TYSABRI (natalizumab)
Benefit/Risk Update &
PML Risk Stratification
FOR HEALTHCARE PROFESSIONALS ONLY
TY-PAN-0597(4) Dat...
This information has been provided
by Biogen Idec Medical Affairs
for healthcare professional use only,
in response to you...
Benefit / Risk
81% reduction in
relapse rate1
PML risk ≈
3.30 in 1,000 3
64% reduction in
disability
progression1
≈1 in...
PML Risk Update
FOR HEALTHCARE PROFESSIONALS ONLY
TY-PAN-0597(4) Date of preparation: September 2013
What causes PML?
• PML is uncommon and likely caused by interplay between multiple factors
1. Presence of
asymptomatic JCV...
PML Risk
• Factors that increase the risk of PML have been identified1
– The presence of anti-JCV antibodies
– Receiving a...
Natalizumab PML Incidence Estimates by
Treatment Epoch
4.0
3.64
Incidence per 1000 patients
3.5
3.30
2.96
2.87
3.0
...
Natalizumab PML Incidence Estimates by
Treatment Epoch (Feb 2010 – Sep 2013)
Biogen Idec, data on file.
FOR HEALTHCARE PR...
Use of Natalizumab in the Post-Marketing Setting*
Worldwide post-marketing data from 23 Nov 2004 to 30 June 2013
Overall
E...
Risk Stratification Tool: The Presence of Anti-JCV Antibodies,
Prior Immunosuppressant Use, Treatment Duration*
Anti-JCV
A...
Risk Stratification Tool: The Presence of Anti-JCV Antibodies,
Prior Immunosuppressant Use, Treatment Duration*
Anti-JCV
A...
Putting risk into context:
Benefits of natalizumab therapy
FOR HEALTHCARE PROFESSIONALS ONLY
TY-PAN-0597(4) Date of prep...
Putting risk into context
• Initiation or continuation of natalizumab therapy
should be based upon an assessment of the
p...
Putting risk into context:
AFFIRM efficacy1,2
In patients with highly active RRMS (≥2 relapses in the prior year and ≥1 Gd...
Putting risk into context:
freedom from disease activity*1
Proportion of Disease-Free Patients (%)
Overall Population
P<...
Original Placebo
Original Natalizumab
Original Placebo – Now on Natalizumab
n=709
n=385
n=456
n=203
n=519
n=244
n=5...
Putting risk into context:
long-term efficacy data from STRATA1
Original Placebo
Cessation/
Treatment Gap*
Original Nata...
Putting risk into context:
real life data from TOP1
N=3976
(P<0.0001)
n=3963
•
n=3971
Annualized relapse rate remained...
Summary
•
As of 30th June 2013, approximately 118,100 patients have received
natalizumab in the post-marketing setting wo...
Supporting information:
PML risk factors & outcomes
FOR HEALTHCARE PROFESSIONALS ONLY
TY-PAN-0597(4) Date of preparation...
Anti-JCV Antibody Testing
•
The 2-step anti-JCV antibody assay has been developed to help identify
patients who have been...
Anti-JCV Antibody Testing
•
Current data on the assay as a risk stratification tool from STRATIFY-1 (n=1096)
–
–
–
46% a...
Anti-JCV Antibody Testing
• As of 3rd September 2013, there are 180 natalizumab-treated MS PML
patients with known pre-PML...
Anti-JCV Antibody Testing
•
Re-testing of anti-JCV antibody negative patients every 6 months is
recommended.1
•
The ant...
Estimated PML Risk Associated with Prior IS Use
•
As of 4th March 2011, 39 of 93 patients (42%) with PML and known prior ...
No Specific Pattern in Type of Prior IS Use
Identified in Patients with PML
• Type of prior IS use varied
• Some patients ...
No Specific Pattern in Duration of Prior IS Use or
Time from Last Dose of IS in Patients with PML
• Duration of prior IS u...
Key Learnings: PML Management
• Heightened clinical vigilance led to prompt natalizumab discontinuation
upon first signs o...
Factors that may affect survival in patients with PML
At this time, there are insufficient data to predict survival outcom...
PML Presenting Symptoms
PML symptom
% PML cases with symptom
Cognitive/behavioral
49%
Motor (eg: hemiparesis)
37%
Sp...
IRIS Presents as Clinical Decline
IRIS symptom
% PML cases with symptom
Motor (eg; hemiparesis)
66%
Speech (eg; dysart...
Key Learnings: Treatment of IRIS
• Monitoring for development of IRIS and appropriate treatment should be
undertaken
• Tre...
PML outcomes: Karnofsky scores
On average, Karnofsky scores decrease at PML diagnosis but remain stable through ≥14
months...
PML outcomes: EDSS scores
On average, EDSS scores increase at PML diagnosis but stabilize at 6-9 months and
remain stable ...
PML outcomes: asymptomatic vs symptomatic
• As of 1st January 2013, 319 PML cases had been confirmed in the postmarketing ...
PML outcomes: asymptomatic vs symptomatic
• On average, EDSS scores increase at PML diagnosis, but stabilize at 6-9
months...
PML Research at Biogen Idec
Our Mission: Via innovative clinical and laboratory research, gain deeper insights into PML
pa...
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Natalizumab benefit risk update september 2013

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


Transcripts - Natalizumab benefit risk update september 2013

  • 1. TYSABRI (natalizumab) Benefit/Risk Update & PML Risk Stratification FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 2. This information has been provided by Biogen Idec Medical Affairs for healthcare professional use only, in response to your request. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 3. Benefit / Risk 81% reduction in relapse rate1 PML risk ≈ 3.30 in 1,000 3 64% reduction in disability progression1 ≈1 in 3 patients free of disease activity2 Risk Other Adverse Events Per Labelling Benefit TYSABRI 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 4. PML Risk Update FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 5. 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: peripheral immune function, genetics 45 nm 4. Drug effects that reduce CNS immune surveillance VP1=viviparous 1; RR=regulatory region; CNS=central nervous system. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 6. 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 September, overall incidence: 3.30 per 1000 patients (95% CI: 2.99 to 3.64 per 1000 patients)2 – 77% of patients are alive with varying levels of disability • As of 3rd September 2013, the duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 91 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 40.0 months2 1. TYSABRI Summary of Product Characteristics 2. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 7. Natalizumab PML Incidence Estimates by Treatment Epoch 4.0 3.64 Incidence per 1000 patients 3.5 3.30 2.96 2.87 3.0 2.78 2.99 2.25 2.5 2.0 2.37 2.01 1.88 1.94 1.5 1.56 0.83 1.0 1.83 1.41 0.64 0.5 0.12 0.0 2.34 0.06 0.48 0.02 Calculations based on exposure through 31st August 2013 and 401 confirmed cases as of 3rd September 2013 Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 8. Natalizumab PML Incidence Estimates by Treatment Epoch (Feb 2010 – Sep 2013) Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 9. Use of Natalizumab in the Post-Marketing Setting* Worldwide post-marketing data from 23 Nov 2004 to 30 June 2013 Overall Exposure 118,100 ≥12 Months 86,700 ≥18 Months 73,100 ≥24 Months 62,100 ≥30 Months 51,900 ≥36 Months ≥42 Months ≥48 Months 43,500 296,471 Patient-Years of natalizumab exposure 36,000 29,000 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 Patients 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 10. Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* Anti-JCV Antibody Status Negative Positive Prior IS Use No Natalizumab Exposure 1–24 months 0.1/1000 95% CI 0.01-0.35 25–48 months 49–72 months Yes No Prior IS Use Prior IS Use 0.7/1000 1.8/1000 95% CI 0.5-1.0 95% CI 1.1-2.7 5.3/1000 11.2/1000 95% CI 4.4-6.2 95% CI 8.6-14.3 6.1/1000 Insufficient data 95% CI 4.8-7.8 Data beyond 6 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure. *Based on natalizumab exposure and 343 confirmed PML cases as of 5 th 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 5 th March 2013. The analysis assumes that 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at least 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000; 95% CI 0.02–0.56). Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 11. 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 1,429 1 in 556 No 1 in 10,000 1 in 189 Natalizumab Exposure 1–24 months 0.1/1000 25–48 months 95% CI 0.01-0.35 1 in 164 49–72 months Yes No Prior IS Use Prior IS Use 0.7/1000 1.8/1000 95% CI 0.5-1.0 95% CI 1.1-2.7 5.3/1000 11.2/1000 95% CI 4.4-6.2 95% CI 8.6-14.3 6.1/1000 Insufficient data 95% CI 4.8-7.8 1 in 89 Data beyond 6 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure. *Based on natalizumab exposure and 343 confirmed PML cases as of 5 th 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 5 th March 2013. The analysis assumes that 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at least 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000; 95% CI 0.02–0.56). Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 12. Putting risk into context: Benefits of natalizumab therapy FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 13. Putting risk into context • 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 1. TYSABRI Summary of Product Characteristics FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 14. 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) • Annualized relapse rate at 2 years • Sustained disability progression (confirmed for 24 weeks) 0.5 1.46 Annualized Relapse Rate 1.4 1.2 81% reduction (p<0.001) 1.0 0.8 0.6 0.4 0.28 Proportion With Sustained Disability Progression 1.6 64% risk reduction Hazard ratio=0.36 (p=0.004) 0.4 0.3 Placebo 26% 0.2 0.1 Natalizumab 10% 0.0 0 12 24 0.2 36 48 60 72 Weeks 84 96 108 120 Number of Patients at Risk 0.0 Placebo n=61 Natalizumab n=148 Placebo Natalizumab 61 57 54 51 47 46 45 42 39 36 148 144 141 140 137 131 130 128 123 123 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. 1. Hutchinson M, et al. J Neurol. 2009; 256:405-15, 1035-7. 2. TYSABRI Summary of Product Characteristics FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 15. Putting risk into context: freedom from disease activity*1 Proportion of Disease-Free Patients (%) Overall Population P<0.0001 Highly Active Patients † P<0.0001 50 Placebo Natalizumab 40 36.7 5 30 16 vs placebo vs placebo 27.4 20 10 7.2 1.7 0 n=304 n=600 n=59 n=146 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. 1. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 16. Original Placebo Original Natalizumab Original Placebo – Now on Natalizumab n=709 n=385 n=456 n=203 n=519 n=244 n=528 n=249 n=282 n=584 n=709 n=385 n=641 n=328 n=381 n=707 n=707 Cessation/ Treatment Gap n=381 Unadjusted Annualized Relapse Rate Putting risk into context: long-term efficacy data from STRATA1 † 1 Year 2 Years 3 Years 4 Years 5 Years STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE. *Includes data on patients dosed with natalizumab; †includes all available on-treatment relapse data. 1. Kappos L, et al. ECTRIMS 2012; P520. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 17. Putting risk into context: long-term efficacy data from STRATA1 Original Placebo Cessation/ Treatment Gap* Original Natalizumab n=142 n=71 n=450 n=205 n=490 n=224 n=491 n=236 n=575 n=275 n=709 n=385 n=552 n=280 n=707 n=381 n=707 n=380 Mean EDSS Score Original Placebo – Now on Natalizumab † 1 Year 2 Years 3 Years 4 Years 5 Years STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE. *P<0.0001; †includes data on patients dosed with natalizumab. EDSS=Expanded Disability Status Scale. 1. Kappos L, et al. ECTRIMS 2012; P520. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 18. Putting risk into context: real life data from TOP1 N=3976 (P<0.0001) n=3963 • n=3971 Annualized relapse rate remained low after 4 years on therapy • The median EDSS score remained stable up to 4 years of follow-up TOP is an ongoing, open-label, prospective, multicentre, observational study generating long-term outcomes data for natalizumab in RRMS patients in the post-marketing setting. 66% of patients (n=2624) analyzed had been followed for ≥1 year; 32% (n=1259) had been followed for ≥2 years; 12% (n=458) had been followed for ≥3 years. 1. Kappos L, et al. AAN 2012; P04.134. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 19. Summary • As of 30th June 2013, approximately 118,100 patients have received natalizumab in the post-marketing setting worldwide • Factors that increase the risk of PML have been identified1 – JCV exposure indicated by anti-JCV antibody positive status – Receiving an immunosuppressant prior to receiving natalizumab – Natalizumab treatment duration, especially >2 years • Clinical vigilance remains key in the early diagnosis of PML – Early diagnosis and aggressive clinical management appears to be associated with improved survival rates observed in post-marketing cases – PML may be fatal or result in severe disability1 • The following factors appear to be associated with improved survival after PML: – – – – • Shorter duration between symptom onset and PML diagnosis Localized PML on MRI at diagnosis Younger age Lower pre-PML EDSS Initiation or continuation of natalizumab therapy should be based upon an assessment of the potential benefit:risk balance for the patient 1. TYSABRI Summary of Product Characteristics FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 20. Supporting information: PML risk factors & outcomes FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 21. 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 22. 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 • • • – 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 • • • 38% of subjects remained consistently anti-JCV antibody negative 52% remained consistently anti-JCV antibody positive 10% changed serostatus 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 23. Anti-JCV Antibody Testing • As of 3rd September 2013, there are 180 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 180 patients, 178 (98.9%) tested anti-JCV antibody positive prior to diagnosis and 2 (1.1%) tested anti-JCV antibody negative. • Serum samples obtained prior to PML in two natalizumab-treated CD patients (one from clinical trials and one post-marketing) both tested antiJCV antibody positive. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 24. 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 natalizumabtreated 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. AntiJCV 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 1. TYSABRI Summary of Product Characteristics 2. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 25. Estimated PML Risk Associated with Prior IS Use • 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 *http://clinicaltrials.gov/ct2/show/NCT00477113 http://clinicaltrials.gov/ct2/show/NCT00483847 Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 26. 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 27. 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 28. 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 weeks2 1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446. 2. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 29. 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 Factors that appear to be associated with decreased associated with improved survival 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 Factors that do not appear to affect 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 Vermersch P, et al. Neurology. 2011;76:1697-1704. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 30. 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 Based on the first 35 PML cases. Biogen Idec, data on file. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 31. 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 32. Key Learnings: Treatment of IRIS • 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, preemptive 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. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 33. PML outcomes: Karnofsky scores On average, Karnofsky scores decrease at PML diagnosis but remain stable through ≥14 months of follow-up 100 90 Karnofsky Scores 80 70 pre-PML PML diagnosis 60 6-9 Months 50 10-13 Months 14+ Months 40 Mean 30 Median 20 10 0 Pre PML Mean Median n PML diagnosis 6-9 months 10-13 months ≥14 months pre-PML 81.1 80 33 PML diagnosis 49.4 50 32 6-9 months 53.1 50 45 10-13 months 49.6 50 27 ≥14 months 52.6 50 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 T, et al. ECTRIMS 2012; P1098. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 34. PML outcomes: 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 EDSS Scores 7 pre-PML 6 PML diagnosis 6-9 Months 5 10-13 Months 4 14+ Months Mean 3 Median 2 1 0 Pre PML Mean Median n PML diagnosis pre-PML 3.7 3.5 90 PML diagnosis 5.2 5.5 75 6-9 months 6-9 months 6.3 6.4 28 10-13 months 10-13 months 6.4 6.8 16 ≥14 months ≥14 months 6.6 7 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 T, et al. ECTRIMS 2012; P1098. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 35. PML outcomes: asymptomatic vs symptomatic • As of 1st January 2013, 319 PML cases had been confirmed in the postmarketing setting; of these 319 patients 21 (6.6%) were identified as asymptomatic and 298 were identified as symptomatic at the time of PML diagnosis − Asymptomatic was defined as patients who had no clinical symptoms of PML, but had MRI findings consistent with PML at the time of diagnosis EDSSa and KPSb scores over time in asymptomatic and symptomatic PML patients P value from Mann-Whitney-Wilcoxon test. aThe mean duration of EDSS follow-up was 13.3 months in asymptomatic patients and 9.7 in symptomatic patients. bThe mean duration of KPS follow-up was 12.8 months in asymptomatic patients and 10.0 in symptomatic patients. Dong-Si T, et al. AAN 2013; P04.271. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 36. PML outcomes: asymptomatic vs symptomatic • On average, EDSS scores increase at PML diagnosis, but stabilize at 6-9 months and remain stable through up to 24 months of follow-up EDSS scores for asymptomatic and symptomatic PML patients measured over time Polynomial regression using the LOWESS algorithm. Outcome of patients with asymptomatic and symptomatic PML Dong-Si T, et al. AAN 2013; P04.271. FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013
  • 37. 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 Objectives Clear and effective risk stratification algorithm JCV antibody assay and further understanding JCV serology Clinical Research New tools for PML risk stratification • JCV assay performance • JCV antibody serostability • JCV antibody levels • Genomics (host, viral) • Blood-based biomarkers (host and JCV mutations) - Hypothesis-driven (targeted) - Discovery (“omics”) • CSF biomarkers • Cell-based/immune system biomarkers Better understanding of PML outcomes JCV Biology Research Biomarker Discovery JCV Serology • 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 Tools for early PML diagnosis • Defining host factors • Improving and developing new systems and animal models • Infection dynamics in tissues (JCV and other pathogens) • Integrated clinical and analytical data analysis • • • • Therapeutic approaches and management of PML Sample Collection • 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) BIIB internal research BIIB - supported SRAs and IITs Innovative technology partnerships PML Consortia-sponsored research FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0597(4) Date of preparation: September 2013

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