Tecfidera FAQ Long Version

Tecfidera™ (dimethyl fumarate):
SPEAKER TRAINING
CONFIDENTIAL. FOR TRAINING PURPOSE ONLY. NOT TO BE COPIED, MODIFIED OR DISSEMINATED. DMF-1001771
Tecfidera™ (dimethyl fumarate)
Frequently Asked Questions
For Your Instruction:
• We are providing this information to you solely for background purposes to

better prepare you to respond reactively to what we believe will be
common unsolicited inquiries about Tecfidera (dimethyl fumarate) you will
receive. (Recall, as part of today’s training, we will explain to you the
process for responding to unsolicited off-label inquiries about Tecfidera you
receive.)
• Please keep in mind that the only information you are able to proactively
present as part of our Tecfidera speaker program is information that is
contained in the promotional deck
• If you have any questions, please see a Biogen Idec representative

for guidance
Back-Up FAQ Slides
Tecfidera (dimethyl fumarate) Mechanism of Action

What is the proposed mechanism of action of Tecfidera?
What is the Nrf2 pathway and what does it do?
Phase 3 Study Design

What MS diagnostic criteria was used in DEFINE and CONFIRM?
How was relapse defined in DEFINE and CONFIRM?
How were relapses analyzed in the clinical trials?
Why have an Independent Neurology Evaluation Committee (INEC)?
What are the key differences in study design between DEFINE and CONFIRM?
How and when was rescue therapy available to patients who met the relapse or disability
progression criteria?
What was the study definition of discontinuation vs withdrawal?
How were discontinuations handled when analyzing efficacy endpoints?
Why was there an MRI subset?
Back-Up FAQ Slides, cont.
DEFINE
Why did DEFINE and CONFIRM have different primary endpoints?
How was compliance assessed in DEFINE and CONFIRM?
Why wasn’t a direct comparison between Tecfidera doses performed?
How does the efficacy observed in DEFINE and CONFIRM compare with that of currently
approved disease-modifying therapies?
Why was disability progression with Tecfidera (dimethyl fumarate) statistically significant in
DEFINE, but not in CONFIRM?
CONFIRM
What can you conclude about the relative efficacy of Tecfidera compared with the open-label
comparator?
Why was a superiority analysis vs the open-label comparator arm NOT part of the CONFIRM
study?
Back-Up FAQ Slides, cont.
Safety and Tolerability

Did the studies address unblinding due to the flushing side effect, which was known for
Tecfidera?
How can I advise my patients on the management of flushing and/or GI side effects while on
Tecfidera?
Was there any renal toxicity/irreversible renal dysfunction?
What was the rate of low lymphocyte counts in Tecfidera vs placebo treated patients?
Was there any evidence of liver toxicity?
What is the proposed mechanism of action
of Tecfidera (dimethyl fumarate)?
Tecfidera (dimethyl fumarate)
Mechanism of Action
• The mechanism by which Tecfidera exerts therapeutic effects
in multiple sclerosis is unknown
• Dimethyl fumarate and the metabolite, monomethyl fumarate
(MMF), have been shown to activate the Nuclear factor
(erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo
in animals and humans
• The Nrf2 pathway is involved in the cellular response to
oxidative stress
• MMF has been identified as a nicotinic acid receptor agonist in
vitro
◄ Return to Table of Contents
Tecfidera Prescribing Information, Biogen Idec Inc., Cambridge, MA.
8
What is the Nrf2 pathway and
what does it do?
The Nrf2 pathway is Involved in the Cellular
Response to Oxidative Stress
Oxidative
stress2,3
1 Under normal conditions,
Nrf2 is sequestered in
the cytoplasm via Keap11
2 Oxidative stress causes
Nrf2 Nrf2 to translocate to the
Keap1 nucleus1
3 Nrf2 activates phase 2
antioxidant response1
Phase 2
Nucleus Antioxidant Response2,3
Cytoplasm
The mechanism by which dimethyl

fumarate (DMF) exerts its therapeutic
effect in multiple sclerosis is unknown.
1. Tecfidera Prescribing Information, Biogen Idec Inc., Cambridge, MA.
2. van Horssen J, et al. Biochim Biophys Acta. 2011;1812:141-150. ◄ Return to Table of Contents
3. Nguyen T, et al. J Biol Chem. 2009;284:13291-13295.
10
What MS diagnostic criteria was used in
DEFINE and CONFIRM?
11
The 2005 McDonald Criteria1-3
Clinical Presentation Additional Data Needed for MS Diagnosis

2 or more relapses and objective
None
clinical evidence of 2 or more lesions
Dissemination in space by MRI or positive CSF and
2 or more relapses and 1 objective
2 or more MRI lesions consistent with MS or further
lesion
clinical attack involving a different site
1 relapse and 2 or more objective
Dissemination in time by MRI or second clinical attack
lesions
Dissemination in space by MRI or positive CSF and 2
1 (mono-symptomatic) relapse and
or more MRI lesions consistent with MS, and
1 objective lesion
dissemination in time by MRI or second clinical attack
MRI=magnetic resonance imaging ; CSF=cerebrospinal fluid (analysis performed by a spinal tap)

1. Polman CH et al. Ann Neurol. 2005;58:840-846.
2. Gold R, et al. N Engl J Med. 2012;367:1098-1107.
3. Fox RJ, et al. N Engl J Med. 2012;367:1087-1097.
12
How were relapses defined in DEFINE and
CONFIRM?
13
Relapse Definitions1,2
• Relapse is defined as new or recurrent neurologic symptoms that

– Are not associated with fever or infection
– Last at least 24 hours
– Are accompanied by new, objective neurological findings upon
examination by the examining neurologist
• New or recurrent neurologic symptoms that occurred fewer than

30 days following the onset of a relapse were to be considered part
of the same relapse
• New or recurrent neurologic symptoms that evolved gradually over

months were to be considered disease progression, not an acute
relapse
1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. ◄ Return to Table of Contents
14
How were relapses analyzed in the clinical
trials?
15
Relapse Measurement1,2
• “Proportion of patients who relapsed at 2 years” = the

proportion of patients who experienced at least one relapse
during the study
• “Annualized Relapse Rate (ARR)” = the total number of
relapses of all patients in each group divided by the total
number of patient-years of observation

16
Why have an Independent Neurology
Evaluation Committee (INEC)?
17
The Independent Neurology Evaluation
Committee (INEC) 1,2
• The INEC provided consistent, independent, blinded determinations of
relapse occurrence
– The INEC included neurologists with expertise in MS
– INEC members were not permitted to be investigators
– Members were assigned on a rotating basis so that different

combinations of members were participating at any given time
• The INEC was a critical component of CONFIRM, where the open-

label comparator arm was not investigator-blinded
• Use of the INEC for both DEFINE and CONFIRM allowed consistent
evaluation of relapses across both studies

18
What are the key differences in study design
between DEFINE and CONFIRM?
19
DEFINE and CONFIRM: Important Differences
Trial Characteristic DEFINE1 CONFIRM2

Tecfidera vs placebo
Tecfidera (dimethyl
Comparisons and the open-label
fumarate) vs placebo
comparator vs placebo
Proportion of patients Annualized relapse rate
Primary endpoint
relapsed at 2 years at 2 years
48 weeks in the study
48 weeks in the study
and 1 or more relapses
and 2 relapse events at
Rescue therapy criteria after 24 weeks OR
any time OR disability
disability progression at
progression at any time
any time
Prior treatment with
Yes, if >3 months prior to
glatiramer acetate/open-label No
study entry
comparator allowed?

20
How and when was rescue therapy available
to patients who met the relapse or disability
progression criteria?
21
Rescue Therapy in DEFINE
• Rescue therapy was available to subjects on blinded study

treatment who experienced either
– an INEC-confirmed relapse at or after week 24 and had
completed 48 weeks on therapy, OR
– protocol-defined disability progression at any time
• Open-label treatment with an approved open-label MS therapy
was permitted
Gold R, et al. N Engl J Med. 2012;367:1098-1107.

22
Rescue Therapy in DEFINE
Percentage of Patients Who Switched to Rescue Therapy
14 13%
Percentage of Patients
12
10
8
6%
6
4
2
0
Placebo Tecfidera
(dimethyl fumarate)
Gold R, et al. N Engl J Med. 2012;367:1098-1107.
23
Rescue Therapy in CONFIRM
• Rescue therapy was available to subjects on blinded study

treatment who experienced either
– 2 INEC-confirmed relapses at any time and had completed
48 weeks on therapy, OR
– protocol-defined disability progression at any time
• Open-label treatment with an approved MS therapy was
permitted
Fox RJ, et al. N Engl J Med. 2012;367:1087-1097.

24
Rescue Therapy in CONFIRM
Percentage of Patients Who Switched to Rescue Therapy
12 11%
Percentage of Patients
10
8 7%
6
0
Placebo Tecfidera
(dimethyl fumarate)
Fox RJ, et al. N Engl J Med. 2012;367:1087-1097. ◄ Return to Table of Contents
25
What was the study definition of
discontinuation vs withdrawal?
26
Discontinuation vs Withdrawal1,2
Discontinuation Discontinues Drug Withdrawal

of Study Drug = but Remains in Study + from Study
The patient permanently The patient discontinues drug The patient is no longer
stops taking his or her but remains in study and part of the study and
randomized treatment follow-up continues follow-up stops
• Discontinuation of study drug is a SUM of

– the patients who discontinued study drug but remain in the study (e.g., went on rescue
medication)
– the patients who withdraw from the study
1. Gold R, et al. N Engl J Med. 2012;367:S1-21. ◄ Return to Table of Contents

2. Fox RJ, et al. N Engl J Med. 2012;367:S1-27.
27
How were discontinuations handled when
analyzing efficacy endpoints?
28
Discontinuations and Efficacy Calculations1,2
• Patients who discontinued drug remained in all relapse and EDSS analyses
– Analyses were conducted on the intention-to-treat (ITT) population, defined as

all patients who were randomized to treatment and received at least one dose
of study treatment
• For patients who withdrew from the study or received rescue therapy, only data after
subject withdrawal or medication switch were excluded; there was no imputation of
clinical data
– This allowed an accurate estimation of the treatment effect of Tecfidera

(dimethyl fumarate) without influence by alternative MS medication
• For MRI endpoints, analysis was additionally based on missing data imputed with
the use of a constant-rate assumption
EDSS= Expanded Disability Status Scale.

29
Why was there an MRI subset?
30
The MRI Cohort1,2
• The MRI cohort represented those sites where

– the required MRI capabilities existed
– the number of patients necessary to provide adequate
power for the MRI endpoints were seen
• Even though a subset of patients were used, the study was
sufficiently powered to examine the on-label MRI endpoints

31
Why did DEFINE and CONFIRM have
different primary endpoints?
32
Primary Endpoints in DEFINE and CONFIRM
DEFINE1 CONFIRM2
• Primary Endpoint: Proportion of • Primary Endpoint: Annualized relapse
patients relapsed at 2 years rate (ARR) at 2 years
• Secondary Endpoint: Annualized • Secondary Endpoint: Proportion of

relapse rate (ARR) at 2 years patients relapsed at 2 years
Primary endpoints in both studies were measured by two

different, clinically-meaningful, and complementary
assessments of disease relapse
33
How was compliance assessed in
DEFINE and CONFIRM?
34
Compliance in DEFINE
• Compliance was assessed through capsule counts

• Mean compliance was calculated based on the duration of
exposure, from first to last dose taken
Placebo Tecfidera
(dimethyl fumarate)
Mean Compliance 92.7% 87.5%
Data on file, Biogen Idec.

35
Compliance in CONFIRM
• Compliance was assessed through capsule counts

• Mean compliance was calculated based on the duration of
exposure, from first to last dose taken
Placebo Tecfidera
(dimethyl fumarate)
Mean Compliance 94% 91%

Data on file, Biogen Idec.
36
Why wasn’t a direct comparison between
Tecfidera (dimethyl fumarate) doses
performed?
37
Tecfidera (dimethyl fumarate)
Dose Comparisons1,2
• Trials were designed to compare each of the 2 active
treatment groups with placebo and powered accordingly
• Studies were not powered for the head-to-head comparison
between the two doses of Tecfidera
• The 240mg TID dose showed no additional benefit over the
Tecfidera 240mg BID dose

38
How does the efficacy observed in DEFINE
and CONFIRM compare with that of currently
approved disease-modifying therapies?
39
Tecfidera (dimethyl fumarate) Efficacy vs Currently
Approved Disease-Modifying Therapies (DMTs)
• Pivotal studies with other DMTs vary in their designs and trial
populations
• Valid comparisons cannot be made across these trials
40
Why was disability progression with
Tecfidera (dimethyl fumarate) statistically
significant in DEFINE, but not in CONFIRM?
41
Disability Progression with Tecfidera
(dimethyl fumarate) in DEFINE and CONFIRM
• Biogen Idec was extremely encouraged by the statistically significant result in the DEFINE trial
and interested in the event rate in the placebo arm in CONFIRM
DEFINE CONFIRM
38% 21%
Relative Relative
Proportion with Confirmed
30 27% reduction in the 30 reduction in the

Disability Progression
risk of disability risk of disability

at 2 years vs at 2 years vs
placebo placebo
20 P = 0.0050 20 17% P = 0.25
16%
13%
10 10
0 0
Placebo Tecfidera Placebo Tecfidera
(dimethyl fumarate) (dimethyl fumarate)

42
What can you conclude about the relative
efficacy of Tecfidera (dimethyl fumarate) vs
the open-label comparator?
43
CONFIRM: Tecfidera (dimethyl fumarate) vs
Open-Label Comparator
• The study was not designed to test the superiority or non-
inferiority of Tecfidera compared to the open-label comparator
arm

Fox RJ, et al. N Engl J Med. 2012;367:1087-1097.
44
Why was a superiority analysis versus the
open-label comparator arm NOT part of the
CONFIRM study?
45
Comparison With Open-Label Comparator
as a Primary Endpoint in CONFIRM
• The open-label comparator arm was included in the trial to
satisfy EU regulatory requirements1
• Based on the results of the Phase 2 study with Tecfidera
(dimethyl fumarate),2 in order for the trial to be powered for
superiority vs the open-label comparator, a much larger trial
would have been required (several thousand participants),
which was not feasible or necessary at the time
1. Fox RJ, et al. N Engl J Med. 2012;367:1087-1097. ◄ Return to Table of Contents

2. Kappos L, et al. Mult Scler. 2012;18:314-21.
46
Did the studies address unblinding due to
the flushing side effect, which was known
to be a common effect of Tecfidera (dimethyl
fumarate)?
47
Flushing and Unblinding1,2
• To ensure that study-group assignments would not be

revealed
– Patients were instructed to take the assigned study drug at
least 4 hours before study visits in case patients in the
Tecfidera groups had a side effect of flushing
– Each study site used separate examining and treating
neurologists, thereby maintaining rater blinding for all study
groups

48
How can I advise my patients on the
management of flushing and/or GI side
effects while on Tecfidera (dimethyl
fumarate)?
49
Patient Counseling on
Flushing and GI Reactions
• Advise patients to contact their healthcare providers if they
experience persistent and/or severe flushing or gastrointestinal
reactions, as taking Tecfidera (dimethyl fumarate) with food
may help

50
Was there any renal toxicity or
irreversible renal dysfunction?
51
Renal Toxicity and Irreversible
Renal Dysfunction in Clinical Trials
• No studies have been conducted in subjects with renal impairment1
• However, renal impairment would not be expected to affect exposure to MMF and
therefore no dosage adjustment is necessary1
• Tecfidera (dimethyl fumarate) did not increase the risk of renal adverse events, nor
were there any renal failure incident2,3
• There were no clinically meaningful differences in BUN or creatinine measures

between Tecfidera and placebo2,3
• "albumin urine present" was reported as an adverse event in 6% of Tecfidera

patients vs 4% on placebo1
• Kidney toxicity was observed after repeated oral administration of dimethyl fumarate
in mice, rats, dogs, and monkeys1
BUN= Blood Urea Nitrogen test
1. Tecfidera Prescribing Information, Biogen Idec Inc., Cambridge, MA.
52
What was the rate of low lymphocyte counts
in Tecfidera (dimethyl fumarate) vs placebo
treated patients?
53
Lymphocyte Counts
Tecfidera
Placebo
(dimethyl fumarate)
Subjects with low lymphocyte <1 6
counts (<0.5x109/L), %
• In clinical trials, mean lymphocyte counts decreased by

approximately 30% during the first year of treatment with
Tecfidera and then remained stable
• Four weeks after stopping Tecfidera, mean lymphocyte counts
increased but did not return to baseline

54
Was there any evidence of liver toxicity?
55
Hepatic Transaminases in Clinical Trials
• An increased incidence of elevations of hepatic transaminases in patients treated
with Tecfidera (dimethyl fumarate) was seen primarily during the first six months of
treatment, and most patients with elevations had levels < 3 times the upper limit of
normal (ULN)
• Elevations of alanine aminotransferase and aspartate aminotransferase to ≥3 times
the ULN occurred in a small number of patients treated with both Tecfidera and
placebo and were balanced between groups
• There were no elevations in transaminases ≥3 times the ULN with concomitant
elevations in total bilirubin >2 times the ULN
• Discontinuations due to elevated hepatic transaminases were <1% and were similar
in patients treated with Tecfidera or placebo
Tecfidera Prescribing Information, Biogen Idec Inc., Cambridge, MA. ◄ Return to Table of Contents
56

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Tecfidera™ (dimethyl fumarate):

• We are providing this information to you solely for background purposes to

• If you have any questions, please see a Biogen Idec representative

Tecfidera (dimethyl fumarate) Mechanism of Action

Phase 3 Study Design

Safety and Tolerability

The mechanism by which dimethyl

Clinical Presentation Additional Data Needed for MS Diagnosis

MRI=magnetic resonance imaging ; CSF=cerebrospinal fluid (analysis performed by a spinal tap)

• Relapse is defined as new or recurrent neurologic symptoms that

• New or recurrent neurologic symptoms that occurred fewer than

• New or recurrent neurologic symptoms that evolved gradually over

• “Proportion of patients who relapsed at 2 years” = the

1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. ◄ Return to Table of Contents

– The INEC included neurologists with expertise in MS

– INEC members were not permitted to be investigators

– Members were assigned on a rotating basis so that different

• The INEC was a critical component of CONFIRM, where the open-

1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. ◄ Return to Table of Contents

Trial Characteristic DEFINE1 CONFIRM2

1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. ◄ Return to Table of Contents

• Rescue therapy was available to subjects on blinded study

Gold R, et al. N Engl J Med. 2012;367:1098-1107.

Percentage of Patients Who Switched to Rescue Therapy

Gold R, et al. N Engl J Med. 2012;367:1098-1107.

• Rescue therapy was available to subjects on blinded study

Fox RJ, et al. N Engl J Med. 2012;367:1087-1097.

Percentage of Patients Who Switched to Rescue Therapy

Fox RJ, et al. N Engl J Med. 2012;367:1087-1097. ◄ Return to Table of Contents

Discontinuation Discontinues Drug Withdrawal

• Discontinuation of study drug is a SUM of

1. Gold R, et al. N Engl J Med. 2012;367:S1-21. ◄ Return to Table of Contents

– Analyses were conducted on the intention-to-treat (ITT) population, defined as

– This allowed an accurate estimation of the treatment effect of Tecfidera

EDSS= Expanded Disability Status Scale.

• The MRI cohort represented those sites where

1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. ◄ Return to Table of Contents

• Secondary Endpoint: Annualized • Secondary Endpoint: Proportion of

Primary endpoints in both studies were measured by two

• Compliance was assessed through capsule counts

Data on file, Biogen Idec.

• Compliance was assessed through capsule counts

◄ Return to Table of Contents

1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. ◄ Return to Table of Contents

◄ Return to Table of Contents

30 27% reduction in the 30 reduction in the

risk of disability risk of disability

◄ Return to Table of Contents

◄ Return to Table of Contents

1. Fox RJ, et al. N Engl J Med. 2012;367:1087-1097. ◄ Return to Table of Contents

• To ensure that study-group assignments would not be

1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. ◄ Return to Table of Contents

◄ Return to Table of Contents

• There were no clinically meaningful differences in BUN or creatinine measures

• "albumin urine present" was reported as an adverse event in 6% of Tecfidera

• In clinical trials, mean lymphocyte counts decreased by

◄ Return to Table of Contents

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