Natalizumab Safety Update & PML        Risk Stratification           Barts Health       25th December 2012         Gavin G...
TY-PAN-0463u Date of preparation: December 2012
Benefit / Risk     81% reduction in     relapse rate1     64% reduction in                                                ...
PML Risk Hypothesis PML is rare and likely caused by interplay between multiple factors                                   ...
A Hypothetical Risk Stratification Tool              Anti-JCV Antibody StatusNegative                                     ...
Risk Stratification Tool: The Presence of Anti-JCV Antibodies,     Prior Immunosuppressant Use, Treatment Duration*       ...
Key Learnings: PML Risk    • Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to      76 doses.1       ...
Natalizumab PML Incidence Estimates by                                              Treatment Duration                    ...
Natalizumab PML Incidence Estimates by                                               Treatment Epoch                      ...
Use of Natalizumab in the Post-Marketing Setting*          Worldwide post-marketing data from 23 Nov 2004 to 30 September ...
Anti-JCV Antibody Testing •    Current data on the assay as a risk stratification tool:       -   Irrespective of MS treat...
Anti-JCV Antibody Testing  •    As of 5th December 2012, 112 natalizumab-treated MS PML MSers with known pre-PML       ant...
Anti-JCV Antibody Testing     •    The anti-JCV antibody should not be used to diagnose PML.     •    Data from a Biogen I...
Geographic Distribution of PML Cases       • Of the 312 cases reported through 5th December 2012:         – 112 are from t...
Status of PML Cases   • As of 5th December 2012:           – 69 MSers have died (22%)           – 243 MSers are alive (78%...
Estimated PML Risk Associated with Prior IS Use     • Prior IS use in the overall natalizumab-treated population was not  ...
No Specific Pattern in Type of Prior IS Use Identified                 in MSers with PML      • Type of prior IS use varie...
No Specific Pattern in Duration of Prior IS Use or     Time from Last Dose of IS in MSers with PML      • Duration of prio...
Risk Stratification Tool: The Presence of Anti-JCV Antibodies,     Prior Immunosuppressant Use, Treatment Duration*       ...
Key Learnings: PML Management      • Heightened clinical vigilance led to prompt natalizumab discontinuation        upon f...
Factors that may affect survival in MSers with PML      At this time, there are insufficient data to predict survival outc...
Clinical Status of PML Cases    On average, Karnofsky scores decrease at PML diagnosis but remain stable through ≥14    mo...
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Natalizum safety and PML risk stratification December 2012

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Natalizum safety and PML risk stratification December 2012

  1. 1. Natalizumab Safety Update & PML Risk Stratification Barts Health 25th December 2012 Gavin Giovannoni Professor of Neurology TY-PAN-0463u Date of preparation: December 2012
  2. 2. TY-PAN-0463u Date of preparation: December 2012
  3. 3. Benefit / Risk 81% reduction in relapse rate1 64% reduction in PML risk ≈ disability 2.77 in 1,000 3 progression1 Risk Benefit Other Adverse >1 in 3 Msers free Events Per of disease activity2 Labelling Natalizumab How can the risk of PML be minimised?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. TY-PAN-0463u Date of preparation: December 2012
  4. 4. PML Risk Hypothesis PML is rare and likely caused by interplay between multiple factors Msers at higher risk of developing PML are likely those: Immunomodulating therapy • Who have JC virus and have the pathogenic form of the virus (i.e. has an altered NCCR and has a pathogenic mutation in VP1). Immune functionHost genetic factors • Who have a compromised immune system that permits viral replication in the brain • Who may have other risk factors such as host genetic factors that make them susceptible to JC virus infection and/or VP1 mutations PML development NCCR rearrangements TY-PAN-0463u Date of preparation: December 2012
  5. 5. A Hypothetical Risk Stratification Tool Anti-JCV Antibody StatusNegative Positive Prior Immunosuppressant Use No Yes Natalizumab Treatment Natalizumab Treatment >2 Years >2 Years No Yes No Yes Lowest1 in 14,285 Highest 1 in 1,666 1 in 192 1 in 555 1 in 94 Relative PML Risk Lowest Highest TY-PAN-0463u Date of preparation: December 2012
  6. 6. 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 555 1 in 1,666 No Yes Natalizumab No Prior IS Use Prior IS Use Exposure 1–24 months 0.6/1000 1.8/1000 95% CI 0.4-0.9 95% CI 1.1-2.8 0.07/1000 95% CI 0-0.38 25–48 5.2/1000 10.6/1000 95% CI 4.3-6.2 95% CI 8.1-13.8 months 1 in 14,285 1 in 192 1 in 94 Data beyond 4 years of treatment are limited. *Based on natalizumab exposure and 285 confirmed PML cases as of September 5, 2012. Prior IS data in overall natalizumab-treated MSers based on proportion of MSers with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML MSers as of September 5, 2012. The analysis assumes that 55% of natalizumab-treated MS MSers were anti-JCV antibody positive and that all PML MSers test positive for anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti- JCV antibody negative MSers is based on the assumption that all MSers received at least 1 dose of natalizumab . Assuming that all MSers received at least 18 doses of natalizumab , the estimate of PML incidence in anti-JCV antibody negative MSers was generally consistent (0.1/1000; 95% CI 0.00–0.62).Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  7. 7. Key Learnings: PML Risk • Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 76 doses.1 – Mean duration of natalizumab dosing at time of PML diagnosis was approximately 38.1 months1 • Overall incidence: 2.77 per 1000 MSers (95% CI; range: 2.47 to 3.09 per 1000 MSers)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 identified 2 – 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. Natalizumab SPC TY-PAN-0463u Date of preparation: December 2012
  8. 8. Natalizumab PML Incidence Estimates by Treatment Duration 6.0 5.54 5.34 5.16 4.97 4.89 5.0 4.93 Incidence per 1000 MSers 4.38 4.68 4.44 4.45 4.11 3.96 4.36 4.11 3.84 4.0 3.92 4.08 3.95 3.09 3.81 3.30 3.49 3.43 3.0 2.93 2.77 2.77 2.61 2.47 2.0 2.19 1.87 1.0 0.0 Calculations based on exposure through November 30, 2012 and 312 confirmed cases as of December 5, 2012Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  9. 9. Natalizumab PML Incidence Estimates by Treatment Epoch 4.0 3.58 3.5 3.09 2.83 2.87 Incidence per 1000 MSers 3.0 2.77 2.5 2.24 2.41 2.47 2.29 2.17 2.0 1.84 1.5 1.83 1.61 1.54 1.49 1.0 0.82 0.61 0.5 0.10 0.45 0.0 0.04 0.01 Calculations based on exposure through November 30, 2012 and 312 confirmed cases as of December 5, 2012Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  10. 10. Use of Natalizumab in the Post-Marketing Setting* Worldwide post-marketing data from 23 Nov 2004 to 30 September 2012 Overall 108,300 Exposure ≥12 Months 75,800 ≥18 Months 63,700 ≥24 Months 53,100 ≥30 Months 44,100 ≥36 Months 36,100 243,846 MSer-Years of natalizumab exposure ≥42 Months 28,600 ≥48 Months 22,000 MSers MSers *Post-marketing data includes MSers exposed since 23 November 2004. This excludes approximately 5,000 MSers exposed in clinical trials: 2,200 exposed for ≥ 12 months; 1,900 exposed for ≥ 18 months; 1,600 exposed for ≥ 24 months; 1,300 exposed for ≥ 30 months; 1,000 exposed for ≥ 36 months; and 700 exposed for ≥ 42 months. Exposure are estimates and may not fully reflect treatment interruptions that are used in certain MSers.Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  11. 11. Anti-JCV Antibody Testing • Current data on the assay as a risk stratification tool: - Irrespective of MS treatment, across studies in MSers, approximately 50-60% of the population tested anti-JCV antibody positive1 - Preliminary data suggest that ~2-3% of MSsers seroconvert annually2. • Seroconversion is defined as a MSer who changed from negative to positive and remained positive - Low false negative rate • STRATA: 2.5% (95% CI 0.05-4.9%)2,3 • STRATIFY-1: 2.7% (95% CI 0.9-6.2%)4 - Preliminary data suggest that ~5-10% of MSers will change serostatus from anti-JCV antibody negative to positive on retest. These MSers include true seroconverters, and those with anti-JCV antibody levels that fluctuate around the cut-point of the anti-JCV assay2.1. Bozic et al. Presented at AAN: April 21-28, 2012; New Orleans, LA. S41.0022. Biogen Idec, data on file.3. Gorelik et al. Ann Neurol. 2010;68:295-303.4. Bozic et al. Ann Neurol. 2011;70(5):742-50. TY-PAN-0463u Date of preparation: December 2012
  12. 12. Anti-JCV Antibody Testing • As of 5th December 2012, 112 natalizumab-treated MS PML MSers 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 112 MSers: – 110 (98%) MSers tested anti-JCV antibody positive at all time points where samples were available. – 1 patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis and anti-JCV antibody positive 6.5 months prior to PML diagnosis. The patient had > 5 years of natalizumab therapy + prior IS use. – 1 patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis; no additional pre- PML samples were available. The patient had received ~ 3-4 years of therapy + no prior IS use. • A sample obtained from one CD clinical trial patient prior to PML diagnosis tested positive. • In addition, one MS patient tested anti-JCV antibody negative 15 months prior to PML diagnosis and tested positive two months before PML diagnosis. The patient had received > 3 years of natalizumab + no prior IS use. At the time of testing positive, the patient had detectable IgM and IgG antibodies. The patient changed antibody status at some point, but the time of serochange is unknown. The patient’s anti-JCV antibody status 6 months prior to PML diagnosis is unknown.Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  13. 13. Anti-JCV Antibody Testing • The anti-JCV antibody should not be used to diagnose PML. • Data from a Biogen Idec study of plasma exchange (PLEX) in Natalizumab-treated MS MSers 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 MSers 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.21. Natalizumab SPC2. Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  14. 14. Geographic Distribution of PML Cases • Of the 312 cases reported through 5th December 2012: – 112 are from the United States – 182 are from the European Economic Area – 18 are from the rest of the worldBiogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  15. 15. Status of PML Cases • As of 5th December 2012: – 69 MSers have died (22%) – 243 MSers are alive (78%) • It is too early to draw conclusions about the outcomes of MSers who develop PML while on natalizumab treatment • PML may be fatal or result in severe disability* The median time to death was 2.2 months (range, 0.1 to 15.2 months) for 44 deaths as of 29th February, 2012.* Natalizumab SPCBiogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  16. 16. Estimated PML Risk Associated with Prior IS Use • Prior IS use in the overall natalizumab-treated population was not known and was therefore estimated from TYGRIS* • Compared to MSers who have never been treated with a prior IS therapy, MSers with prior IS use have ~3-4-fold greater risk of PML*http://clinicaltrials.gov/ct2/show/NCT00477113 and http://clinicaltrials.gov/ct2/show/NCT00483847 Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  17. 17. No Specific Pattern in Type of Prior IS Use Identified in MSers with PML • Type of prior IS use varied: – Some MSers 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 MSers with PML as of 29th February 2012(Prior IS status was unknown for 15 MSers and they were excluded from the analysis).Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  18. 18. No Specific Pattern in Duration of Prior IS Use or Time from Last Dose of IS in MSers 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 MSers with PML as of 29th February 2012(Prior IS status was unknown for 15 MSers and they were excluded from the analysis).Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  19. 19. 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 555 1 in 1,666 No Yes Natalizumab No Prior IS Use Prior IS Use Exposure 1–24 months 0.6/1000 1.8/1000 95% CI 0.4-0.9 95% CI 1.1-2.8 0.07/1000 95% CI 0-0.38 25–48 5.2/1000 10.6/1000 95% CI 4.3-6.2 95% CI 8.1-13.8 months 1 in 14,285 1 in 192 1 in 94 Data beyond 4 years of treatment are limited. *Based on natalizumab exposure and 285 confirmed PML cases as of September 5, 2012. Prior IS data in overall natalizumab-treated MSers based on proportion of MSers with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML MSers as of September 5, 2012. The analysis assumes that 55% of natalizumab-treated MS MSers were anti-JCV antibody positive and that all PML MSers test positive for anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti- JCV antibody negative MSers is based on the assumption that all MSers received at least 1 dose of natalizumab . Assuming that all MSers received at least 18 doses of natalizumab , the estimate of PML incidence in anti-JCV antibody negative MSers was generally consistent (0.1/1000; 95% CI 0.00–0.62).Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  20. 20. 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 MSers 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 MSers with PML, Immune Reconstitution Inflammatory Syndrome (IRIS) has occurred after discontinuation or removal (by PLEX) of natalizumab • In MSers who have undergone PLEX, IRIS has occurred within days to several weeks21. Clifford DB, et al. Lancet Neurol. 2010;9:438–4462. Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  21. 21. Factors that may affect survival in MSers with PML At this time, there are insufficient data to predict survival outcomes in MSers treated with natalizumab who develop PML. Longer-term data are required in order to more accurately predict such outcomes. Factors that appear to be associatedthat appear to be Factors with decreased Factors that do not appear to affect associated with improved survival survival survival • Younger age at PML • Gender diagnosis • Prior immunosuppressant • Lower pre-PML EDSS therapy • Shorter time from first • MS duration symptoms of PML to • Natalizumab exposure at diagnosis PML diagnosis • Localized PML extension • JCV DNA load in CSF at PML on MRI at diagnosis diagnosis • Gd enhancement on MRI at diagnosisVermersch P, et al. Neurology. 2011;76:1697-1704.Biogen Idec, data on file. TY-PAN-0463u Date of preparation: December 2012
  22. 22. Clinical Status of PML Cases On average, Karnofsky scores decrease at PML diagnosis but remain stable through ≥14 months of follow-up 100 90 80 70 Karnofsky Scores pre-PML 60 PML diagnosis 6-9 Months 50 10-13 Months 40 14+ Months Mean 30 Median 20 10 0 Pre PML PML diagnosis 6-9 months 10-13 months ≥14 months 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 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 MSers for whom KPS scores were available for a given interval are shown.Dong-Si et al. ECTRIMS. 2012; P1098. TY-PAN-0463u Date of preparation: December 2012

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