1) A clinical trial was designed to evaluate the efficacy and safety of clobazam for the orphan pediatric indication of Dravet syndrome. 2) Challenges included a lack of dosing data in young children, capturing baseline seizure frequency variability, and conducting a placebo-controlled trial when clobazam was already available. 3) Pharmacokinetic modeling was used to determine appropriate dosing and sample sizes to supplement limited data, and regulatory and external input helped address challenges.

1. STRATEGIES FOR MAXIMIZING PEDIATRIC STUDIES:
ORPHAN INDICATIONS
Deborah Lee, MD,PhD, Sr. Medical Director, Clinical Affairs, Lundbeck, USA
Evolution summit: best practices in north american clinical trials, May 6-8, 2015,Evolution summit: best practices in north american clinical trials, May 6 8, 2015,
Palm Beach, Florida

2. DisclaimerDisclaimer
Dr. Lee is an employee of Lundbeck. The information provided here is based on her
opinion and expertise and does not necessarily represent Lundbeck.
Information presented is for a clinical trial for clobazam in Dravet syndrome. This is a
non-approved indication and considered off-labeled use by FDA.
2

3. AgendaAgenda
Opportunities and Challenges for Orphan Indications in Life Cycle
Management (LCM)
Example: Dravet Syndrome and Clobazam
3

4. Opportunities and Challenges for
Orphan Indications in LCMOrphan Indications in LCM
4

5. Opportunities for studies in pediatric
orphan indicationsorphan indications
May be part of a company's commitment to unmet need
LCM may be the first opportunity for a pediatric orphan indication after approval for ay pp y p p pp
non-orphan indication in adults, especially for new chemical entities
FDA has 2 routes for pediatric studies
PREA M b i d b h lth th iti t f P di t i R h E it A t (US)PREA: May be required by health authorities as part of Pediatric Research Equity Act (US)
NOT required if primary indication is orphan
BPCA:
May be beneficial to the company (pediatric exclusivity)- not required by FDA
No risk- no need to make commitment until final Written Request (WR) received
Trial done after product on market
May be a logical extension of previous indications
The primary indication may be an orphan indication, for example Lennox-Gastaut
syndrome and clobazam in the US
5

6. Advantages of conducting trials in
orphan indications as part of LCMorphan indications as part of LCM
May be easier to establish positive business case
There may also be cases where orphan indication trials are conducted asy p
part of the LCM when the primary indication was also an orphan indication
(Dravet and clobazam)
Does not need to be the same indication as initial approval
May be more real-world data regarding the effect of the drug on
others indications, including orphan indications
More safety data may be available, especially important in pediatric
trials
Prior data may allow for more flexibility (for example safety data)
Advocacy groups may be readily available to assist with study designy g p y y y g
and getting word out about the study
6

7. Challenges of conducting trials
as part of LCMas part of LCM
Drug is already on the market
Might be some experience with the drug in the orphan indicationg p g p
which may be a positive but could be considered a negative if drug is
adopted as standard of care with too little evidence (may make
indication trials difficult)
Interest from investigators may be lower
Less incentives for patients
Potential for independent investigator trials (IITs) which mayPotential for independent investigator trials (IITs) which may
cannibalize investigator participation
Other novel drugs may provide more interest/excitement
Trial may be considered unethical by some because of placebo andTrial may be considered unethical by some because of placebo and
belief of efficacy, even without sufficient evidence (lack of equipoise)
7

8. Example: Dravet syndrome
and clobazamand clobazam
8

9. Dravet syndrome and clobazamDravet syndrome and clobazam
A trial to study the efficacy of clobazam in Dravet syndrome
Indication NOT APPROVED in the US by FDA
9

10. Objective of the Onfi (clobazam)
LCM programLCM program
To address unmet needs-no approved drug in US for Dravet
syndrome
To evaluate the efficacy of clobazam in Dravet syndrome
To obtain Pediatric Exclusivity
10

11. Requirements of a US pediatric program
(BPCA)(BPCA)
Not required by FDA for orphan drugs
Occurs after drug approval: LCMg pp
Company can suggest program (Proposed Pediatric Study Request)
Must be in pediatrics
Must be approved by FDA (Written Request)Must be approved by FDA (Written Request)
Studies must be conducted and submitted 15 months prior to the end of
exclusivity
If sponsor conducts studies in compliance with Written Request, anspo so co ducts stud es co p a ce t tte equest, a
additional 6 months pediatric exclusivity will be granted.
Legal agreement
This is in addition to any and all existing patents and exclusivitiesy g
11

12. ClobazamClobazam
Approved in the US in the fall of 2011 for seizures associated with
Lennox-Gastaut Syndrome (LGS)
Orphan indication
For patients ≥ 2 years of age
Classic triad of:
Variety of seizures including drop attacks
Developmental delay
Slow spike and wave on EEGp
12

13. Clobazam pediatric exclusivity:
regulatory chronologyregulatory chronology
2012
16 MAR: Proposed Pediatric Study Request (PPSR) submitted: 1 PK study
29 JUN: FDA response: 4 studies (complex partial seizures in children)
31 AUG: Suggested epileptic encephalopathies
11 OCT: FDA response: 3 studies (Dravet Syndrome)
07 NOV: FDA teleconference: (confirmed Dravet Syndrome)07 NOV: FDA teleconference: (confirmed Dravet Syndrome)
2013
30 JAN: Resubmitted PPSR with Dravet Syndrome
26 SEP: Received final WR-confirmed only 2 studies requiredy q
07 NOV: Submitted Dose Modeling Report for dosing in patients under 2 years
2014
04 APR: Received final approval on protocol and SAP (protocol submitted to FDA
under SPA)under SPA)
2015
11 FEB: Received approval for Amendments
13

14. Summary of Written RequestSummary of Written Request
Study A: Randomized, double-blind study in Dravet Syndrome
N=54 patients, 1 to 16 yearsp , y
Placebo versus maximum dose 2mg/kg/d clobazam
Primary endpoint: % reduction from baseline in average seizure
raterate
Study B: Long-term open label safety study
May include patients from Study A
N 40 ti t t t lN=40 patients total
30 patients @ 6m still enrolled
20 patients @ 1y still enrolled
10% between ages 1-2 year
14

15. Dravet SyndromeDravet Syndrome
First described in 1978 “severe myoclonic epilepsy of infancy” by
Charlotte Dravet
Considered an epileptic encephalopathy
Epileptic activity contributes to severe cognitive/behavioral changes
ILAE classification (1989):ILAE classification (1989):
Febrile and afebrile generalized and unilateral, clonic or tonic-clonic,
seizures, that occur in the first year of life in an otherwise normal infant
and are later associated with myoclonus, atypical absences, and partial
seizures.
All seizure types are resistant to antiepileptic drugs (AEDs)
Developmental delay becomes apparent within the second year of life and
i f ll d b d fi it iti i i t d lit di dis followed by definite cognitive impairment and personality disorder.
15

16. Dravet SyndromeDravet Syndrome
Rare syndrome: approximately 1 per 20,000-40,000 children
With seizure onset before 1 year: 3-5%y %
With seizure onset prior to 3 years: 6-7%
Prevalence in the US in 2008 was between 2,000-8,000
Part of a spectrum: GEFS+ SMEB Dravet SyndromePart of a spectrum: GEFS+ → SMEB → Dravet Syndrome
Mortality due to Dravet syndrome estimated to be 15% by
adulthood compared to other chronic epilepsies (5%)
20.8% died by early 30s
16% died at a mean age of 11
Older: SUDEP
Younger: Status epilepticus
16

17. Dravet Syndrome-cont.Dravet Syndrome cont.
Pathology: SCN1A mutation found in 70-80% of cases of Dravet
syndrome: other mutations include SCN1B, PCDH19, GABABR,
others
Treatment:
Usual: valproate, clobazam, topiramate, stiripentolp , , p , p
Sodium channel blockers can make seizures worse
Cannabinoids?
17

18. Why did a trial in Dravet Syndrome
spark interest?spark interest?
Only one RCT published
Chiron et al: Lancet 2000;356:1638;
All Dravet patients already on clobazam and valproate
In addition to clobazam and valproate, one half of the patients received
stiripentol while the other half received placebo
% responders:
73% stiripentol arm
5% placebo armp
Concern: Stiripentol inhibits metabolism of clobazam
Question: Was the response due to the addition of stiripentol, increased
clobazam and N-clobazam levels or a combination of both?
Result:
Approval for stiripentol in the EU
Not approved in the USpp
18

19. Challenges faced in designing this trial:
Use of pharmacokinetic modeling for dosingUse of pharmacokinetic modeling for dosing
No clobazam dosing information available for children < 2
Two-compartment linear PK model with first order absorptionp p
Used data from previous trials in children and adults to predict appropriate
dose- commonalities between LGS and Dravet Syndrome allowed for
ability to move forward without PK Phase I trial
Model allows for maturation of CYP system
19

20. Challenges faced in designing this trial:
Use of pharmacokinetic modeling for efficacyUse of pharmacokinetic modeling for efficacy
How to determine sample size?
Assumed ½ of the effect size seen in the stiripentol trial was due top
stiripentol and the other ½ due to increased clobazam levels.
Power: 85%
Clobazam is available
Dravet Syndrome is a rare disease
Developed exposure-response modeling as supportive evidence of
efficacy
Sophisticated modelling allows ability to utilize minimal data to
demonstrate
Needed to be modelled before hand to predict when to draw samples!
20

21. Challenges faced in designing this
trial cont. 1trial cont. 1
How to match exposure levels seen in the stiripentol trial in naïve
patients (i.e. 2mg/kg/day)?
Titrate too fast and decreased tolerability
Titrate too slow and time on placebo is too long
How to capture baseline seizure frequency when young patients willp q y y g p
have less frequent but more severe seizures while older patients will
have more frequent, less severe seizures?
How to conduct a placebo-controlled trial when clobazam isp
available?
How long will patients remain in the trial (especially placebo arm)?
Clobazam will be adjunctive treatment in the trial but usually first orj y
second choice for Dravet syndrome
How to complete long-term safety study with enough patients in
appropriate timelines given?
21

22. Challenges faced in designing this trial
cont. 2cont. 2
How to keep patients from taking 1 dose of blinded drug in the
efficacy trial and then enrolling into the open label study?
How to transition patients from Study A to Study B?
Some patients will be naïve
Some patients will be on very high doses of clobazamp y g
22

23. Protocol development (external
contributors)contributors)
FDA
2 advisory boardsy
Patient advocacy groups
Steering Committee: 5 pediatric neurologists and 1 patient advocate
Important to have a lot of input but need to control the process
23

24. B li Tit ti
Maintenance
M i t BS i
Study 14362A
Baseline Titration A Maintenance B
2 OR 4
weeks
4 weeks 4 weeks1
8 weeks
1.5 mg/kg/day 1.5-2 mg/kg/day
Screening
(max 60 mg)
g g y
(max 80 mg)
LTOLSS4
R
Taper
Period5:
5 10
Placebo Placebo
D Week
5-10
mg/week
Day
1 Titration period: week 1: 0.25mg/kg/day (max 10mg/day); week 2: 0.5mg/kg/day (max 20mg/day); week 3: 1.0mg/kg/day
(max 40mg/day); week 4: 1.5mg/kg/day (max 60mg/day). All dose adjustments will be done at either scheduled or unscheduled visits.
2 If <2 seizures in 2-week baseline period, may increase baseline period to 4 weeks
Day
-28 to 0 2
Week
0
Week
4
Week
8 3
Week
16 or
End of Study/Stable Dose
Week
12
Day
42 to
-15
3 For patients demonstrating inadequate response to treatment , the investigator may consider increasing the patient’s dose.
4 Long Term Open Label Safety Study
5 For patients tapering off drug only
24

25. Sample assessmentsSample assessments
Seizure diary (all seizure types)
24hr-video EEG (for myoclonic/ atypical absence seizures which can( y yp
be difficult to detect by parent/caregiver; requested by FDA)
Global evaluation-parent/caregiver and physician ( 7 point Likert
scale))
C-SSRS
Vineland Adaptive Behavioral Scale
Gene testingGene testing
25

26. Primary stopping/ withdrawal criteriaPrimary stopping/ withdrawal criteria
Required by FDA
Developed with input from Steering Committee
100% increase in seizure frequency compared to baseline as
determined by investigator
Serious or severe AE that was considered related and impact riskp
Serious non-compliance (e.g. missing > 50% of doses, not
returning IMP, missing doses, as determined by investigator)
Patient did not tolerate at least 1 mg/kg/day when completingPatient did not tolerate at least 1 mg/kg/day when completing
titration period
For enrollment into LTOLSS
Complete at least 8 weeks in A trial (4 week titration plus 4 weeksComplete at least 8 weeks in A trial (4 week titration plus 4 weeks
maintenance
Meet the 100% increase in seizure frequency stopping criteria
NO severe or serious related adverse eventNO severe or serious related adverse event
26

27. Study 14362B
Screening1 Open-label, flexible-dose Treatment Period4
2
weeks
2 days
Starting
dose2,3
52 weeks
Baseline1
Continue on
commercialcommercial
product
Taper
Period:
5-10
mg/week
Day
28 t 0
Wk
5
Wk
12 5
Wk
52 or
Wk
36 5
Day
2
Day
12 3
Wk
85
Wk 24
5
Day
14 to 0
mg/week
1Only for patients who did not participate in lead-in Study 14362A
2Start at 0.5mg/kg/d for 48 hours
3Patients who did not participate in study 14362A will enter on current prescribed clobazam dose
4Doses may be adjusted throughout the trial. All dose adjustments will be made at a scheduled or unscheduled visits
5D il S i Di i ill b k t f th 30 d ft th i it
-28 to 0
5,6
45 12 5 52 or
End of Study 6,7
36 5212,3 85 5-14 to 0
5,6
5Daily Seizure Diaries will be kept for the 30 days after the visit
6Daily seizure diary will be kept for 30 days PRIOR to visit
7Except for patients tapering off medication
27

28. Patient Disposition: Study 14362BPatient Disposition: Study 14362B
Lead-in
St dStudy
14362A Assess number
of patients in LTOLSS; if inadequate, can enroll
patients already on clobazam
Study
14362B
Dravet
patients
already14362B
(screening)
already
prescribed
clobazam
Study
14362B
1 year
28
1 year
LTOLSS

29. ConclusionConclusion
Clinical trials during LCM can be challenging especially in orphan pediatric
indications
S f th diffi lti b b th i t f PK/PDSome of the difficulties can be overcome by the appropriate use of PK/PD
modeling
Dosing: Modelling may be able to substitute for Phase 1
Support efficacy (exposure response): Must be preplanned so that PKSupport efficacy (exposure-response): Must be preplanned so that PK
draws are done at the appropriate time
Important to identify risks to timelines in advance
Direct enrollment of a limited number of patients into LTOLSS to ensureDirect enrollment of a limited number of patients into LTOLSS to ensure
sufficient exposure data
When designing a trial, it is important to solicit guidance from expert
practitioners but also patient advocacy groups.
This is important for placebo-controlled trials in pediatric orphan
indications, especially when the drug is commercially available.
They can provide advice that can important to regulatory agencies,
h i i d hphysicians and other parents
29