Natalizumb benefit risk update August 2013

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  • 1. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY TYSABRI (natalizumab) Benefit/Risk Update & PML Risk Stratification
  • 2. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY This information has been provided by Biogen Idec Medical Affairs for healthcare professional use only, in response to your request.
  • 3. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Benefit / Risk Benefit Risk TYSABRI 81% reduction in relapse rate1 64% reduction in disability progression1 >1 in 3 patients free of disease activity2 PML risk ≈ 3.28 in 1,000 3 Other Adverse Events Per Labelling 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.
  • 4. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY PML Risk Update
  • 5. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY VP1=viviparous 1; RR=regulatory region; CNS=central nervous system. 1. Presence of asymptomatic JCV 2. Viral factors: VP1 mutations, RR permutations 3. Host factors: peripheral immune function, genetics 4. Drug effects that reduce CNS immune surveillance 45 nm JC virion What causes PML? • PML is uncommon and likely caused by interplay between multiple factors
  • 6. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY PML Risk • Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 91 doses1 – Mean duration of natalizumab dosing at time of PML diagnosis was approximately 40.0 months1 • Overall incidence: 3.28 per 1000 patients (95% CI: 2.96 to 3.61 per 1000 patients)1 – Currently the average post-marketing natalizumab exposure worldwide is approximately 2 or more years of natalizumab exposure • Factors that increase the risk of PML have been identified2 – JCV exposure indicated by anti-JCV antibody positive status – Receiving an immunosuppressant prior to receiving natalizumab – Natalizumab treatment duration, especially >2 years 1. Biogen Idec, data on file. 2. TYSABRI Summary of Product Characteristics
  • 7. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Natalizumab PML Incidence Estimates by Treatment Duration Biogen Idec, data on file. Calculations based on exposure through 31st July 2013 and 395 confirmed cases as of 6th August 2013 Incidenceper1000patients 3.61 4.85 5.55 6.11 5.92 5.77 5.45 4.60 4.27 3.69 2.96 3.97 4.52 4.95 4.67 4.43 4.04 3.18 2.74 2.09 3.28 4.39 5.02 5.51 5.27 5.07 4.71 3.84 3.44 2.81 0.0 1.0 2.0 3.0 4.0 5.0 6.0
  • 8. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Natalizumab PML Incidence Estimates by Treatment Epoch Incidenceper1000patients Calculations based on exposure through 31st July 2013 and 395 confirmed cases as of 6th August 2013 Biogen Idec, data on file. 3.61 0.12 0.84 2.28 2.87 2.99 2.73 2.96 0.02 0.49 1.58 1.93 1.84 1.35 3.28 0.06 0.65 1.91 2.37 2.36 1.96 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
  • 9. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Use of Natalizumab in the Post-Marketing Setting* Patients Biogen Idec, data on file. Worldwide post-marketing data from 23 Nov 2004 to 30 June 2013 *Post-marketing data includes patients exposed since 23 November 2004. This excludes approximately 5,100 patients exposed 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. 118,100 86,700 73,100 62,100 51,900 43,500 36,000 29,000 Overall Exposure ≥12 Months ≥18 Months ≥24 Months ≥30 Months ≥36 Months ≥42 Months ≥48 Months Patients 296,471 Patient-Years of natalizumab exposure
  • 10. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Geographic Distribution of PML Cases • Of the 395 cases reported through 6th August 2013: – 131 are from the United States – 232 are from the European Economic Area – 32 are from the rest of the world Biogen Idec, data on file.
  • 11. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Status of PML Cases • As of 6th August 2013: – 92 patients have died (23%) – 303 patients are alive (77%) • It is too early to draw conclusions about the outcomes of patients who develop PML while on natalizumab treatment • PML may be fatal or result in severe disability1 The median time to death was 2.2 months (range, 0.1 to 15.2 months) for 44 deaths as of 29th February 2012. 1. TYSABRI Summary of Product Characteristics 2. Biogen Idec, data on file.
  • 12. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 0.1/1000 95% CI 0.01-0.35 No Yes Anti-JCV Antibody Status Negative Positive Prior IS Use Natalizumab Exposure No Prior IS Use Prior IS Use 1–24 months 0.7/1000 95% CI 0.5-1.0 1.8/1000 95% CI 1.1-2.7 25–48 months 5.3/1000 95% CI 4.4-6.2 11.2/1000 95% CI 8.6-14.3 49–72 months 6.1/1000 95% CI 4.8-7.8 Insufficient data Data beyond 6 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 5th 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 5th 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 least 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. Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration*
  • 13. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 0.1/1000 95% CI 0.01-0.35 No Yes Anti-JCV Antibody Status Negative Positive Prior IS Use Natalizumab Exposure No Prior IS Use Prior IS Use 1–24 months 0.7/1000 95% CI 0.5-1.0 1.8/1000 95% CI 1.1-2.7 25–48 months 5.3/1000 95% CI 4.4-6.2 11.2/1000 95% CI 8.6-14.3 49–72 months 6.1/1000 95% CI 4.8-7.8 Insufficient data Data beyond 6 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 5th 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 5th 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 least 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. Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* 1 in 10,000 1 in 1,429 1 in 556 1 in 89 1 in 164 1 in 189
  • 14. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: Benefits of natalizumab therapy
  • 15. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY • Initiation or continuation of natalizumab therapy should be based upon an assessment of the potential for benefit and risk1 • Benefits and risks of natalizumab therapy are individual, and should be considered by both the physician and the patient1 Putting risk into context 1. TYSABRI Summary of Product Characteristics
  • 16. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 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) 1. Hutchinson M, et al. J Neurol. 2009; 256:405-15, 1035-7. 2. TYSABRI Summary of Product Characteristics 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 AnnualizedRelapseRate 1.46 0.28 Natalizumab n=148 Placebo n=61 81% reduction (p<0.001) Number of Patients at Risk Placebo Natalizumab ProportionWith SustainedDisabilityProgression 0.0 0.1 0.2 0.4 0.5 Weeks 24 Placebo 26% Natalizumab 10% 61 57 54 51 148 144 141 140 0 120 0.3 72 1089648 47 46 45 42 39 36 137 131 130 128 123 123 12 36 60 84 64% risk reduction Hazard ratio=0.36 (p=0.004) • Annualized relapse rate at 2 years • Sustained disability progression (confirmed for 24 weeks) 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.
  • 17. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 1. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60. ProportionofDisease-FreePatients(%) n=304 n=600 n=59 n=146 Overall Population P<0.0001 Highly Active Patients † P<0.0001 7.2 1.7 36.7 27.4 0 10 20 30 40 50 Placebo Natalizumab 5 vs placebo 16 vs placebo Putting risk into context: freedom from disease activity*1 Post hoc analysis of AFFIRM. *Freedom from disease activity defined as the composite of freedom from clinical disease activity (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.
  • 18. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: long-term efficacy data from STRATA1 1. Kappos L, et al. ECTRIMS 2012; P520. Cessation/ Treatment Gap n=381 n=707 n=381 n=707 n=328 n=641 n=385 n=709 n=282 n=584 n=385 n=709 n=244 n=519 n=203 n=456 n=249 n=528 † 1 Year 2 Years 3 Years 4 Years 5 Years Original Placebo Original Natalizumab Original Placebo – Now on Natalizumab UnadjustedAnnualizedRelapseRate 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. *Includes data on patients dosed with natalizumab; †includes all available on-treatment relapse data.
  • 19. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: long-term efficacy data from STRATA1 1. Kappos L, et al. ECTRIMS 2012; P520. n=380 n=707 n=381 n=707 n=280 n=552 n=385 n=709 n=275 n=575 n=71 n=142 n=224 n=490 n=205 n=450 n=236 n=491 † 1 Year 2 Years 3 Years 4 Years 5 Years Cessation/ Treatment Gap* Original Placebo Original Natalizumab Original Placebo – Now on Natalizumab MeanEDSSScore 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. *P<0.0001; †includes data on patients dosed with natalizumab. EDSS=Expanded Disability Status Scale.
  • 20. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: real life data from TOP1 N=3976 (P<0.0001) • Annualized relapse rate remained low after 4 years on therapy 1. Kappos L, et al. AAN 2012; P04.134. n=3963 n=3971 • The median EDSS score remained stable up to 4 years of follow-up 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. 66% of patients (n=2624) analyzed had been followed for ≥1 year; 32% (n=1259) had been followed for ≥2 years; 12% (n=458) had been followed for ≥3 years.
  • 21. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Supporting information: PML risk factors & outcomes
  • 22. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY • 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. Anti-JCV Antibody Testing
  • 23. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY • 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 baseline1 – False negative rate: 2.2% at baseline2 and 2.4% over 18 months3 – Over 18 months, with testing every 6 months:1 • 38% of subjects remained consistently anti-JCV antibody negative • 52% remained consistently anti-JCV antibody positive • 10% changed serostatus – 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 • 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 months1 – 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. Anti-JCV Antibody Testing
  • 24. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Anti-JCV Antibody Testing • As of 6th August 2013, there are 174 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 174 patients, 172 (98.9%) tested anti-JCV antibody positive prior to diagnosis and 2 (1.1%) 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 anti-JCV antibody positive. Biogen Idec, data on file.
  • 25. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY Anti-JCV Antibody Testing 1. TYSABRI Summary of Product Characteristics 2. Biogen Idec, data on file. • 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 natalizumab- treated 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. Anti- 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.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
  • 26. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY • 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 Estimated PML Risk Associated with Prior IS Use *http://clinicaltrials.gov/ct2/show/NCT00477113 http://clinicaltrials.gov/ct2/show/NCT00483847 Biogen Idec, data on file.
  • 27. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 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) Biogen Idec, data on file. Data based on prior IS agents reported in 68 out of 197 patients with PML as of 29th February 2012 (Prior IS status was unknown for 15 patients and they were excluded from the analysis).
  • 28. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 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) Biogen Idec, data on file. Data based on prior IS agents reported in 68 out of 197 patients with PML as of 29th February 2012 (Prior IS status was unknown for 15 patients and they were excluded from the analysis).
  • 29. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446. 2. Biogen Idec, data on file. • 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 Key Learnings: PML Management
  • 30. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 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 may affect survival in patients with PML Vermersch P, et al. Neurology. 2011;76:1697-1704. Biogen Idec, data on file. Factors that appear to be associated with decreased 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 Factors that do not appear to affect survival Factors that appear to be associated with improved 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
  • 31. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 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 Biogen Idec, data on file. Based on the first 35 PML cases.
  • 32. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 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.
  • 33. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY • Monitoring for development of IRIS and appropriate treatment should be undertaken • Treatment of IRIS with IV corticosteroids: – Experts uniformly recommend corticosteroids at onset after PLEX1 – 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 steroids1 – 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 management1 1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446. Key Learnings: Treatment of IRIS
  • 34. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY PML outcomes: Karnofsky scores 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. pre-PML PML diagnosis 6-9 months 10-13 months ≥14 months Mean 81.1 49.4 53.1 49.6 52.6 Median 80 50 50 50 50 n 33 32 45 27 25 Dong-Si T, et al. ECTRIMS 2012; P1098. 0 10 20 30 40 50 60 70 80 90 100 KarnofskyScores pre-PML PML diagnosis 6-9 Months 10-13 Months 14+ Months Mean Median Pre PML PML diagnosis 6-9 months 10-13 months ≥14 months On average, Karnofsky scores decrease at PML diagnosis but remain stable through ≥14 months of follow-up
  • 35. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY PML outcomes: EDSS scores 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. On average, EDSS scores increase at PML diagnosis but stabilize at 6-9 months and remain stable through ≥14 months of follow-up 0 1 2 3 4 5 6 7 8 9 10 EDSSScores pre-PML PML diagnosis 6-9 Months 10-13 Months 14+ Months Mean Median pre-PML PML diagnosis 6-9 months 10-13 months ≥14 months Mean 3.7 5.2 6.3 6.4 6.6 Median 3.5 5.5 6.4 6.8 7 n 90 75 28 16 21 Pre PML PML diagnosis 6-9 months 10-13 months ≥14 months
  • 36. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY PML outcomes: asymptomatic vs symptomatic • As of 1st January 2013, 319 PML cases had been confirmed in the post- marketing setting; of these 319 patients 21 (6.6%) were identified as asymptomatic and 298 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 Dong-Si T, et al. AAN 2013; P04.271. EDSSa and KPSb scores over time in asymptomatic and symptomatic PML patients P value from Mann-Whitney-Wilcoxon test. aThe mean duration of EDSS follow-up was 13.3 months in asymptomatic patients and 9.7 in symptomatic patients. bThe mean duration of KPS follow-up was 12.8 months in asymptomatic patients and 10.0 in symptomatic patients.
  • 37. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY • On average, EDSS scores increase at PML diagnosis, but stabilize at 6-9 months and remain stable through up to 24 months of follow-up Dong-Si T, et al. AAN 2013; P04.271. EDSS scores for asymptomatic and symptomatic PML patients measured over time Outcome of patients with asymptomatic and symptomatic PML Polynomial regression using the LOWESS algorithm. PML outcomes: asymptomatic vs symptomatic
  • 38. TY-PAN-0597(3) Date of preparation: August 2013FOR HEALTHCARE PROFESSIONALS ONLY 1. TYSABRI Summary of Product Characteristics Summary • As of 30th June 2013, approximately 118,100 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