Natalizumab Safety Update & PML Risk Stratification Professor Gavin Giovannoni Barts and The London ...
Benefit / Risk 81% reduction in relapse rate1 64% reduction in ...
What causes PML? • PML is uncommon and likely caused by interplay between multiple factors 1...
Key Learnings: PML Risk • Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 76 doses1 ...
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 31 De...
Anti-JCV Antibody Testing• The 2-step anti-JCV antibody assay has been developed to help identify patients who have b...
Anti-JCV Antibody Testing • Current data on the assay as a risk stratification tool from STRATIFY-1 (n=1096) – ...
Anti-JCV Antibody Testing • As of 5th March 2013, 133 natalizumab-treated MS PML patients with known pre-PML anti- ...
Anti-JCV Antibody Testing • Re-testing of anti-JCV antibody negative patients every 6 months is recommended....
Geographic Distribution of PML Cases • Of the 343 cases reported through 5th March 2013: – 121 are from the ...
Status of PML Cases • As of 5th March 2013: – 79 patients have died (23%) – 264 patients are alive (77%)...
Estimated PML Risk Associated with Prior IS Use • As of 4 March 2011, 39 of 93 patients (42%) with PML and known pr...
No Specific Pattern in Type of Prior IS Use Identified in Patients with PML • Type of prior IS use va...
No Specific Pattern in Duration of Prior IS Use or Time from Last Dose of IS in Patients with PML • Duration of ...
Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* ...
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 patients with PML At this time, there are insufficient data to predict survival ou...
PML Presenting Symptoms PML symptom % PML cases with symptom Cognitive/beh...
IRIS Presents as Clinical Decline IRIS symptom % PML cases wit...
Clinical Status of PML Cases: Karnofsky scores On average, Karnofsky scores decrease at PML diagnosis but remain stable...
Clinical Status of PML Cases: EDSS scores On average, EDSS scores increase at PML diagnosis but stabilize at 6-9 months...
Summary • As of 31st December 2012, approximately 112,200 patients received natalizumab in post-marketing sett...
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Natalizumab safety and pml risk stratification march 2013

Published on: Mar 3, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Natalizumab safety and pml risk stratification march 2013

  • 1. Natalizumab Safety Update & PML Risk Stratification Professor Gavin Giovannoni Barts and The London TY-PAN-0587(2) Date of preparation: March 2013
  • 2. Benefit / Risk 81% reduction in relapse rate1 64% reduction in PML risk ≈ disability 2.96 in 1,000 3 progression1 Risk Benefit Other Adverse >1 in 3 patients free Events Per of disease activity2 Labelling Natalizumab1. 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-0587(2) Date of preparation: March 2013
  • 3. 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: 45 nm peripheral immune function, genetics 4. Drug effects that reduce CNS immune surveillanceVP1=viviparous 1; RR=regulatory region; CNS=central nervous system. TY-PAN-0587(2) Date of preparation: March 2013
  • 4. Key Learnings: PML Risk • Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 76 doses1 – Mean duration of natalizumab dosing at time of PML diagnosis was approximately 39.0 months1 • Overall incidence: 2.96 per 1000 patients (95% CI: 2.65 to 3.29 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 years1. Biogen Idec, data on file.2. Natalizumab Summary of Product Characteristics TY-PAN-0587(2) Date of preparation: March 2013
  • 5. Natalizumab PML Incidence Estimates by Treatment Duration 6.0 5.75 5.52 5.34 5.19 5.05 5.14 5.0 4.57 4.86 Incidence per 1000 patients 4.66 4.63 4.24 4.58 4.29 3.93 4.0 4.11 4.17 4.26 3.59 3.29 4.00 3.69 3.46 3.62 3.0 3.07 2.96 2.59 2.78 2.65 2.0 2.35 1.80 1.0 0.0 Calculations based on exposure through 28 February 2013 and 343 confirmed cases as of 5 March 2013Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 6. Natalizumab PML Incidence Estimates by Treatment Epoch 4.0 3.5 3.29 Incidence per 1000 patients 2.97 3.06 2.85 3.0 2.96 2.5 2.26 2.65 2.33 2.30 2.0 2.09 1.87 1.88 1.5 1.74 1.53 0.85 1.36 1.0 0.65 0.5 0.11 0.49 0.0 0.05 0.02 Calculations based on exposure through 28 February 2013 and 343 confirmed cases as of 5 March 2013Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 7. Use of Natalizumab in the Post-Marketing Setting* Worldwide post-marketing data from 23 Nov 2004 to 31 December 2012 Overall 112,200 Exposure ≥12 Months 79,100 ≥18 Months 67,100 ≥24 Months 56,100 ≥30 Months 46,700 ≥36 Months 38,700 261,990 Patient-Years ≥42 Months 31,200 of natalizumab exposure ≥48 Months 24,300 Patients Patients *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.Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 8. 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. TY-PAN-0587(2) Date of preparation: March 2013
  • 9. 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 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%31. Plavina et al. Presented at AAN: March 18-23, 2013, San Diego, CA. S30.0012. Lee et al. J Clin Virol. 2013 [Epub ahead of print]3. Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 10. Anti-JCV Antibody Testing • As of 5th March 2013, 133 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 133 patients: – 131 (98%) patients 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 natalizumab 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-0587(2) Date of preparation: March 2013
  • 11. 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 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.21. Natalizumab Summary of Product Characteristics2. Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 12. Geographic Distribution of PML Cases • Of the 343 cases reported through 5th March 2013: – 121 are from the United States – 201 are from the European Economic Area – 21 are from the rest of the worldBiogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 13. Status of PML Cases • As of 5th March 2013: – 79 patients have died (23%) – 264 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. Natalizumab Summary of Product Characteristics2. Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 14. Estimated PML Risk Associated with Prior IS Use • As of 4 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 4 March 2011, prior IS status was unknown for 9 patients and they were excluded from the analysis. • As of 23 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 and http://clinicaltrials.gov/ct2/show/NCT00483847 Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 15. 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. TY-PAN-0587(2) Date of preparation: March 2013
  • 16. 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. TY-PAN-0587(2) Date of preparation: March 2013
  • 17. 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 0.6/1000 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 months 5.2/1000 10.6/1000 95% CI 4.3-6.2 95% CI 8.1-13.8 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 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 5, 2012. 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 (0.1/1000; 95% CI 0.00–0.62).Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 18. 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 1,667 1 in 556 No Yes 1 in 14,286 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 months 5.2/1000 10.6/1000 95% CI 4.3-6.2 95% CI 8.1-13.8 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 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 5, 2012. 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 (0.1/1000; 95% CI 0.00–0.62).Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 19. 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-0587(2) Date of preparation: March 2013
  • 20. 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;76:1697-1704.Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 21. 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 categoriesBased on the first 35 PML cases.Biogen Idec, data on file. TY-PAN-0587(2) Date of preparation: March 2013
  • 22. 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. TY-PAN-0587(2) Date of preparation: March 2013
  • 23. Clinical Status of PML Cases: Karnofsky scores 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 patients for whom KPS scores were available for a given interval are shown.Dong-Si et al. ECTRIMS. 2012; P1098. TY-PAN-0587(2) Date of preparation: March 2013
  • 24. Clinical Status of PML Cases: 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 7 pre-PML EDSS Scores 6 PML diagnosis 6-9 Months 5 10-13 Months 4 14+ Months Mean 3 Median 2 1 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 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 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 et al. ECTRIMS. 2012; P1098. TY-PAN-0587(2) Date of preparation: March 2013
  • 25. Summary • As of 31st December 2012, approximately 112,200 patients received natalizumab in 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 EDSS1. Natalizumab Summary of Product Characteristics TY-PAN-0587(2) Date of preparation: March 2013

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