processes progressing rapidly Dead