STRATEGIES FOR MAXIMIZING PEDIATRIC STUDIES: ORPHAN INDICATIONSDeborah 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

DisclaimerDisclaimerDr. 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

AgendaAgenda

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

3

Opportunities and Challenges for Orphan Indications in LCMOrphan Indications in LCM

4

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 a y pp y p p ppnon-orphan indication in adults, especially for new chemical entities

FDA has 2 routes for pediatric studiesPREA 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) receivedTrial done after product on market

May be a logical extension of previous indicationsThe primary indication may be an orphan indication, for example Lennox-Gastaut syndrome and clobazam in the US

5

Advantages of conducting trials in orphan indications as part of LCMorphan indications as part of LCM

May be easier to establish positive business caseThere may also be cases where orphan indication trials are conducted as y ppart 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 indicationsMore safety data may be available, especially important in pediatric trialsPrior data may allow for more flexibility (for example safety data)Advocacy groups may be readily available to assist with study design y g p y y y gand getting word out about the study

6

Challenges of conducting trials as part of LCMas part of LCM

Drug is already on the marketMight be some experience with the drug in the orphan indication g p g pwhich 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 patientsPotential for independent investigator trials (IITs) which mayPotential for independent investigator trials (IITs) which may cannibalize investigator participationOther novel drugs may provide more interest/excitementTrial 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

Example: Dravet syndrome and clobazamand clobazam

8

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

Objective of the Onfi (clobazam) LCM programLCM program

To address unmet needs-no approved drug in US for Dravet syndromeTo evaluate the efficacy of clobazam in Dravet syndromeTo obtain Pediatric Exclusivity

10

Requirements of a US pediatric program(BPCA)(BPCA)

Not required by FDA for orphan drugsOccurs after drug approval: LCMg ppCompany can suggest program (Proposed Pediatric Study Request)

Must be in pediatricsMust 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 exclusivityIf sponsor conducts studies in compliance with Written Request, an spo so co ducts stud es co p a ce t tte equest, aadditional 6 months pediatric exclusivity will be granted.

Legal agreementThis is in addition to any and all existing patents and exclusivitiesy g

11

ClobazamClobazam

Approved in the US in the fall of 2011 for seizures associated with Lennox-Gastaut Syndrome (LGS)

Orphan indicationFor patients ≥ 2 years of ageClassic triad of:

Variety of seizures including drop attacksDevelopmental delaySlow spike and wave on EEG p

12

Clobazam pediatric exclusivity: regulatory chronologyregulatory chronology

201216 MAR: Proposed Pediatric Study Request (PPSR) submitted: 1 PK study29 JUN: FDA response: 4 studies (complex partial seizures in children)31 AUG: Suggested epileptic encephalopathies11 OCT: FDA response: 3 studies (Dravet Syndrome)07 NOV: FDA teleconference: (confirmed Dravet Syndrome)07 NOV: FDA teleconference: (confirmed Dravet Syndrome)

201330 JAN: Resubmitted PPSR with Dravet Syndrome26 SEP: Received final WR-confirmed only 2 studies requiredy q07 NOV: Submitted Dose Modeling Report for dosing in patients under 2 years

201404 APR: Received final approval on protocol and SAP (protocol submitted to FDA under SPA)under SPA)

201511 FEB: Received approval for Amendments

13

Summary of Written RequestSummary of Written Request

Study A: Randomized, double-blind study in Dravet SyndromeN=54 patients, 1 to 16 yearsp , yPlacebo versus maximum dose 2mg/kg/d clobazamPrimary endpoint: % reduction from baseline in average seizure raterate

Study B: Long-term open label safety studyMay include patients from Study AN 40 ti t t t lN=40 patients total

30 patients @ 6m still enrolled20 patients @ 1y still enrolled10% between ages 1-2 year

14

Dravet SyndromeDravet Syndrome

First described in 1978 “severe myoclonic epilepsy of infancy” by Charlotte DravetConsidered an epileptic encephalopathy

Epileptic activity contributes to severe cognitive/behavioral changesILAE 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

Dravet SyndromeDravet Syndrome

Rare syndrome: approximately 1 per 20,000-40,000 childrenWith 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 2,000-8,000Part of a spectrum: GEFS+ SMEB Dravet SyndromePart of a spectrum: GEFS+ → SMEB → Dravet SyndromeMortality due to Dravet syndrome estimated to be 15% by adulthood compared to other chronic epilepsies (5%)

20.8% died by early 30s16% died at a mean age of 11Older: SUDEPYounger: Status epilepticus

16

Dravet Syndrome-cont.Dravet Syndrome cont.

Pathology: SCN1A mutation found in 70-80% of cases of Dravet syndrome: other mutations include SCN1B, PCDH19, GABABR, othersTreatment:

Usual: valproate, clobazam, topiramate, stiripentol p , , p , pSodium channel blockers can make seizures worseCannabinoids?

17

Why did a trial in Dravet Syndrome spark interest?spark interest?

Only one RCT publishedChiron et al: Lancet 2000;356:1638;

All Dravet patients already on clobazam and valproateIn addition to clobazam and valproate, one half of the patients received stiripentol while the other half received placebo % responders:

73% stiripentol arm5% placebo armp

Concern: Stiripentol inhibits metabolism of clobazamQuestion: 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 EUNot approved in the USpp

18

Challenges faced in designing this trial:Use of pharmacokinetic modeling for dosingUse of pharmacokinetic modeling for dosing

No clobazam dosing information available for children < 2Two-compartment linear PK model with first order absorptionp pUsed 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 trialModel allows for maturation of CYP system

19

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 to pstiripentol 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 efficacySophisticated modelling allows ability to utilize minimal data to demonstrateNeeded to be modelled before hand to predict when to draw samples!

20

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 tolerabilityTitrate too slow and time on placebo is too long

How to capture baseline seizure frequency when young patients will p q y y g phave 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 is pavailable?

How long will patients remain in the trial (especially placebo arm)?Clobazam will be adjunctive treatment in the trial but usually first or j ysecond choice for Dravet syndrome

How to complete long-term safety study with enough patients in appropriate timelines given?

21

Challenges faced in designing this trialcont. 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

Protocol development (external contributors)contributors)

FDA2 advisory boardsyPatient advocacy groupsSteering Committee: 5 pediatric neurologists and 1 patient advocate

Important to have a lot of input but need to control the process

23

B li Tit tiMaintenance

M i t BS i

Study 14362ABaseline 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

TaperPeriod5:5 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 DoseWeek

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 Study5 For patients tapering off drug only

24

Sample assessmentsSample assessments

Seizure diary (all seizure types)24hr-video EEG (for myoclonic/ atypical absence seizures which can ( y ypbe difficult to detect by parent/caregiver; requested by FDA)Global evaluation-parent/caregiver and physician ( 7 point Likert scale))C-SSRSVineland Adaptive Behavioral ScaleGene testingGene testing

25

Primary stopping/ withdrawal criteriaPrimary stopping/ withdrawal criteriaRequired by FDADeveloped with input from Steering Committee

100% increase in seizure frequency compared to baseline as determined by investigatorSerious or severe AE that was considered related and impact riskpSerious 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 LTOLSSComplete 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 maintenanceMeet the 100% increase in seizure frequency stopping criteriaNO severe or serious related adverse eventNO severe or serious related adverse event

26

Study 14362BScreening1 Open-label, flexible-dose Treatment Period4

2 weeks

2 days

Starting dose2,3

52 weeks

Baseline1

Continue oncommercialcommercial

product

TaperPeriod:5-10

mg/week

Day28 t 0

Wk 5

Wk 12 5

Wk 52 or

Wk 36 5

Day2

Day 12 3

Wk 85

Wk 24 5

Day14 to 0

mg/week

1Only for patients who did not participate in lead-in Study 14362A2Start at 0.5mg/kg/d for 48 hours3Patients who did not participate in study 14362A will enter on current prescribed clobazam dose4Doses may be adjusted throughout the trial. All dose adjustments will be made at a scheduled or unscheduled visits5D 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 6,736 5212,3 85 5-14 to 0 5,6

5Daily Seizure Diaries will be kept for the 30 days after the visit6Daily seizure diary will be kept for 30 days PRIOR to visit7Except for patients tapering off medication27

Patient Disposition: Study 14362BPatient Disposition: Study 14362B

Lead-in St dStudy

14362A Assess numberof patients in LTOLSS; if inadequate, can enrollpatients already on clobazam

Study14362B

Dravet patients already14362B

(screening)already

prescribed clobazam

Study14362B1 year

28

1 year LTOLSS

ConclusionConclusionClinical trials during LCM can be challenging especially in orphan pediatric indicationsS 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 1Support 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 advanceDirect 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