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Natalizumab benefit risk update   january 2014
 

Natalizumab benefit risk update january 2014

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    Natalizumab benefit risk update   january 2014 Natalizumab benefit risk update january 2014 Presentation Transcript

    • Tysabri (natalizumab) Benefit/Risk Update & PML Risk Stratification FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Benefit / Risk 81% reduction in relapse rate1 PML risk ≈ 3.45 in 1,000 3 64% reduction in disability progression 1 Risk Other Adverse Events Per Labelling Benefit >1 in 3 patients free of disease activity2 Natalizumab 1. Hutchinson M, et al. J Neurol. 2009;256:405-415. 2. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60. 3. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • PML Risk Update FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • What causes PML? • PML is uncommon and likely caused by interplay between multiple factors 1. Presence of asymptomatic JCV JC virion 2. Viral factors: VP1 mutations, RR permutations 3. Host factors: peripheral immune function, genetics 45 nm 4. Drug effects that reduce CNS immune surveillance VP1=viviparous 1; RR=regulatory region; CNS=central nervous system. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • PML Risk • Factors that increase the risk of PML have been identified1 – The presence of anti-JCV antibodies – Receiving an immunosuppressant prior to receiving natalizumab – Natalizumab treatment duration, especially >2 years • As of 6th January 2014, overall incidence: 3.45 per 1000 patients (95% CI: 3.13 to 3.79 per 1000 patients)2 – 77% of patients are alive with varying levels of disability • As of 6th January 2014, the duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 91 doses; approximately 16% had between 1-24 doses and 84% had >24 doses at the time of PML diagnosis.2 – Mean duration of natalizumab dosing at time of PML diagnosis was approximately 41 months2 1. Tysabri Summary of Product Characteristics 2. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Natalizumab PML Incidence Estimates by Treatment Epoch Incidence per 1000 patients 4.0 3.5 3.0 3.79 3.45 2.93 2.78 3.13 2.55 2.5 2.15 2.30 2.35 2.0 1.80 1.5 0.85 1.0 1.89 1.49 1.85 1.32 0.67 0.5 0.13 0.0 1.86 0.06 0.51 0.03 Calculations based on exposure through 31st December 2013 and 430 confirmed cases as of 6th January 2014 Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Natalizumab PML Incidence Estimates by Treatment Epoch (Apr 2010 – Jan 2014) 4.5 1-12 infusions 13-24 infusions Incidence per 1000 patients 4 25-36 infusions 3.5 37-48 infusions 3 49-60 infusions 61-72 infusions 2.5 2 1.5 1 0.5 Jan. 2014 Oct. 2013 Jul. 2013 Apr. 2013 Jan. 2013 Oct. 2012 Jul. 2012 Apr. 2012 Jan. 2012 Oct. 2011 Jul. 2011 Apr. 2011 Jan. 2011 Oct. 2010 Jul. 2010 Apr. 2010 0 Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Use of Natalizumab in the Post-Marketing Setting* Worldwide post-marketing data from 23 Nov 2004 to 30 Sep 2013 Overall Exposure 120,500 ≥12 Months 90,400 ≥18 Months 76,600 ≥24 Months 64,900 ≥30 Months 54,600 ≥36 Months ≥42 Months ≥48 Months 45,700 313,560 Patient-Years of natalizumab exposure 38,100 31,200 Patients *Post-marketing data includes patients exposed since 23 November 2004. This excludes approximately 5,100 patients exposed Patients in clinical trials; 2,200 exposed for ≥12 months; 1,900 exposed for ≥18 months; 1,700 exposed for ≥24 months; 1,300 were exposed ≥30 months; 1,000 were exposed ≥36 months; 700 were exposed ≥42 months; and 700 were exposed for ≥48 months. Exposures are estimates and may not fully reflect treatment interruptions that are used in certain patients. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* Anti-JCV Antibody Status Negative Positive Prior IS Use No Natalizumab Exposure 1–24 months 0.1/1000 95% CI 0.01-0.35 25–48 months 49–72 months Yes No Prior IS Use Prior IS Use 0.7/1000 1.8/1000 95% CI 0.5-1.0 95% CI 1.1-2.7 5.3/1000 11.2/1000 95% CI 4.4-6.2 95% CI 8.6-14.3 6.1/1000 Insufficient data 95% CI 4.8-7.8 Data beyond 4 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure. *Based on natalizumab exposure and 343 confirmed PML cases as of 5 th March 2013. Prior IS data in overall natalizumab-treated patients based on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of 5 th March 2013. The analysis assumes that 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. The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at le ast 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000; 95% CI 0.02–0.56). Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* Anti-JCV Antibody Status Negative Positive Prior IS Use 1 in 1,429 1 in 556 No 1 in 10,000 1 in 189 Natalizumab Exposure 1–24 months 0.1/1000 25–48 months 95% CI 0.01-0.35 1 in 164 49–72 months Yes No Prior IS Use Prior IS Use 0.7/1000 1.8/1000 95% CI 0.5-1.0 95% CI 1.1-2.7 5.3/1000 11.2/1000 95% CI 4.4-6.2 95% CI 8.6-14.3 6.1/1000 Insufficient data 95% CI 4.8-7.8 1 in 89 Data beyond 4 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure. *Based on natalizumab exposure and 343 confirmed PML cases as of 5 th March 2013. Prior IS data in overall natalizumab-treated patients based on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of 5 th March 2013. The analysis assumes that 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. The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at le ast 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000; 95% CI 0.02–0.56). Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context: Benefits of natalizumab therapy FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context • Initiation or continuation of natalizumab therapy should be based upon an assessment of the potential for benefit and risk 1 • Benefits and risks of natalizumab therapy are individual, and should be considered by both the physician and the patient1 1. Tysabri Summary of Product Characteristics FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context: AFFIRM efficacy1,2 In patients with highly active RRMS (≥2 relapses in the prior year and ≥1 Gd+ lesion at baseline) • Annualized relapse rate at 2 years • Sustained disability progression (confirmed for 24 weeks) 0.5 1.46 Annualized Relapse Rate 1.4 1.2 81% reduction (p<0.001) 1.0 0.8 0.6 0.4 0.28 Proportion With Sustained Disability Progression 1.6 64% risk reduction Hazard ratio=0.36 (p=0.004) 0.4 0.3 Placebo 26% 0.2 0.1 Natalizumab 10% 0.0 0 0.2 12 24 36 48 60 72 Weeks 84 96 108 120 Number of Patients at Risk 0.0 Placebo n=61 Natalizumab n=148 Placebo Natalizumab 61 57 54 51 47 46 45 42 39 36 148 144 141 140 137 131 130 128 123 123 Post hoc analysis of AFFIRM. AFFIRM was a 2 year, phase 3, randomized, double-blind, placebo-controlled, multicentre study of natalizumab in RRMS (N=942). RRMS=relapsing remitting multiple sclerosis. 1. Hutchinson M, et al. J Neurol. 2009; 256:405-15, 1035-7. 2. Tysabri Summary of Product Characteristics FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context: freedom from disease activity*1 Proportion of Disease-Free Patients (%) Overall Population P<0.0001 Highly Active Patients † P<0.0001 50 Placebo Natalizumab 40 36.7 5 30 16 vs placebo vs placebo 27.4 20 10 7.2 1.7 0 n=304 n=600 n=59 n=146 Post hoc analysis of AFFIRM. *Freedom from disease activity defined as the composite of freedom from clinical disease activit y (no relapses and no increase in EDSS) and freedom from radiologic disease activity (no new or enlarging T2 lesions and no Gd+ lesions). † Patients with ≥2 relapses in the prior year and ≥1 Gd+ lesion at baseline. EDSS=Expanded Disability Status Scale . 1. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context: long-term efficacy data from STRATA1 STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE. 1. Rudick, et al. ECTRIMS 2013; P593. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context: long-term efficacy data from STRATA1 STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE. EDSS=Expanded Disability Status Scale. 1. Rudick, et al. ECTRIMS 2013; P593. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context: real life data from TOP1 ARR per 12-month interval over time Overall median EDSS scores over time §P value is from the negative binomial model for the comparison of ARRs before and after natalizumab treatment • Overall, after a median treatment duration of 22 months (range: 1–74 months), mean ARR decreased from 1.99 at baseline to 0.31 on natalizumab therapy (P<0.0001) • Median EDSS remained stable over 4 years TOP is an ongoing, open-label, prospective, multicentre, observational study generating long-term outcomes data for natalizumab in RRMS patients in the post-marketing setting. As of 1 st December 2012, 4821 patients were enrolled. 1. Wiendl H, et al. ENS 2013; P372. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Putting risk into context: real life data from TOP in the UK1 Baseline and on-treatment ARR, overall and by relapse history Baseline and on-treatment ARR by baseline EDSS score N=3976 (P<0.0001) P<0.0001 for all baseline versus postbaseline comparisons shown. CI=confidence interval. P<0.0001 for both baseline versus postbaseline comparisons shown. • • Annualised relapse rate significantly decreased on natalizumab regardless of baseline relapse history Annualised relapse rate significantly decreased on natalizumab regardless of baseline disability status (EDSS) TOP is an ongoing, open-label, prospective, multicentre, observational study generating long-term outcomes data for natalizumab in RRMS patients in the post-marketing setting. As of 1st December 2012, 119 patients were enrolled in the UK; 80.7% of patients (n=96) had been followed for ≥ 12 months; 60.5% (n=72) had been followed for ≥ 18 months. 1. Hanna J, et al. ABN 2013; P140. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Summary • As of 30th September 2013, approximately 120,500 patients have received natalizumab in the post-marketing setting worldwide • Factors that increase the risk of PML have been identified1 – JCV exposure indicated by anti-JCV antibody positive status – Receiving an immunosuppressant prior to receiving natalizumab – Natalizumab treatment duration, especially >2 years • Clinical vigilance remains key in the early diagnosis of PML – Early diagnosis and aggressive clinical management appears to be associated with improved survival rates observed in post-marketing cases – PML may be fatal or result in severe disability1 • The following factors appear to be associated with improved survival after PML: – – – – • Shorter duration between symptom onset and PML diagnosis Localized PML on MRI at diagnosis Younger age Lower pre-PML EDSS Initiation or continuation of natalizumab therapy should be based upon an assessment of the potential benefit:risk balance for the patient 1. Tysabri Summary of Product Characteristics FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Supporting information: PML risk factors & outcomes FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Anti-JCV Antibody Testing • The 2-step anti-JCV antibody assay has been developed to help identify patients who have been exposed to the JC virus. It is designed to detect the presence of antibodies to JCV in the serum or plasma. • Anti-JCV antibody testing may be considered for: – All MS patients with disease activity who are contemplating a start/change in MS therapy where antibody status could be a factor in assessing therapeutic choice; – Patients treated with natalizumab who have not had their serostatus assessed. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Anti-JCV Antibody Testing • Current data on the assay as a risk stratification tool from STRATIFY-1 (n=1096) – – – 46% anti-JCV antibody negative and 54% anti-JCV antibody positive at baseline 1 False negative rate: 2.2% at baseline 2 and 2.4% over 18 months 3 Over 18 months, with testing every 6 months:1 • • • – In patients who tested anti-JCV antibody negative at baseline:1 • • – 84% (274/328) remained negative at 18 months 16% (54/328) changed serostatus In the subjects who changed serostatus:1 • • • 38% of subjects remained consistently anti-JCV antibody negative 52% remained consistently anti-JCV antibody positive 10% changed serostatus 31% (17/54) had intermittent positive results 69% (37/54) changed to anti-JCV antibody positive and remained positive for the duration of the study The probability of consistently testing anti-JCV antibody negative over time increases with the number of sequential anti-JCV antibody negative test results. – – In subjects who tested anti-JCV antibody negative at baseline (n=328), the probability of remaining anti-JCV antibody negative after 3 tests performed at 6-monthly intervals was 93.5% over 18 months 1 In subjects who tested anti-JCV antibody negative at baseline in AFFIRM (n=241), the probability of remaining anti-JCV antibody negative after 3 tests performed at 6-monthly intervals was 95%3 1. Plavina T, et al. Presented at AAN: March 18-23, 2013, San Diego, CA. S30.001. 2. Lee P, et al. J Clin Virol. 2013;57(2):141-6. 3. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Anti-JCV Antibody Testing • As of 6th January 2014, there are 197 natalizumab-treated MS PML patients with known pre-PML anti-JCV antibody status who had samples tested for anti-JCV antibodies, all of which were collected at least 6 months prior to PML diagnosis (range 6-187 months). Of these 197 patients, 195 (99%) tested anti-JCV antibody positive prior to diagnosis and 2 (1%) tested anti-JCV antibody negative. • Serum samples obtained prior to PML in two natalizumab-treated CD patients (one from clinical trials and one post-marketing) both tested antiJCV antibody positive. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Anti-JCV Antibody Testing • Re-testing of anti-JCV antibody negative patients every 6 months is recommended.1 • The anti-JCV antibody assay should not be used to diagnose PML.1 • Data from a Biogen Idec study of plasma exchange (PLEX) in natalizumabtreated MS patients demonstrated that anti-JCV antibody levels are decreased by 2-5 fold after PLEX and thus may lead to an anti-JCV antibody negative result in some patients with a relatively low titer before PLEX. AntiJCV 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.1 • One sample, collected from a patient at the time of PML diagnosis following a cycle of PLEX tested negative for anti-JCV antibodies. Because this sample was collected immediately following PLEX, and PLEX removes antibodies from the circulation, the information obtained from this sample is unreliable.2 1. Tysabri Summary of Product Characteristics 2. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Estimated PML Risk Associated with Prior IS Use • As of 4th March 2011, 39 of 93 patients (42%) with PML and known prior IS status had been treated with IS therapy before initiating natalizumab. Of the total 102 confirmed PML patients as of 4th March 2011, prior IS status was unknown for 9 patients and they were excluded from the analysis. • As of 23rd November 2010, the proportion of all patients treated with natalizumab in the TYGRIS Observational Study* who had been treated with an IS prior to receiving natalizumab was 20.3% (13.9% in US and 23.6% in EU/ROW). • Compared to patients who have never been treated with a prior IS therapy, patients with prior IS use had a ~3-4-fold greater risk of PML. • In patients with PML, there was no specific pattern in: – type of prior IS therapy – duration of prior IS therapy – time from last dose of IS to initiation of natalizumab therapy *http://clinicaltrials.gov/ct2/show/NCT00477113 http://clinicaltrials.gov/ct2/show/NCT00483847 Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • No Specific Pattern in Type of Prior IS Use Identified in Patients with PML • Type of prior IS use varied • Some patients had received more than one type of IS therapy • Types of prior IS use included: – Mitoxantrone (n=38) – Azathioprine (n=11) – Methotrexate (n=9) – Cyclophosphamide (n=14) – Mycophenolate (n=6) – Other (n=8) Data based on prior IS agents reported in 68 out of 197 patients with PML as of 29 th February 2012 (Prior IS status was unknown for 15 patients and they were excluded from the analysis). Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • No Specific Pattern in Duration of Prior IS Use or Time from Last Dose of IS in Patients with PML • Duration of prior IS use varied: – Mean 19.9 months, median 12.5 months (minimum 0.03 month, maximum 204 months) • Time from last dose of IS until start of natalizumab varied: – Mean 25.8 months, median 17.2 months (minimum 0.5 months and maximum 95.4 months) Data based on prior IS agents reported in 68 out of 197 patients with PML as of 29 th February 2012 (Prior IS status was unknown for 15 patients and they were excluded from the analysis). Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Key Learnings: PML Management • Heightened clinical vigilance led to prompt natalizumab discontinuation upon first signs or symptoms suggestive of PML – Median duration from symptom onset to PML diagnosis is approximately 1 month 1 • The majority of patients who developed PML in the post-marketing setting received plasma exchange (PLEX) and/or immunoadsorption (IA) to accelerate removal of natalizumab • In the majority of natalizumab-treated patients with PML, Immune Reconstitution Inflammatory Syndrome (IRIS) has occurred after discontinuation or removal (by PLEX) of natalizumab • In patients who have undergone PLEX, IRIS has occurred within days to several weeks2 1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446. 2. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Factors that may affect survival in patients with PML At this time, there are insufficient data to predict survival outcomes in patients treated with natalizumab who develop PML. Longer-term data are required in order to more accurately predict such outcomes. Factors that appear to be Factors that appear to be associated with decreased associated with improved survival survival • Younger age at PML diagnosis • Lower pre-PML EDSS • Shorter time from first symptoms of PML to diagnosis • Localized PML extension on MRI at diagnosis Factors that do not appear to affect survival • Gender • Prior immunosuppressant therapy • MS duration • Natalizumab exposure at PML diagnosis • JCV DNA load in CSF at PML diagnosis • Gd enhancement on MRI at diagnosis Vermersch P, et al. Neurology. 2011;76:1697-1704. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • PML Presenting Symptoms PML symptom % PML cases with symptom Cognitive/behavioral 49% Motor (eg: hemiparesis) 37% Speech (eg: dysarthria, aphasia) 31% Visual (eg: hemianopsia) 26% Cerebellar (eg: ataxia) 17% Seizure (eg: focal motor, generalized) 17% Sensory (eg: paresthesia) 3%  Neurologic deficits evolved over several weeks  Individual PML cases frequently presented with symptoms in multiple categories Based on the first 35 PML cases. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • IRIS Presents as Clinical Decline IRIS symptom % PML cases with symptom Motor (eg; hemiparesis) 66% Speech (eg; dysarthria, aphasia) 38% Cognitive/behavioral 34% Seizure 19% Visual (eg; hemianopsia) 13% Cerebellar (eg; ataxia) 13% Fever 6%  May be rapid, can lead to serious neurological complications or death  Individual cases frequently presented with IRIS symptoms in multiple categories. Based on the first 35 PML cases. At the time of the analysis, 32 of 35 PML cases reported the occurrence of IRIS. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • Key Learnings: Treatment of IRIS • Monitoring for development of IRIS and appropriate treatment should be undertaken • Treatment of IRIS with IV corticosteroids: – Experts uniformly recommend corticosteroids at onset after PLEX 1 – Majority of patients have been treated with IV corticosteroids for IRIS, typically 1 gram IV methylprednisolone daily for 5 days, followed by tapered dose of oral steroids 1 – Duration and timing of corticosteroid use remains to be refined. In many cases, repeated courses of IV corticosteroids were given1 – Does not appear to be associated with increased mortality • Prophylaxis of IRIS with corticosteroids has not been systematically evaluated – Given the severe nature of IRIS and its consistent presentation in most patients, pre emptive treatment starting immediately after PLEX might be justified. A randomized comparison of these alternatives would be helpful to refine IRIS management 1 1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • PML outcomes: Karnofsky scores On average, Karnofsky scores decrease at PML diagnosis but remain stable through ≥14 months of follow-up 100 90 Karnofsky Scores 80 70 pre-PML PML diagnosis 60 6-9 Months 50 10-13 Months 14+ Months 40 Mean 30 Median 20 10 0 Pre PML Mean Median n PML diagnosis 6-9 months 10-13 months ≥14 months pre-PML 81.1 80 33 PML diagnosis 49.4 50 32 6-9 months 53.1 50 45 10-13 months 49.6 50 27 ≥14 months 52.6 50 25 Karnofsky Performance Scale (KPS) scores for 80 PML survivors for whom data were available. Each point represents the score of an individual patient at the indicated interval relative to PML diagnosis; only those patients for whom KPS scores were available for a given interval are shown. Dong-Si T, et al. ECTRIMS 2012; P1098. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • PML outcomes: EDSS scores On average, EDSS scores increase at PML diagnosis but stabilize at 6-9 months and remain stable through ≥14 months of follow-up 10 9 8 EDSS Scores 7 pre-PML 6 PML diagnosis 6-9 Months 5 10-13 Months 4 14+ Months Mean 3 Median 2 1 0 Pre PML Mean Median n PML diagnosis pre-PML 3.7 3.5 90 PML diagnosis 5.2 5.5 75 6-9 months 6-9 months 6.3 6.4 28 10-13 months 10-13 months 6.4 6.8 16 ≥14 months ≥14 months 6.6 7 21 EDSS scores for 118 PML survivors for whom data were available. Each point represents the score of an individual patient at the indicated interval relative to PML diagnosis; only those patients for whom EDSS scores were available for a given interval are shown. Dong-Si T, et al. ECTRIMS 2012; P1098. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • PML outcomes: asymptomatic vs symptomatic • As of 5th June 2013, 372 PML cases had been confirmed in the post-marketing setting; of these 372 patients 30 (8.1%) were identified as asymptomatic and 342 (91.9%) were identified as symptomatic at the time of PML diagnosis − Asymptomatic was defined as patients who had no clinical symptoms of PML, but had MRI findings consistent with PML at the time of diagnosis Mean EDSS and KPS scores over time in asymptomatic and symptomatic PML patients P value from Mann-Whitney-Wilcoxon test. EDSS=Expanded Disability Status Scale; KPS=Karnofsky Performance Scale Dong-Si T, et al. ECTRIMS 2013; P879. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014
    • 0 PML outcomes: asymptomatic vs symptomatic −24 −18 −12 −6 100 −30 Karnofsky Score Functional Assessments Relative to Dia gnosis 80 • Over time, EDSS scores scores were consistently better in asymptomatic PML patients than in symptomatic PML patients. 60 20 0 40 6 4 Symptomatic Asymptomatic −30 2 EDSS Score 8 10 − Similar results were seen with KPS scores (EDSS-KPS correlation coefficient, 0.712). −24 −18 −12 −6 0 Months F −30 −24 −18 −12 −6 diagnosis 6 12 18 24 30 Months From PML Diagnosis Survival, n (%) Death, n (%) 80 All PML patients (n=372) 258 (75.4) 287 (77.2) 1 (3.3)a 60 Symptomatic PML patients (n=342) 29 (96.7) 84 (24.6) 85 (22.8) was reported as suicide caused by depression that was secondary to increasing disability and PML sequelae. 20 aDeath Asymptomatic PML patients (n=30) 40 Outcome Karnofsky Score 100 • Natalizumab-associated PML may be associated with better survival in asymptomatic patients than in patients who were symptomatic at diagnosis Symptomatic Asymptomatic 0 Dong-Si T, et al. ECTRIMS 2013; P879. −30 FOR HEALTHCAREdiagnosis 6 −24 −18 −12 −6 PROFESSIONALS ONLY 24 TY-PAN-0597(8) Date of preparation: January 2014 12 18 30
    • PML Research at Biogen Idec Our Mission: Via innovative clinical and laboratory research, gain deeper insights into PML pathogenesis, and develop PML risk stratification, diagnosis and management tools Objectives JCV antibody assay and further understanding JCV serology Clear and effective risk stratification algorithm Clinical Research • Pharmacovigilance and clinical data collection • Treatment duration/interruption • MRI use for early PML detection • Immune reconstitution • Prevention and treatment of IRIS • Research on PML outcome and management • Anti-JCV drug screening New tools for PML risk stratification Tools for early PML diagnosis JCV Biology Research Biomarker Discovery JCV Serology • JCV assay performance • JCV antibody serostability • JCV antibody levels • Genomics (host, viral) • Blood-based biomarkers (host and JCV mutations) - Hypothesis-driven (targeted) - Discovery (“omics”) • CSF biomarkers • Cell-based/immune system biomarkers Better understanding of PML outcomes • Defining host factors • Improving and developing new systems and animal models • Infection dynamics in tissues (JCV and other pathogens) • Integrated clinical and analytical data analysis • • • • Therapeutic approaches and management of PML Sample Collection • Clinical trials • Biobanking initiatives • Outreach to physicians • Pre-PML and at-PML diagnosis longitudinal samples are essential for discovery and validation of new biomarkers. - Serum/plasma - PBMC - CSF - DNA - RNA - Biopsies (brain, skin) BIIB internal research BIIB - supported SRAs and IITs Innovative technology partnerships PML Consortia-sponsored research FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(8) Date of preparation: January 2014