The following MS experts were involved in the development of this Position Statement:

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1 Position Statement for TYSABRI (natalizumab) and STRATIFY JCV TM in Multiple Sclerosis Rationale for this Position Statement This Position Statement was developed by ten Australian neurologists who specialise in the management of multiple sclerosis (MS). The Statement includes information on TYSABRI and its key features in relation to the treatment of MS patients, in addition to information on STRATIFY JCV TM, which is an assay for detecting JC Virus (JCV) antibodies and its role in the risk stratification and management of PML. The following MS experts were involved in the development of this Position Statement: Dr Michael Barnett Professor Bruce Brew Professor Simon Broadley Associate Professor Helmut Butzkueven Professor William Carroll Dr Suzanne Hodgkinson Professor Allan Kermode Associate Professor John King Dr Christopher Kneebone Professor Richard Macdonell Working sessions of the above experts were organised with the support of Biogen Idec Australia. This Position Statement was developed on the basis of the experts experience and knowledge of the use of natalizumab. Medical writing and editorial support was provided by Ms Kate Trimble from Nitecs Pty Limited and was funded by Biogen Idec Pty Limited. The Product Information for TYSABRI should also be consulted for more detailed information on the product. TYSABRI Clinical Profile TYSABRI is a highly specific α4-integrin antagonist and was approved in Australia for the treatment of patients with MS with the relapsing-remitting form of the disease on the basis of its targeted mode of action and its positive effects on various clinical and magnetic resonance imaging (MRI) outcomes in the placebo-controlled clinical studies. The studies included AFFIRM 1 (Natalizumab Safety and Efficacy in Relapsing-Remitting MS), SENTINEL 2 (Safety and Efficacy of Natalizumab in Combination with Avonex IFNB- 1a in Patients with Relapsing-Remitting MS) and GLANCE 3 (Glatiramer Acetate and Natalizumab Combination Evaluation). Further evidence of real world efficacy of TYSABRI has been confirmed in the ongoing TYSABRI Observational Program (TOP). 4 TYSABRI is indicated as monotherapy for the treatment of patients with relapsing remitting multiple sclerosis (MS) to delay the progression of physical disability and to reduce the frequency of relapse. Tysabri PS-V Page 1 of 6

2 TYSABRI Safety Profile, PML Risk and the Role of STRATIFY JCV TM TYSABRI Safety Profile In placebo-controlled studies involving 1,617 MS patients treated for up to 2 years, 43.5% of patients treated with TYSABRI reported adverse effects compared to 39.6% of placebo treated patients. Adverse effects reported more frequently with TYSABRI included headache, fatigue, urinary tract infections and arthralgia. A range of infusion reactions, each relatively infrequent, have been reported (23.1% of patients treated with TYSABRI versus 18.7% with placebo). Hypersensitivity reactions were observed in 4% of patients treated with TYSABRI and anaphylactic reactions were reported in less than 1% of patients. Treatment of the anaphylactic reactions included immediate discontinuation of the TYSABRI infusion and administration of antihistamines and/or corticosteroids. In cases of hypersensitivity reaction, treatment with TYSABRI must be discontinued. In some cases, infusion reactions may be managed by pre-treatment with steroids and antihistamines. Development of antibodies against natalizumab was observed in 10% of patients and persisting antibodies were identified in 6% of patients which results in loss of efficacy of TYSABRI. Opportunistic infections have been reported with the use of TYSABRI predominantly in immunosuppressed patients or those with significant comorbidity. TYSABRI should not be administered to patients with increased risk for opportunistic infections, including those immunocompromised due to current or recent immunosuppressive therapies (e.g. azathioprine, mitoxantrone), or systemic medical conditions resulting in significantly compromised immune system function (e.g. human immunodeficiency virus (HIV), organ transplant, active malignancy). TYSABRI should not be administered in combination with immunomodulatory agents (e.g. interferon beta or glatiramer acetate). Overall, TYSABRI has shown a very good tolerability profile, however use of natalizumab has been associated with an increased risk of developing a rare viral brain infection, progressive multifocal leukoencephalopathy (PML) which may lead to severe disability or even death. PML is an opportunistic infection of the CNS caused by the JC virus, a type of human polyomavirus. The infection rate and therefore seroprevalence of JCV in humans is estimated at around 50-60%, with primary infection usually occurring in childhood, almost always having an asymptomatic course. The virus persists in the kidneys, bone marrow or lymphatic tissue, and controversially in the brain. It is often intermittently shed in the urine of healthy individuals. The underlying pathology of PML involves active replication of the JC virus in glial cells of the brain causing lytic death of oligodendrocytes. Previously the infection typically arose in severely immunocompromised patients such as those with HIV infection or organ transplantation. PML is extremely rare in immunocompetent individuals. Patients with PML may present with cognitive or behavioural symptoms, which have been most commonly observed either alone, or in association with motor, language, or visual symptoms. Any new neurological symptoms or personality changes lasting more than two days should be reviewed by the treating clinician. MRI findings show typical subcortical lesions often with gadolinium enhancement, which is usually less intense and more granular or punctate than that typically observed with MS lesions. It is still too early to draw broad conclusions about outcomes in patients who have developed PML whilst receiving TYSABRI as data are insufficient, however preliminary findings indicate Tysabri PS-V Page 2 of 6

3 that early diagnosis of PML, heightened clinical vigilance, and cessation of TYSABRI on suspicion of PML are associated with better outcomes for MS patients. 5 Whilst TYSABRI use has been associated with an increased risk of PML, the absolute risk for PML in patients treated with TYSABRI cannot be precisely estimated. As of 1 st August 2012 on the basis of post-marketing reports, the estimated overall risk of PML is 2.54 per 1000 patients (95% CI per 1,000 patients). 6 In TYSABRI patients who develop PML, Immune Reconstitution Inflammatory Syndrome (IRIS) occurs in almost all cases after withdrawal or removal of TYSABRI, e.g. by plasma exchange (PLEX), and PLEX is recommended when PML is suspected. IRIS is thought to result from the restoration of CNS immune function in patients with PML. IRIS presents as a worsening in neurological status that may be rapid, which can lead to serious neurological complications and may be fatal. Monitoring for development of IRIS, which has occurred within days to several weeks after plasma exchange in TYSABRI treated patients with PML, is essential and appropriate treatment of the associated inflammation during recovery from PML should be undertaken, using high dose intravenous glucocorticoids. The role of prophylactic glucocorticoids to prevent or reduce the severity of IRIS is recommended by some experts, as IRIS is an almost universal occurrence in TYSABRI related PML. Moreover, there is a reasonably large body of anecdotal evidence that PML does not worsen when corticosteroids in high dose are given over short periods. PML Risk Stratification and the Role of STRATIFY JCV TM Given the widespread use of TYSABRI and the potentially life-threatening consequences of PML, there is a need to identify patients who may be at a higher risk of developing PML. There are three risk factors that have been identified for MS patients receiving treatment with TYSABRI and the development of PML: 1. Treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 4 years of TYSABRI treatment. Therefore, the risk of PML in these patients cannot currently be estimated. 2. Immunosuppressant use at any time prior to receiving TYSABRI. 3. The presence of anti-jcv antibodies. A two-step JCV antibody assay known as STRATIFY JCV TM has been developed, which combines ELISA with an immunoadsorption step. Preliminary assessments detected JCV antibodies in 54% of MS patients who were tested. 7 An annual seroconversion rate of 2-3% has been observed, whereby patients convert from JCV antibody negative to persistent positive status. 7 With this assay, assessment of JCV antibodies in archived serum samples obtained from 75 TYSABRI-treated patients at months prior to PML diagnosis showed that samples from all patients tested positive for JCV antibodies. 8 Therefore, detection of JCV antibodies in combination with other known risk factors such as prior use of immunosuppressants and duration of TYSABRI treatment could stratify PML risk in patients with MS who are being treated, or are being considered for treatment, with TYSABRI. Patients who have all three of the above risk factors have the highest risk of PML, being approximately 10 in 1,000 patients treated, as determined during studies using the STRATIFY JCV assay. Table 1 shows the estimated risk of PML development when the three risk factors are taken into consideration. Tysabri PS-V Page 3 of 6

4 Table 1 PML risk stratification 9 JCV antibody negative 0.09/1000 TYSABRI exposure JCV Antibody positive no prior IS use JCV Antibody positive with prior IS use 1-24 infusions 0.56/ / infusions 4.6/ /1000 Adapted from Bloomgren et al PML incidence data based on 212 confirmed PML cases as of February 29, 2012; analysis assumes 55% of natalizumab-treated MS patients were anti-jcv antibody positive and that all PML patients test positive for anti-jcv antibodies prior to the onset and diagnosis of PML; 34.5% had prior immunosuppressant (IS) use. Calculation assumes one expected case of JCV antibody negative PML in patients exposed to at least 18 months of therapy. The risks and benefits of continuing treatment with TYSABRI should be carefully considered in patients who have all three of these risk factors for PML. Patients with no prior exposure to JCV have a very low risk of PML irrespective of duration of treatment and prior immunosuppressant use. TYSABRI should be administered with caution to patients who have previously received immunosuppressants in the recent or distant past, and only with knowledge of JCV antibody status, to assess the risk of developing PML. Data beyond 4 years of treatment are limited. Considerations for the use of TYSABRI and STRATIFY JCV TM Antibody Assay TYSABRI therapy is to be initiated and supervised by neurologists, in centres with timely access to MRI. Prescribing neurologists must discuss the benefits and risks of TYSABRI therapy with the patient, provide them with the Consumer Medicine Information and a Patient Alert Card and obtain individual, written, fully informed consent from the patient (or legal guardian where appropriate) for the use of TYSABRI. Neurologists should counsel patients on the importance of uninterrupted dosing, particularly in the early months of treatment. The Alert Card reminds patients that because of the risks of PML and opportunistic infections with TYSABRI, they must contact their doctor if they have unusual or prolonged new neurological symptoms or if they have severe or prolonged symptoms of infection. Patients should be instructed that they should inform all their healthcare providers that they are receiving treatment with TYSABRI. At a minimum the neurologist should re-evaluate the patient 3 months after the first infusion, 6 months after the first infusion and every 6 months thereafter. More frequent monitoring may be warranted for patients in higher risk groups for developing PML. Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic benefit beyond 6 months. Continued therapy beyond 2 years should be considered only following a reassessment of the potential for benefit and risk. Testing of MS patients for JCV antibodies with STRATIFY JCV is recommended as part of the benefit-risk evaluation for treatment decisions as follows: For all patients treated with TYSABRI in whom JCV antibody status is unknown For all patients where the neurologist is considering commencing TYSABRI Tysabri PS-V Page 4 of 6

5 If the STRATIFY JCV assay indicates a positive result, other risk factors should be carefully considered together with other possible treatment alternatives before starting/continuing TYSABRI. In patients who have all three PML risk factors (i.e., JCV antibody positive, prior immunosuppressant use and >2 years exposure to TYSABRI) the risk-benefits of continuing therapy with TYSABRI should be carefully re-evaluated. In the case of a negative result, TYSABRI is a suitable treatment earlier in the disease, even in situations where the disease activity is not high, or in the case of adverse events or continuing disease activity in response to other treatments. TYSABRI treated patients who are JCV antibody negative should be retested every 6 months, and the benefit-risk balance should be reassessed should their serostatus change to positive. In the case of a JCV antibody positive result, no repeat JCV antibody testing is required. JCV antibody assays should not be used alone to diagnose PML: seropositivity is necessary as an indicator of JCV infection but not sufficient for the diagnosis. JCV antibody testing should not be performed during or for at least two weeks following plasma exchange due to the removal of antibodies from the serum. Before initiation of treatment with TYSABRI, a recent (usually within 3 months) MRI should be available as a reference. In JCV negative patients this should be repeated on a yearly routine basis to update this reference. In JCV positive patients the MRI should be repeated after the first 12 months of therapy and subsequently MRIs are recommended to be performed at 6 monthly intervals. If there has been prior immunosuppressant use, increasing the MRI frequency to 3 monthly is recommended. MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML; FLAIR (fluid-attenuated inversion recovery) and DWI (diffusion-weighted imaging) sequences should be included in the MRI as this is a more sensitive method than T2 for distinguishing PML from MS lesions. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If new neurological symptoms suggestive of PML occur, further dosing is to be suspended until PML has been excluded. If any doubt exists, further evaluation, including MRI scan (compared with pre-treatment and previous post-treatment MRI), CSF testing for JCV DNA and repeat neurological assessments, should be performed. If initial investigations prove negative, but clinical suspicion for PML still remains, TYSABRI should not be restarted and repeat investigations should be undertaken. Once the clinician has excluded PML, dosing of TYSABRI may resume. Physicians should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of. If a patient develops PML, the dosing of TYSABRI must be permanently discontinued to enable reconstitution of the immune system in the CNS. Treatment with corticosteroids should be administered to reduce the severity of IRIS. Tysabri PS-V Page 5 of 6

6 References 1. Polman CH, O Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: Goodman AD, Rossman H, Bar-Or A, et al. GLANCE: Results of a phase 2, randomized, double-blind, placebo-controlled study. Neurology 2009; 72: Kappos L, Belachew S, Butzkueven H, Pellegrini F, Trojano M, Wiendl H, Zhang A, Hotermans C. Multiple Sclerosis Patients Treated with Natalizumab in the TYSABRI Observational Program (TOP). P AAN, New Orleans, Kappos L, Bates D, Edan G, et al. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol 2011; 10: accessed 12/09/ Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010; 68: Goelz SE, Gorelik L, Subramanyam M. Assay design and sample collection can affect anti-john Cunningham virus antibody detection. Ann Neurol 2011; 69: Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, and Bozic C. Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. NEJM 2012; 366 (20): Tysabri PS-V Page 6 of 6