TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
TYSABRI (natalizumab)
Benefit/Risk Update...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Benefit / Risk
Benefit
Risk
Natalizumab
8...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
PML Risk Update
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
VP1=viviparous 1; RR=regulatory region;
C...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
PML Risk
• Factors that increase the risk...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Natalizumab PML Incidence Estimates by
Tr...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Natalizumab PML Incidence Estimates by
Tr...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Use of Natalizumab in the Post-Marketing ...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
0.1/1000
95% CI 0.01-0.35
No Yes
Anti-JCV...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
0.1/1000
95% CI 0.01-0.35
No Yes
Anti-JCV...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
Benefits of na...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
• Initiation or continuation of natalizum...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
AFFIRM efficac...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
1. Havrdova E, et al. Lancet Neurol. 2009...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
long-term effi...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
long-term effi...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
real life data...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
real life data...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
1. Tysabri Summary of Product Characteris...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Supporting information:
PML risk factors ...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
• The 2-step anti-JCV antibody assay has ...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
• Current data on the assay as a risk str...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Anti-JCV Antibody Testing
• As of 3rd Apr...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
Anti-JCV Antibody Testing
1. Tysabri Summ...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
• As of 4th March 2011, 39 of 93 patients...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
No Specific Pattern in Type of Prior IS U...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
No Specific Pattern in Duration of Prior ...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
1. Clifford DB, et al. Lancet Neurol. 201...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
At this time, there are insufficient data...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
PML Presenting Symptoms
PML symptom % PML...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
IRIS Presents as Clinical Decline
IRIS sy...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
• Monitoring for development of IRIS and ...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
PML outcomes: Karnofsky scores
Karnofsky ...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
PML outcomes: EDSS scores
EDSS scores for...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
PML outcomes: asymptomatic vs symptomatic...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
• Over time, EDSS scores scores were cons...
TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY
PML Research at Biogen Idec
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Tysabri benefit risk update april 2014 ty pan 0597

  1. 1. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY TYSABRI (natalizumab) Benefit/Risk Update & PML Risk Stratification
  2. 2. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Benefit / Risk Benefit Risk Natalizumab 81% reduction in relapse rate1 64% reduction in disability progression1 >1 in 3 patients free of disease activity2 PML risk ≈ 3.563 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.
  3. 3. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY PML Risk Update
  4. 4. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  5. 5. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY 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 3rd April 2014, overall incidence: 3.563 per 1000 patients (95% CI: 3.243 to 3.905 per 1000 patients)2 – 76% of patients are alive with varying levels of disability • As of 3rd April 2014, the duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 92 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 42 months2 1. Tysabri Summary of Product Characteristics 2. Biogen Idec, data on file.
  6. 6. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Natalizumab PML Incidence Estimates by Treatment Epoch Calculations based on exposure through 31st March 2014 and 454 confirmed cases as of 3rd April 2014 Biogen Idec, data on file. 3.91 0.12 0.84 2.09 2.73 2.93 2.693.24 0.03 0.50 1.45 1.87 1.88 1.46 3.56 0.06 0.66 1.75 2.27 2.36 2.01 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Incidenceper1000patients
  7. 7. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Natalizumab PML Incidence Estimates by Treatment Epoch (Apr 2010 – Apr 2014) Biogen Idec, data on file. 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Apr.2010 Jul.2010 Oct.2010 Jan.2011 Apr.2011 Jul.2011 Oct.2011 Jan.2012 Apr.2012 Jul.2012 Oct.2012 Jan.2013 Apr.2013 Jul.2013 Oct.2013 Jan.2014 Apr.2014 Incidenceper1000patients 1-12 infusions 13-24 infusions 25-36 infusions 37-48 infusions 49-60 infusions 61-72 infusions
  8. 8. TY-PAN-0597(11) Date of preparation: April 2014FOR 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 31 Dec 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. 329,554 Patient-Years of natalizumab exposure 123,000 93,400 79,800 67,600 57,400 48,100 40,300 33,400 Overall Exposure ≥12 Months ≥18 Months ≥24 Months ≥30 Months ≥36 Months ≥42 Months ≥48 Months Patients
  9. 9. TY-PAN-0597(11) Date of preparation: April 2014FOR 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 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 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). Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* Biogen Idec, data on file.
  10. 10. TY-PAN-0597(11) Date of preparation: April 2014FOR 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 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 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). 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 Biogen Idec, data on file.
  11. 11. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: Benefits of natalizumab therapy
  12. 12. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  13. 13. TY-PAN-0597(11) Date of preparation: April 2014FOR 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.
  14. 14. TY-PAN-0597(11) Date of preparation: April 2014FOR 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.
  15. 15. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: long-term efficacy data from STRATA1 1. Rudick, et al. ECTRIMS 2013; P593. 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.
  16. 16. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY 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.
  17. 17. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: real life data from TOP1 • 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) 1. Butzkueven et al. J Neurol Neurosurg Psychiatry 2014. Published online • Mean 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 1st December 2012, 4821 patients were enrolled. §P value is from the negative binomial model for the comparison of ARRs before and after natalizumab treatment ARR per 12-month interval over time Overall mean EDSS scores over time 3.5 3.3 3.3 3.3 3.3 1 1.5 2 2.5 3 3.5 4 Baseline Year 1 Year 2 Year 3 Year 4 n=4797 n=2064 n=1304 n=744 n=325
  18. 18. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Putting risk into context: real life data from TOP in the UK1 • Annualised relapse rate significantly decreased on natalizumab regardless of baseline relapse history 1. Hanna J, et al. ABN 2013; P140. • 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. 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. Baseline and on-treatment ARR, overall and by relapse history Baseline and on-treatment ARR by baseline EDSS score
  19. 19. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY 1. Tysabri Summary of Product Characteristics Summary • As of 31st December 2013, approximately 123,000 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
  20. 20. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Supporting information: PML risk factors & outcomes
  21. 21. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  22. 22. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  23. 23. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY Anti-JCV Antibody Testing • As of 3rd April 2014, there are 217 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 217 patients, 215 (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 Crohn’s Disease patients (one from clinical trials and one post-marketing) both tested anti-JCV antibody positive. Biogen Idec, data on file.
  24. 24. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  25. 25. TY-PAN-0597(11) Date of preparation: April 2014FOR 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.
  26. 26. TY-PAN-0597(11) Date of preparation: April 2014FOR 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).
  27. 27. TY-PAN-0597(11) Date of preparation: April 2014FOR 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).
  28. 28. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  29. 29. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  30. 30. TY-PAN-0597(11) Date of preparation: April 2014FOR 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.
  31. 31. TY-PAN-0597(11) Date of preparation: April 2014FOR 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.
  32. 32. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  33. 33. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  34. 34. TY-PAN-0597(11) Date of preparation: April 2014FOR 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
  35. 35. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY 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 Dong-Si T, et al. ECTRIMS 2013; P879. 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
  36. 36. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY • Over time, EDSS scores scores were consistently better in asymptomatic PML patients than in symptomatic PML patients. − Similar results were seen with KPS scores (EDSS-KPS correlation coefficient, 0.712). Dong-Si T, et al. ECTRIMS 2013; P879. PML outcomes: asymptomatic vs symptomatic Outcome Asymptomatic PML patients (n=30) Symptomatic PML patients (n=342) All PML patients (n=372) Survival, n (%) 29 (96.7) 258 (75.4) 287 (77.2) Death, n (%) 1 (3.3)a 84 (24.6) 85 (22.8) aDeath was reported as suicide caused by depression that was secondary to increasing disability and PML sequelae. 0246810 EDSSScore −30 −24 −18 −12 −6 diagnosis 6 12 18 24 30 Symptomatic Asymptomatic Months From PML Diagnosis • Natalizumab-associated PML may be associated with better survival in asymptomatic patients than in patients who were symptomatic at diagnosis
  37. 37. TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY 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 Clear and effective risk stratification algorithm New tools for PML risk stratification Tools for early PML diagnosis Therapeutic approaches and management of PML ObjectivesObjectives Sample Collection • JCV assay performance • JCV antibody serostability • JCV antibody levels • Defining host factors • Improving and developing new systems and animal models • Infection dynamics in tissues (JCV and other pathogens) • 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) • 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 • BIIB internal research • BIIB - supported SRAs and IITs • Innovative technology partnerships • PML Consortia-sponsored research JCV Biology Research JCV Serology Clinical Research JCV antibody assayJCV antibody assay and further understanding JCV serology Better understanding of PML outcomes • Integrated clinical and analytical data analysis • Genomics (host, viral) • Blood-based biomarkers (host and JCV mutations) ‐ Hypothesis-driven (targeted) ‐ Discovery (“omics”) • CSF biomarkers • Cell-based/immune system biomarkers Biomarker Discovery
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