Natalizumab Safety Update & PML        Risk Stratification          Barts Health         September 2012         Gavin Giov...
Benefit / Risk     81% reduction in     relapse rate1     64% reduction in                                                ...
PML Risk Hypothesis PML is rare and likely caused by interplay between multiple factors                                  P...
A Hypothetical Risk Stratification Tool           Anti-JCV Antibody StatusNegative                                        ...
A Hypothetical Risk Stratification Tool                Anti-JCV Antibody Status Negative                                  ...
Key Learnings: PML Risk    • Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to      72 doses.1       ...
Natalizumab PML Incidence Estimates by                                                            Treatment Duration      ...
Natalizumab PML Incidence Estimates by                                                        Treatment Epoch             ...
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 June 20...
Anti-JCV Antibody testing     •   Current data on the assay as a risk stratification tool:           -    Irrespective of ...
Anti-JCV Antibody testing  •     As of 5th September 2012, 91 natalizumab-treated MS PML patients with known pre-PML      ...
Anti-JCV Antibody testing •    As of 5th September, 2012, there are 118 natalizumab-treated MS PML patients who had at    ...
Geographic Distribution • Of the 285 cases reported through 5th September 2012:   – 102 are from the United States   – 169...
Status of PML Cases   • As of 5th September 2012:          – 62 patients have died (22%)                 • Most of the dea...
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                         Patients with PML      • Type of prior I...
No Specific Pattern in Duration of Prior IS Use or Time from             Last Dose of IS in Patients with PML      • Durat...
Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior                Immunosuppressant Use, Treatment Durat...
Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior                Immunosuppressant Use, Treatment Durat...
Key Learnings: PML Management      • Heightened clinical vigilance led to prompt natalizumab discontinuation        upon f...
Factors that may affect survival in Patients with PML     At this time, there are insufficient data to predict survival ou...
Clinical Status of PML Cases      Based on outcomes from the 140 survivors out of the 175 confirmed PML cases as of 21st  ...
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Natalizumab Safety Update September 2012

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Natalizumab Safety Update September 2012

  1. 1. Natalizumab Safety Update & PML Risk Stratification Barts Health September 2012 Gavin Giovannoni Professor of Neurology TY-PAN-0463r Date of preparation: September 2012
  2. 2. Benefit / Risk 81% reduction in relapse rate1 64% reduction in PML risk ≈ disability 2.63 in 1,000 progression1 Risk Benefit Other Adverse >1 in 3 patients free Events Per of disease activity2 Labelling Natalizumab How can the risk of PML be minimised?1. Hutchinson et al. J Neurol 2009;256:405-415.2. Havrdova E et al. Lancet Neurol 2009;8(3):254-603. Biogen Idec Data on File TY-PAN-0463r Date of preparation: September 2012
  3. 3. PML Risk Hypothesis PML is rare and likely caused by interplay between multiple factors Patients 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-0463r Date of preparation: September 2012
  4. 4. 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 Lowest Highest Relative PML Risk TY-PAN-0463r Date of preparation: September 2012
  5. 5. A Hypothetical Risk Stratification Tool Anti-JCV Antibody Status Negative Positive Prior Immunosuppressant Use No Yes Natalizumab Treatment Natalizumab Treatment >2 Years >2 Years No Yes No Yes< 1 Lowest in 11,000 1 in 1,786 1 in 217 1 in 625 Highest90 1 in Relative PML Risk TY-PAN-0463r Date of preparation: September 2012
  6. 6. Key Learnings: PML Risk • Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 72 doses.1 – Mean duration of natalizumab dosing at time of PML diagnosis was approximately 37.5 months1 • Overall incidence: 2.63 per 1000 patients (95% CI; range: 2.33 to 2.95 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 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-0463r Date of preparation: September 2012
  7. 7. Natalizumab PML Incidence Estimates by Treatment Duration 6.0 5.34 5.07 4.79 4.83 5.0 Incidence per 1000 patients 4.57 4.72 4.20 4.41 4.25 4.0 4.11 3.71 3.74 4.15 3.78 2.95 3.76 3.81 3.0 3.47 3.31 2.90 2.63 3.10 2.0 2.33 2.23 1.0 0.0 Calculations based on exposure through August 31, 2012 and 285 confirmed cases as of September 5, 2012Biogen Idec Data on File TY-PAN-0463r Date of preparation: September 2012
  8. 8. Natalizumab PML Incidence Estimates by Treatment Epoch 3.0 2.95 2.79 2.63 2.63 Incidence per 1000 patients 2.5 2.33 2.32 2.23 2.0 1.90 1.94 1.76 1.5 1.54 1.38 1.0 0.82 0.61 0.5 0.45 0.11 0.05 0.0 0.02 Calculations based on exposure through August 31, 2012 and 285 confirmed cases as of September 5, 2012Biogen Idec Data on File TY-PAN-0463r Date of preparation: September 2012
  9. 9. Natalizumab PML Incidence Estimates by Treatment Epoch 3.0 1 in 448 2.95 1 in 515 2.79 2.63 2.63 1 in 526 Incidence per 1000 patients 2.5 2.33 2.32 2.23 2.0 1 in 380 1.94 1.90 1.76 1.5 1.54 1.38 1.0 1 in 1639 0.82 0.61 0.5 0.45 Please note 285 cases of PML! 1 in 20,000 0.11 0.05 0.0 0.02 Calculations based on exposure through August 31, 2012 and 285 confirmed cases as of September 5, 2012Biogen Idec Data on File TY-PAN-0463r Date of preparation: September 2012
  10. 10. Use of Natalizumab in the Post-Marketing Setting* Worldwide post-marketing data from 23 Nov 2004 to 30 June 2012 Overall 104,300 Exposure ≥12 Months 72,400 ≥18 Months 60,300 ≥24 Months 50,300 ≥30 Months 41,400 224,718 Patient-Years of Natalizumab exposure ≥36 Months 33,500 ≥42 Months 26,100 ≥48 Months 19,600 Patients Patients*Post-marketing data includes patients exposed since 23 November 2004. This excludes approximately 5,000 patients exposedin clinical trials: 2,200 exposed for ≥ 12 months; 1,900 exposed for ≥ 18 months; 1,600 exposed for ≥ 24 months; 1,300exposed for ≥ 30 months; 1,000 exposed for ≥ 36 months; and 700 exposed for ≥ 42 months. Exposure are estimates and maynot fully reflect treatment interruptions that are used in certain patients.Biogen Idec, Data on file. TY-PAN-0463r Date of preparation: September 2012
  11. 11. Anti-JCV Antibody testing • Current data on the assay as a risk stratification tool: - Irrespective of MS treatment, across studies in MS patients, approximately 50-60% of the population tested anti-JCV antibody positive1 - Preliminary data suggest that ~2-3% of patients seroconvert annually2. • Seroconversion is defined as a patient 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 patients will change serostatus from anti-JCV antibody negative to positive on retest. These patients 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: 295-3034. Bozic et al. Ann Neurol 2011 Nov;70(5):742-50 TY-PAN-0463r Date of preparation: September 2012
  12. 12. Anti-JCV Antibody testing • As of 5th September 2012, 91 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 91 patients: – 89 (98%) patients tested anti-JCV antibody positive at all time points where samples were available. – 1 recent 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-0463r Date of preparation: September 2012
  13. 13. Anti-JCV Antibody testing • As of 5th September, 2012, there are 118 natalizumab-treated MS PML patients who had at least one sample collected at or around the time of PML diagnosis. All tested anti-JCV antibody positive1. – In addition, a sample collected at the time of PML diagnosis after plasma exchange (PLEX) tested negative1. – Data from a Biogen Idec study of PLEX in natalizumab-treated MS patients demonstrated that anti-JCV antibody levels are decreased 2-5 fold after PLEX and may lead to a negative result in some patients. Anti-JCV antibody testing should not be performed during or for at least two weeks following PLEX2.1. Biogen Idec, data on file.2. Natalizumab SPC TY-PAN-0463r Date of preparation: September 2012
  14. 14. Geographic Distribution • Of the 285 cases reported through 5th September 2012: – 102 are from the United States – 169 are from the European Economic Area – 14 are from the rest of the worldBiogen Idec Data on file. TY-PAN-0463r Date of preparation: September 2012
  15. 15. Status of PML Cases • As of 5th September 2012: – 62 patients have died (22%) • Most of the deaths have occurred within approximately 2-3 months after PML diagnosis – 223 patients are alive (78%) • 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 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. The median duration of follow-up in survivors was 13.7 months (0.5 – 44.3 months) for 166 survivors as of 29th February, 2012.*Natalizumab SPCBiogen Idec Data on file. TY-PAN-0463r Date of preparation: September 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 patients who have never been treated with a prior IS therapy, patients with prior IS use have ~3-4-fold greater risk of PML*http://clinicaltrials.gov/ct2/show/NCT00477113 andhttp://clinicaltrials.gov/ct2/show/NCT00483847Biogen Idec Data on file. TY-PAN-0463r Date of preparation: September 2012
  17. 17. 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)*Based on 68 out of 197 patients with PML as of February 29 th 2012(Prior IS status was unknown for 15 patients and they were excluded from the analysis).Biogen Idec Data on file. TY-PAN-0463r Date of preparation: September 2012
  18. 18. 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 (priorIS status was unknown for 15 patients and they were excluded from the analysis)Biogen Idec Data on file. TY-PAN-0463r Date of preparation: September 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 No Yes Natalizumab No Prior IS Use Prior IS Use Exposure 1–24 months 0.56/1000 1.6/1000 ≤0.09/1000 95% CI 0.36-0.83 95% CI 0.91-2.6 95% CI 0-0.48 25–48 months 4.6/1000 11.1/1000 95% CI 3.7-5.6 95% CI 8.3-14.5 Data beyond 4 years of treatment are limited. *Based on Natalizumab exposure data as of February 29, 2012; PML incidence data based on 212 confirmed PML cases as of February 29, 2012; 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 September 1, 2011. 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 and assumes 1 hypothetical PML case that tested negative for anti-JCV antibodies prior the onset and diagnosis of PML. Assuming that all patients received at least 18 doses of Natalizumab and that there was 1 hypothetical PML case that tested anti-JCV antibody negative prior to PML diagnosis, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent, 0.14 (95% CI: 0.00–0.79).Bloomgren et al. N Engl J Med. 2012;366:1870-80 TY-PAN-0463r Date of preparation: September 2012
  20. 20. Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* Anti-JCV Antibody Status Negative Positive *IS = immunosuppression Prior IS Use 1 in 1,786 1 in 625 No Yes Natalizumab No Prior IS Use* Prior IS Use* Exposure 1–24 months 0.56/1000 1.6/1000 ≤0.09/1000 95% CI 0.36-0.83 95% CI 0.91-2.6 95% CI 0-0.48 25–48 months 4.6/1000 11.1/1000 95% CI 3.7-5.6 95% CI 8.3-14.5 < 1 in 11,000 1 in 217 1 in 90Bloomgren et al. N Engl J Med. 2012;366:1870-80 TY-PAN-0463r Date of preparation: September 2012
  21. 21. 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 weeks21. Clifford DB, et al. Lancet Neurol. 2010;9:438–4462. Biogen Idec Data on file. TY-PAN-0463r Date of preparation: September 2012
  22. 22. 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 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 – 1704Biogen Idec Data on file. TY-PAN-0463r Date of preparation: September 2012
  23. 23. Clinical Status of PML Cases Based on outcomes from the 140 survivors out of the 175 confirmed PML cases as of 21st October 2011 Functional Status of Survivors Follow-up Survivors at Follow- Time From up Time with Mild Moderate Severe PML Diagnosis Karnofsky** reported, Disability, Disability, Disability, n (months) n n (%) n (%) (%) ≥6 58 6 (10%) 29 (50%) 23 (40%)* ≥9 28 3 (11%) 16 (57%) 9 (32%) *Majority of patients with severe disability at ≥ 6 months from diagnosis (21/23, 91%) had Karnofsky scores of 40 which is at the interface between moderate and severe disability • Of the 58 patients with ≥ 6 months follow-up and Karnofsky scores, 19 patients also had pre-PML Karnofsky scores reported: • Mean change in Karnofsky following PML: Decrease by 26 • Median change in Karnofsky following PML: Decrease by 20 Pre-PML Functional Status (N=19) Functional Status following PML Mild disability pre-PML (N=12) Mild Disability 2 (16%) Moderate Disability 5 (42%) Severe Disability 5 (42%) Moderate disability pre-PML (N=7) Moderate Disability 6 (86%) Severe Disability 1 (14%)Biogen Idec, Data on file.** Karnofsky DA, Burchenal JH. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents.New York, NY: Columbia University Press; 1948:196. TY-PAN-0463r Date of preparation: September 2012
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