2 nd Line Disease Modifying Therapies

1. 2nd Line Disease Modifying Therapies

2. TYSABRI

3. Introduction • Overview • Mode of action • Indications for use • Administration • Side effects • Contra indications/risks

4. History of Tysabri • Licensed in USA in 2005 • Withdrawn later in 2005 following 3 cases of PML – 2 in pwMS • Re-licensed with new prescribing criteria - 2006 • Licensed in Europe in 2006 • Provisionally turned down by NICE in April 2007 as not being cost effective • Approved by NICE August 2007

5. What is Tysabri? • Monoclonal antibody bioengineered from part of a mouse antibody to closely resemble a human antibody. • Monoclonal antibodies are produced in cell culture in a laboratory setting and they can be designed to bind to proteins on the body’s normal cells • By recognising these cells, monoclonal antibodies can interfere with or alter normal or abnormal cellular responses. • Tysabri binds to a receptor on circulating white cells and prevents any interaction between the receptor and adhesion molecules. This is thought to block migration of inflammatory cells across the blood/brain barrier

6. Mode of action • Binds to an adhesion molecule (alpha-4-integrin) on the T cell • Reduces the passage of the activated T cells across the blood brain barrier • Therefore reducing the inflammatory activity that leads to axonal and myelin damage

7. Inflammatory Response in MS Connella B et al. Ann Neurol. 1995;37:424-435. von Adrian UH et al. N Engl J Med. 2003;34:68-72

8. Role of41 Integrins in MS Trans-endothelial migration of activated T-cells across BBB in EAE mediated by integrins Lobb RR et al. J Clin Invest. 1994;94:1722-1728

9. Indications for TYSABRI • TYSABRI is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis (RRMS) for the following patient groups: • Patients with rapidly evolving severe relapsing remitting multiple sclerosis Patients with rapidly evolving severe relapsing remitting multiple sclerosis, defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to previous recent MRI or • Patients with high disease activity despite treatment with a beta-interferon Patients who have failed to respond to a full and adequate course of beta-interferon. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion NICE, 2007, LONDON

10. Tysabri Data • Reduction in relapses by 81% v. placebo - as opposed to ~33% seen with other disease modifying therapies • Reduction in disability and sustained disability progression by 64% as assessed over two years • Similar number of adverse and serious events in comparison to placebo patients

11. Key studies • Sentinel Natalizumab and beta interferon vs beta interferon alone • Affirm

12. The Affirm Study • Randomized, double-blind, placebo-controlled, multicentre, parallel-group design • Sample size: 942 patients with highly active RRMS • Treatment arms • 627 patients randomized to natalizumab 300 mg • 315 patients randomized to placebo • Intravenous (IV) infusions every 4 weeks for ≤116 weeks Polman CH, et al. N Engl J Med. 2006;354:899-910

13. Key Inclusion Criteria • Diagnosis of relapsing MS • Age, 18–50 years • EDSS score, 0–5.0 • 1 documented clinical relapse within the prior 12 months • Lesions on MRI consistent with MS McDonald WI, et al. Ann Neurol. 2001;50:121-7; Polman CH, et al. N Engl J Med. 2006;354:899-910

14. TYSABRI Efficacy Summary • 68% Reduction in annual relapses v placebo over 2 years • 54% reduction of disability progression sustained for 24 weeks • 28% of patients free from relapse, disability progression, Gd enhanced lesions, T1 weighted hypointense lesions & T2 weighted hyperintense lesions TYSABRI SmPC; Polman CH, et al. NEJM 2006; 354: 899-910; TY00-004, Data on file. Biogen Idec Ltd

15. Efficacy Summary – Rapidly Evolving Severe (RES) RRMS subgroup • A subgroup of data was examined from 209 patients with RES • Findings: • 81% reduction in relapse rate v placebo over 2 yrs • 64% reduction in the risk of EDSS progression sustained for 24 weeks AFFIRM rapidly evolving subgroup* 1 (n= 148 for TYSABRI, 61 for PBO)

16. Preparation and administration • 300mg IV infusion once every 4 weeks. • Diluted and then infused over 1 hour at a rate of approx 2ml/ minute • Patients require observation during infusion and for 1 hour after the completion for signs and symptoms of hypersensitivity reactions. • Tysabri must not be administered as a bolus injection • If usual dose is missed drug should be administered as soon as possibleand then continue with 4weekly infusion • Patients should receive the patient alert card prior to their first infusion 1) TYSABRI SmPC; 2) TYSABRI Patient Information Leaflet

17. Common side effects • Urinary tract infection • Nasopharyngitis • Urticaria • Headache and dizziness • Vomiting and nausea • Arthralgia • Rigors, pyrexia and fatigue

18. TYSABRI - Contraindications • Hypersensitivity • Patients with increased risk for opportunistic infections, including immunocompromised patients • Combination with beta-interferons or glatiramer acetate • Known active malignancies, except in patients with cutaneous basal cell carcinoma • Children and adolescents • Pregnancy and breastfeeding • PML (Progressive multifocal leucoencephalopathy) TYSABRI SPC

19. Progressive Multifocal Leucoencephalopathy (PML) • Rapidly progressive CNS disease caused by the opportunistic pathogen JC Virus. • PML primarily affects immunocompromised individuals • 3 Cases of PML were observed in phase III clinical trials of TYSABRI • 2 cases in MS in patients receiving con-comitant interferon-beta • 1 case in a Crohn’s Disease patient with a history of receiving immunosuppressive drugs (Azothioprine) • Tysabri is therefore indicated only as mono-therapy Yousry T, et al. N Engl J Med. 2006;354:924-33; TYSABRI SPC

20. PML 2012 UPDATE • By 2012, there have been 271 confirmed cases of PML worldwide. • Risk factors: - previous exposure to JC virus (JCV antibody test available) - previous immunosuppression - duration of Tysabri treatment

21. PML • The risk of PML appears to increase the longer a patient is on treatment, especially if they have been on treatment for more than two years. • It is not known if the chance of getting PML continues to rise, remains the same or falls after they have been on TYSABRI for more than three years due to limited data. • Currently, there are no known interventions that can reliably prevent PML or adequately treat PML if it occurs.

22. Switching To Tysabri • Patients can switch directly from beta-interferon or glatiramer acetate to Tysabri providing there are no signs of relevant treatment-related abnormalities e.g. neutropenia. • It is important to ensure that patients are not immunocompromised (if previously treated with immunosuppresive agents) before commencing treatment with Tysabri. TYSABRI SmPC

23. Precautions when stopping Tysabri • Pharmacodynamic effects lasts up to 12 weeks • Therefore caution if commencing other immunosuppressive therapies

24. Important considerations • Patient education and informed consent • Staff training • Cost • Long term capacity/ resource issues

25. Appendix