Tysabri benefit risk update Feb 2017

FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(7) Date of preparation: Feb 2017

Natalizumab▼ (Tysabri) Benefit/Risk Update

Q4 2016


This information has been provided by Biogen Medical

for healthcare professional use only, in response to your request.


Benefit / Risk

Benefit

Risk

Natalizumab

In highly active patients at 2 years*: • 81% reduction in

relapse rate vs. placebo1

(ARR 0.28 natalizumab vs. 1.46 placebo)

• 64% reduction in disability progression vs. placebo1

(10% natalizumab vs. 26% placebo)

• 27% of patients free of disease activity vs. 2% of placebo patients 2

PML risk ≈ 4.18 in 1,000 3

Other Adverse Events Per Labelling

* Post hoc analysis of highly active subgroup from AFFIRM 1. Hutchinson M, et al. J Neurol. 2009;256:405-41.; 2. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60; 3. Biogen, data on file.


PML Risk Update


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


• As of 30th November 2016, overall PML incidence: 4.18 per 1000 patients (95% CI: 3.88 to 4.51 per 1000 patients)1

• As of 1st December 2016 there have been 698 confirmed PML cases (695 MS, 3 CD), (194 US, 438 EEA, 66 ROW)1

• 77% of patients are alive with varying levels of disability*1

• As of 1st December 2016, the duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 118 doses.1

• Mean duration of natalizumab dosing at time of PML diagnosis was approximately 48 months1

*Based on follow-up data for at least 6 months after PML diagnosis US = United States; EEA = European Economic Area; ROW = Rest of World 1. Biogen, data on file.

PML Risk in Natalizumab-Treated Patients


Global Natalizumab PML Risk Estimates by Treatment Epoch: March 2016

4.48

0.12 0.90

1.87

2.59 2.78

2.29

3.83

0.03

0.58

1.33

1.87 1.92

1.39

4.15

0.07

0.73

1.58

2.21 2.32

1.80

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Inci

denc

e pe

r 100

0 pa

tient

s

Natalizumab PML Risk Estimates by Treatment Epoch

Due to the consistency of the incidence over time, this figure will be updated annually after the March 2016 Safety Update. The observed clinical trial PML incidence in patients who received a mean of 17.9 monthly doses of natalizumab was 1.00 per 1000 natalizumab -treated patients (95% CI 0.20-2.80) (Yousry TA, et al. N Engl J Med. 2006;354:924-933). The postmarketing rate is calculated as the number of PML cases since reintroduction in patients that have had at least 1 dose of natalizumab. The incidence for each epoch is calculated as the number of PML cases divided by the number of patients exposed to natalizumab (e.g., for 25 to 36 infusions all PML cases diagnosed during this period is divided by the total number of patients ever exposed to at least 25 infusions and therefore having risk of developing PML during this time). Biogen, data on file.


Natalizumab PML Incidence Estimates by Treatment Epoch (Apr 2010 – Mar 2016)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5A

pr. 2

010

Jul.

2010

Oct

. 201

0

Jan.

201

1

Apr

. 201

1

Jul.

2011

Oct

. 201

1

Jan.

201

2

Apr

. 201

2

Jul.

2012

Oct

. 201

2

Jan.

201

3

Apr

. 201

3

Jul.

2013

Oct

. 201

3

Jan.

201

4

Apr

. 201

4

Jul.

2014

Oct

. 201

4

Dec

. 201

4

Mar

. 201

5

Jun.

201

5

Sep

. 201

5

Dec

. 201

5

Mar

. 201

6

Inci

denc

e pe

r 100

0 pa

tient

s

1-12 infusions13-24 infusions25-36 infusions37-48 infusions49-60 infusions61-72 infusions

Due to the consistency of the incidence over time, this figure will be updated annually after the March 2016 Safety Update. The observed clinical trial PML incidence in patients who received a mean of 17.9 monthly doses of natalizumab was 1.00 per 1000 natalizumab-treated patients (95% CI 0.20-2.80) (Yousry TA, et al. N Engl J Med. 2006;354:924-933). The post-marketing rate is calculated as the number of PML cases since reintroduction in patients that have had at least 1 dose of natalizumab. Incidence estimates by treatment epoch are calculated based on natalizumab exposure and confirmed cases of PML. Data are from the specified month as indicated. The incidence for each epoch is calculated as the number of PML cases divided by the number of patients exposed to natalizumab at each time point (e.g., for 25 to 36 infusions the number of all PML cases diagnosed during this period is divided by the total number of patients ever exposed to at least 25 infusions and therefore having risk of developing PML during this time). Biogen, data on file.


Use of Natalizumab in the Post-Marketing Setting*

Patients

Biogen, data on file.

*Postmarketing 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.

Worldwide post-marketing data from 23 Nov 2004 to 30 Sept 2016

527,159 Patient-Years of natalizumab exposure

161,300

121,900

106,800

94,300

82,300

72,800

64,600

56,700

48,900

41,800

35,400

29,500

OverallExposure

≥12 Months

≥18 Months

≥24 Months

≥30 Months

≥36 Months

≥42 Months

≥48 Months

≥54 Months

≥60 Months

≥66 Months

≥72 Months


Updated Risk Estimates for PML in Natalizumab-Treated Patients

PML risk estimates in anti-JCV antibody positive patients were derived using Life Table method based on the pooled cohort of 21,696 patients who participated in the STRATIFY-2, TOP, TYGRIS and STRATA clinical studies. Further stratification of PML risk by anti-JCV antibody index interval for patients with no prior history of immunosuppressant use were derived from combining the overall yearly risk with the antibody index distribution. The risk of PML in anti-JCV antibody negative patients was estimated based on post-marketing data from approximately 125,000 exposed patients.

Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016


Putting risk into context: Benefits of natalizumab therapy


• 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® (natalizumab) Summary of Product Characteristics

Putting risk into context


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® (natalizumab) Summary of Product Characteristics.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Annu

aliz

ed R

elap

se R

ate

1.46

0.28

Natalizumab n=148

Placebo n=61

81% reduction (p<0.001)

Number of Patients at Risk Placebo Natalizumab

Prop

ortio

n W

ith

Sust

aine

d D

isab

ility

Prog

ress

ion

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

72 108 96 48

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.

Putting risk into context: AFFIRM efficacy1,2


1. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60.

Pro

porti

on o

f Dis

ease

-Fre

e P

atie

nts

(%)

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

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.

Putting risk into context: freedom from disease activity1


STRATA was an 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.

Putting risk into context: long-term efficacy data from STRATA1

1. O’Connor P, et al. Neurology. 2014; 83(1):78-86.


STRATA was an 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; LOCF=last observation carried forward.

1. O’Connor P, et al. Neurology. 2014; 83(1):78-86.

Putting risk into context: long-term efficacy data from STRATA1


• 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 H, et al. J Neurol Neurosurg Psychiatry. 2014; 85(11):1190-7.

• Mean EDSS remained stable over 4 years of treatment

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

3.53.3 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

Putting risk into context: real life data from TOP1


• Annualised relapse rate significantly decreased on natalizumab regardless of treatment history

1. Nicholas R, et al. ABN 2016; P114.

• Natalizumab significantly reduced relapse rates in patients irrespective of number of relapses in the year prior to starting natalizumab

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 May 2015, the TOP UK cohort included 134 patients and had a total exposure of 383.30 patient-years, with a median of 43 (range, 1–64) doses.

Baseline and on-treatment ARR by treatment history Baseline and on-treatment ARR depending on # of relapses in year prior to natalizumab

Putting risk into context: real life data from TOP in the UK1

P<0.0001, CI=confidence interval.


• Annualised relapse rate declined after natalizumab treatment by 89.8% (P<0.0001) compared with the period before natalizumab treatment

1. McGuigan C, et al. ECTRIMS 2015; EP1462.

• EDSS scores were stable from the time of starting natalizumab through to the end of the study period.

iTOP is an ongoing, open-label, prospective and retrospective, multicentre, observational study generating long-term outcomes data for natalizumab in RRMS patients in the post-marketing setting in the Republic of Ireland. As of December 2013, 119 patients were enrolled.

Mean ARR during natalizumab treatment

Mean EDSS scores during natalizumab treatment

Putting risk into context: real life data from iTOP1


Supporting information: PML risk factors, monitoring &

outcomes

For further detail including information on patient monitoring please refer to the Physician Information and Management Guidelines for Multiple Sclerosis patients on

Tysabri Therapy and the Tysabri Summary of Product Characteristics.


For patients treated with natalizumab, the following risk factors are

associated with an increased risk of PML:

•The presence of anti-JCV antibodies

•Treatment duration, especially beyond 2 years. After 2 years all patients should be re-informed about the risk of PML

•Prior immunosuppressant use

Additionally, in anti-JCV antibody positive patients who have not used prior immunosuppressants the level of anti-JCV antibody response (index) is associated with the level of risk for PML

1. TYSABRI® (natalizumab) Summary of Product Characteristics.

PML Risk Factors


• Exposure to the JC virus is a pre-requisite for developing PML.1

• 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 status identifies different levels of risk for PML in natalizumab treated patients.

Anti-JCV Antibody Testing

1. TYSABRI® (natalizumab) Summary of Product Characteristics.


• Seroprevalence: • An analysis of the two-step anti-JCV antibody assay (STRATIFY JCV) in over 6,000 MS

patients has demonstrated the prevalence of anti-JCV antibodies to be approximately 55%. Anti-JCV antibody prevalence in the EU was reported as ranging from 48.8% to 69.5% in the EU in a cross-sectional study of MS patients irrespective of treatment.1,2

• In general, anti-JCV antibody prevalence did not appear to be affected by prior IS use, prior exposure to natalizumab, or duration of natalizumab exposure1

• In the MS population, anti-JCV antibody prevalence increased with age and was lower in women than in men in all cohorts tested1

1. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016; 2. Bozic C, et al. Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial. Eur J Neurol 2014, 21: 299–304;



• Serostability: • In the STRATIFY-1 clinical study, approximately 11% of patients changed serostatus from anti-JCV antibody negative to positive per year.1, 2

• Approximately 12-16% serostatus change from antibody negative to positive in the second generation assay was reported in Unilabs real world data over a median duration of 12 months.2

• In the STRATIFY-2 clinical study, approximately 6% of patients changed serostatus from anti-JCV antibody positive to negative per year. 2

• Patients who test anti-JCV antibody positive at any time should be considered to be at an increased risk for developing PML, independent from any prior or subsequent antibody test results. 2

1.Chan A, et al. ECTRIMS, 2014; 2. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016



In patients who have not received prior immunosuppressant therapy and are anti-JCV Ab positive, the level of anti-JCV Ab response (index) is associated with the level of risk of PML1,2

1. Kuesters G et al AAN 2015; P4.031; 2. TYSABRII® (natalizumab) Summary of Product Characteristics

• Current evidence suggests that the risk of PML is low at an index equal to or below 0.9 and increases substantially above 1.5 for patients who have been on treatment with natalizumab for longer than 2 years2


1. TYSABRI® (natalizumab) Summary of Product Characteristics; 2. Subramanyam M, et al. The effect of plasma exchange on serum anti-JC virus antibodies. Mult Scler J ;19(7) 912 –919.

• Re-testing of anti-JCV antibody negative patients every 6 months is recommended.1

• Patients with low anti-JCV antibody index values and no history of prior immunosuppressant use should be retested every 6 months once they reach the 2-year treatment point.1

• Data from a Biogen 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.2

• 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

• The anti-JCV antibody assay should not be used to diagnose PML. Use of PLEX or intravenous immunoglobulin (IVIg) can affect meaningful interpretation of serum anti-JCV antibody testing. Patients should not be tested for anti-JCV antibodies within 2 weeks of PLEX due to removal of antibodies from the serum, or within 6 months of IVIg (i.e. 6 months = 5x half-life for immunoglobulins).1



• Anti-JCV antibody negative patients may still be at risk of PML for reasons

such as a new JCV infection, fluctuating antibody status or a false negative test.1

• The percentage of natalizumab-treated MS PML patients with pre-PML samples, collected at least 6 months prior to PML diagnosis, testing negative for anti-JCV antibody prior to diagnosis has consistently been below the estimated false-negative rate of 2.2%, which is the assay limitation.2,3

1. TYSABRII® (natalizumab) Summary of Product Characteristics ; 2. Biogen Data on File; 3. Lee P, et al. J Clin Virol. 2013;57(2):141-6.



Anti-JCV Antibody Status

Prior Immunosuppressant Use

Positive

Treatment Duration >2 years

Treatment Duration ≤2 years

Negative

No Prior Immunosuppressant Use

Low Index High Index

• Yearly brain MRI

• Anti-JCV antibody testing every 6 months

• Yearly brain MRI • Yearly brain MRI • Abbreviated brain MRI protocol

(T2, FLAIR and DWI) every 3-6 months

• Yearly brain MRI

• Anti-JCV antibody testing every 6 months with Index

Recommended Patient Monitoring Based on PML Risk

Current evidence suggests that the risk of PML is low at index value ≤0.9, and increases substantially at values above 1.5 in patients who have been on treatment with natalizumab for longer than 2 years.

Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016.


• For anti-JCV antibody positive patients who have used IS previously: These patients are at an increased risk of PML, since prior IS use is recognised as an independent risk factor for PML1,2

• In the Tysabri Global Observational Program in Safety (TYGRIS) study, a total

of 34.5% of natalizumab-treated patients with PML, as compared with 20.3% of all natalizumab-treated patients in the TYGRIS study (14.0% in the USA and 23.5% in the EU), had received one or more IS medications before the initiation of therapy.3

• The IS used most frequently among natalizumab-treated patients with PML and among natalizumab-treated patients in the TYGRIS study included mitoxantrone, methotrexate, cyclophosphamide, azathioprine, and mycophenolate mofetil.3

• In patients with PML, there was no specific pattern in:

• duration of prior IS therapy • time from last dose of IS to initiation of natalizumab therapy3

1. TYSABRI® (natalizumab) Summary of Product Characteristics; 2. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016 ; 3. Bloomgren G, et al. N Engl J Med, 2012; 366(20): 1870-80.

Estimated PML Risk Associated with Prior IS Use


• In the current PML risk estimate algorithm, risk estimates for patients with prior immunosuppressants is based on natalizumab clinical trial data where prior IS use comprised the following 5 IS therapies: mitoxantrone, methotrexate, azathioprine, cyclophosphamide and mycophenolate mofetil.1

• The exact mechanism by which these 5 IS therapies lead to an increased PML risk is unknown.1

• In patients with prior IS current data does not show an association between higher index and PML risk. The underlying biological explanation for this effect is unknown.1-3

1. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016; 2. TYSABRI® (natalizumab) Summary of Product Characteristics; 3. Kuesters G et al AAN 2015; P4.031;

Estimated PML Risk Associated with Prior IS Use


• PML should be considered as a differential diagnosis in any MS patient taking natalizumab presenting with neurological symptoms and/or new brain lesions in MRI1.

• JC virus also causes JCV granule cell neuronopathy (GCN) which has been reported in patients treated with natalizumab. Symptoms of JCV GCN are similar to symptoms of PML (i.e. cerebellar syndrome)1.

• PML has been reported following discontinuation of natalizumab in patients who did

not have findings suggestive of PML at the time of discontinuation. Patients and physicians should be alert for any new signs or symptoms that may be suggestive of PML for approximately 6 months following discontinuation of natalizumab1.

• Cases of asymptomatic PML based on MRI and positive JCV DNA in the cerebrospinal

fluid have been reported.

Physicians should refer to the Physician Information and Management Guidelines for further information on managing the risk of PML in Tysabri-treated patients.

PML Diagnosis

1. TYSABRI® (natalizumab) Summary of Product Characteristics;


PML Diagnosis

1. TYSABRI® (natalizumab) Summary of Product Characteristics; 2. Kappos L et al. Lancet Neurol. 2011;10:745-758; 3. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016; 4. Dong-Si T, et al. Ann Clin Transl Neurol. 2014; 1(10):755-64.

• Clinical vigilance and early recognition of suspicious signs or symptoms is important - patients must be monitored at regular intervals and should be instructed together with their caregivers on early signs and symptoms of PML1-3

• Data suggest that PML in asymptomatic patients, diagnosed on the basis of brain MRI findings and the presence of JCV DNA in the CSF or on brain biopsy, is associated with better survival compared with PML patients who were symptomatic at diagnosis3,4

• Management algorithms have been developed and are available in the Physician Information and Management Guidelines2,3

Diagnostic algorithm components:1-3

• In all cases where further investigation of change in neurological status or change in brain MRI is indicated, TYSABRI must be suspended and not restarted until non-MS pathology has been confidently excluded. Suspension of TYSABRI therapy for short duration (days or weeks), is not expected to compromise therapeutic efficacy based on the pharmacodynamics of the drug.


• Patients with higher risk are defined as:

Higher risk patient definition for MRI monitoring purposes applies to some of the Anti-JCV Ab positive patients

Patients who have all three known risk factors for PML (presence of anti-JCV Ab, prior

immunosuppressant and > 2 years of natalizumab therapy)

Patients with a high anti-JCV antibody index, without prior

history of immunosuppressant therapy

and > 2 years of natalizumab therapy

TYSABRI® (natalizumab) Summary of Product Characteristics Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016.

• No studies have been performed to evaluate the efficacy and safety of natalizumab when switching patients from DMTs with an immunosuppressant effect. It is unknown if patients switching from these therapies to natalizumab have an increased risk of PML, therefore these patients should be monitored more frequently (i.e. similarly to patients switching from immunosuppressants to natalizumab).


• The CSF JCV DNA test is available for patients previously or currently

treated with natalizumab to facilitate the diagnosis of a suspected case of PML in clinical practice

• A suspected case in this context is one where the patient either has symptoms and/or an MRI scan potentially suggestive of PML

• In the absence of clinical suspicion, if positive, this test does not make the diagnosis of PML. The diagnosis of PML is based on either detection of JCV infection on brain tissue, or detection of JCV DNA in the CSF of patients with radiological findings and/or a clinical presentation consistent with PML.

CSF JCV DNA Testing


• Reference CSF JCV DNA testing is available from Unilabs (Denmark) and Focus

Diagnostics (US). Both laboratories offer a real time PCR assay with a Limit of Detection (LoD) of ~10 copies/ml. Biogen are not in a position to certify any laboratory, however benefits of the Unilabs option include:

– No customs invoices required for samples sent to Unilabs (within EU)

– Test results can be emailed or faxed (Focus Diagnostics fax results only)

– Turnaround time for receipt of Unilabs test results is up to 5 working days

• A negative CSF JCV DNA test does not necessarily rule out PML, e.g. if the level is too low to detect. If suspicion of PML remains then additional testing may be warranted

CSF JCV DNA Testing Facilities


1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446.; 2. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016 3. Biogen, 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 month1

• Data suggest that early detection and treatment of PML when the disease is

asymptomatic (is still in the initial stages and shows no symptoms) may improve patients’ outcomes2

• 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 weeks3

Key Learnings: PML Management


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.

Vermersch P, et al. Neurology. 2011;76:1697-1704; Dong-Si T, et al. J Neurovirol. 2015; 21(6):637-44; Dong-Si T, et al. Ann Clin Transl Neurol. 2014; 1(10):755-64; Biogen, data on file.

Factors that appear to be associated with decreased

survival

• Gender

• Prior immunosuppressant therapy

• MS duration

• Natalizumab exposure 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

• Lower JC viral load at diagnosis

• More localised brain involvement by MRI at the time of diagnosis

• Asymptomatic at diagnosis

Factors that may affect survival in patients with PML


– It should be noted that the table is not all-inclusive and there may be a great deal of overlap between symptoms of the two conditions

– Individual PML cases have frequently presented with a variety of symptoms3 1. Kappos et al. 2011; 2. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016; 3. Biogen, data on file.

Clinical features of MS and PML1,2


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% *Based on the first 35 PML cases.1 At the time of the analysis, 32 of 35 PML cases reported the occurrence of IRIS.

1. Biogen, data on file; 2. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016.

IRIS Presents as Clinical Decline • The clinical worsening is a result of local inflammatory reaction, including oedema, and

manifests as a worsening of neurological symptoms, dependent on the site of IRIS. Decline may be rapid, can lead to serious neurological complications or death.1,2


• Monitoring for development of IRIS and appropriate treatment should be undertaken • Does not appear to be associated with increased mortality

• Diagnosis and management of IRIS is a controversial issue and there is no consensus

concerning its treatment2 • It has been suggested that corticosteroids may be useful to treat IRIS, particularly in

patients with severe to life-threatening IRIS1-3

• The following steroid regimens have been reported for the treatment of IRIS in the literature: • Oral prednisone 1.5 mg/kg/day x 2 weeks with taper over 2 months • IV methylprednisolone (1 g/day for 3 or 5 days) with oral taper over 2 months

• If further deterioration occurs during steroid taper and this is judged to be due to continuing or new inflammatory reactions a further course of higher dose steroids may be necessary2

• Prophylactic steroid treatment is currently not recommended2

1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446; 2. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016; 3. Tan et al., Neurol. 2009;72:1458-1464.

Key Learnings: Treatment of IRIS


• Each point represents the EDSS score of an individual patient at the indicated interval relative to PML diagnosis. • Analysis: weighted polynomial regression using the LOWESS algorithm. • In this analysis, 254 of 336 patients (76%) were survivors and 82 of 336 patients (24%) were nonsurvivors. • The mean follow-up time from PML diagnosis was 16.1 months for survivors.

1. Dong-Si T, et al. J Neurovirol. 2015; 21(6):637-44.

• Karnofsky scores: Surviving PML patients demonstrated stabilised functional disability, measured by Karnofsky score, at 6 months post-PML diagnosis and remained relatively stable even beyond 18 months post PML diagnosis1

• EDSS scores: As shown below, EDSS scores increased at PML diagnosis but remained relatively stable during the follow up period. Increases at diagnosis were more marked in non-survivors1

PML outcomes - survivors and non-survivors (as of August 2013)


• Cases of asymptomatic PML, have been reported that were initially suspected based on MRI findings and later confirmed by positive JCV DNA in the CSF.

• Asymptomatic patients appear to have less accrual of disability overtime as reflected by lower EDSS scores (shown below) and higher Karnofsky scores after PML diagnosis compared to symptomatic patients (symptomatic patients did, however, have a slightly higher level of disability pre-PML compared to asymptomatic patients).1,2

1. Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016; 2. Carrillo-Infante C, et al. ECTIMS 2016 EP1528.

PML outcomes – asymptomatic patients (compared to symptomatic patients, as of June 2015)

Symptomatic (n= 566)

Asymptomatic (n= 62)

Asymptomatic PML Patients

Total n (%) 62/566 (10.9)

n (%) with follow up available 48/62 (77.4)

Mean/median follow up, months 12.4/11.8

n (%) without clinical symptoms at follow up 34/48 (70.8)

Vs symptomatic PML

• Shorter time from suspicion of PML to diagnosis of PML

• More localized PML on brain MRI at the time of suspicion

• Higher % with unilobar lesions (60% vs 37%) • Less accrual disability overtime

Survival 95% asymptomatic vs 74% symptomatic

Death, n (%) 3/62 (5)

Update 4 June 2015 Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016.

PML outcomes – asymptomatic patients (compared to symptomatic patients, as of June 2015)


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

Objectives

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 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

PML Research at Biogen


Supporting information: Back-up slides


Cumulative PML risk over time for anti-JCV antibody positive patients stratified by prior IS

Physician Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI Therapy, V16 June 2016.

Healthcare

Tysabri benefit risk update Feb 2017