NDA 21-514 DAYTRANATM (methylphenidate transdermal system) Psychopharmacologic Drugs Advisory Committee

1
NDA 21-514 DAYTRANATM (methylphenidate
transdermal system)Psychopharmacologic Drugs
Advisory Committee
co-developed by Noven Pharmaceuticals,
Inc.Shire Pharmaceuticals

• Douglas Hay, PhD Senior Vice President, Global
  Regulatory Affairs
• Shire Pharmaceuticals

2
Proposed Indication for Methylphenidate
Transdermal System (MTS)

• DAYTRANATM (methylphenidate transdermal system)
  is indicated for the treatment of Attention
  Deficit Hyperactivity Disorder (ADHD)

3
External Consultants

• Stephen V. Faraone, PhD
• Professor of Psychiatry and Director Child and
  Adolescent Psychiatric ResearchSUNY, Upstate
  Medical University, SyracuseDrug Effects on
  Growth in ADHD
• Marc Lerner, MD
• Clinical Professor of PediatricsUniversity of
  California, IrvineDevelopmental Pediatrics and
  ADHD
• Judith Owens, MD, MPH
• Associate Professor of PediatricsBrown
  University School of Medicine, Providence,
  RISleep Disorders in ADHD
• Sharon Wigal, PhD
• Associate Clinical Professor of Pediatrics
  University of California, IrvineClinical Trials
  in ADHD

4
External Consultants

• David Heal, PhD, DSc
• Director RenaSci Consultancy Ltd, UK
  Methylphenidate Pharmacology
• Jack Henningfield, PhD
• Adjunct Professor, Behavioral BiologyThe Johns
  Hopkins University School of Medicine
• Vice President, Pinney Associates, Bethesda,
  MDRisk Management

5
Agenda

• Introduction
• ADHD Current Treatment
• Marc Lerner, MD
• University of California, Irvine
• Clinical Efficacy of MTS in the Treatment of ADHD
• Liza Squires, MDSr. Director, Clinical Research,
  Shire Pharmaceuticals
• Safety and Tolerability of MTS in Children with
  ADHD
• Raymond Pratt, MD Vice President, Global
  Clinical Medicine, Shire Pharm.
• Clinical Perspective of MTS Treatment of ADHD
• Sharon Wigal, PhD University of California,
  Irvine
• Overall Benefit/Risk of MTS in the Treatment of
  ADHD
• Raymond Pratt, MD

6
Rationale for the Development of Transdermal
Methylphenidate

• Alternative for patients with difficulty
  swallowing pills
• Caregivers indicate 15 of children with ADHD
  have extreme or high difficulty in swallowing
  pills
• Avoids any food effect
• Concern with many oral ADHD medications
• Opportunity to visibly monitor compliance
• Sustained treatment without need for supplemental
  therapy
• Flexible period of treatment in children
  requiring an altered regimen

7
Methylphenidate Transdermal System

• Backing is a vinyl acetate laminate film
• Inner polyester release liner removed before use
• DOT Matrix Technology
• concentrated drug-in-microacrylic cells
• acrylic cells homogenously dispersed in
  pressure-sensitive silicone

Backing
Drug/Adhesive Mix
Release Liner
8
Methylphenidate Transdermal System

• Thin and transparent
• Effective drug delivery over a small patch area
• No need for irritating enhancers
• Excellent adhesion

9
Methylphenidate Transdermal Patch Current Dose
Strengths
Dose (mg) delivered over 9-h wear time Patch Surface Area
10 mg (1.1 mg/h x 9 h) 12.5 cm2
16 mg (1.8 mg/h x 9 h) 18.75 cm2
20 mg (2.2 mg/h x 9 h) 25 cm2
27 mg (3.0 mg/h x 9 h) 37.5 cm2
Methylphenidate doses delivered by the MTS patch are comparable to other sustained-release methylphenidate-based products on the market Methylphenidate doses delivered by the MTS patch are comparable to other sustained-release methylphenidate-based products on the market
Nominal delivery rate per hour in pediatric
subjects aged 6-12
10
MTSRegulatory / Development History

• NDA 21-514 submitted by Noven June 2002
• 12-hour wear time
• FDA Action Letter April 2003
• acknowledged efficacy of MTS
• identified incidence of insomnia, anorexia, and
  weight loss as unacceptable
• recommended consideration of shorter duration of
  wear time to potentially mitigate these, as well
  as dermal effects
• Noven and Shire signed collaborative agreement in
  2003
• Discussions with FDA regarding subsequent
  clinical program 9-hour wear time
• NDA resubmission on June 28, 2005

11
Noven / ShireMTS Clinical Development Program

• Pharmacokinetic (PK) and Biopharmaceutic Studies
• 8 studies in volunteers (n407)
• PK, dose proportionality, skin irritation and
  sensitization, and abuse potential
• 4 studies in pediatric patients (n97)
• application site, patch size, and wear time on PK
• Initial Dose-ranging Studies (n24)
• 2 studies with an early formulation
• classroom and laboratory settings

12
Noven / ShireMTS Clinical Development Program
Study Type Study Description Study Number Number of Subjects
Phase II, Controlled, Short-Term Studies Placebo-controlled, crossover safety and efficacy studies in a summer treatment program setting N17-009 N17-015 63
Phase II, Controlled, Short-Term Studies Placebo-controlled, multi-dose, crossover safety and efficacy study in a classroom setting 9 hour SPD485-201 93
Phase III, Controlled, Short-Term Studies Placebo- and active-controlled, multi-dose, randomized, safety and efficacy studies 12 hour N17-010 N17-018 210 211
Phase III, Controlled, Short-Term Studies Placebo- and active-controlled, multi-dose, randomized, safety and efficacy study 9 hour SPD485-302 282
Uncontrolled, Long-Term Studies Open-label, long-term safety studies 12 hour N17-011 N17-013 N17-021 118 20 191
Uncontrolled, Long-Term Studies Open-label, long-term safety study 9 hour SPD485-303 289
13
ADHD Current Treatment

• Marc Lerner, MDClinical Professor of Pediatrics
• University of California, Irvine

14
Prevalence and Public Health Impact of ADHD

• ADHD affects 3-5 of all school-age children1
• Recent data suggests rates up to 7.5 in
  school-aged children2
• Diagnosed in boys at rates up to 4 times more
  than in girls3,4
• ADHD accounts for up to 50 of mental health
  referrals for children5
• ADHD often persists throughout childhood into
  adolescence and adulthood6,7,8

15
Risks Associated with ADHD

• Academic1,2,3,4,5,6
• Poor academic performance
• Higher drop-out rate
• Suspension / expulsion
• Social8,9
• Interaction problems with teachers, peers and
  parents
• Adult, more often separated, divorced, or
  unmarried
• Work6,7
• More frequent job changes quit, fired
• Lower status jobs
• More often unemployed
• Personal10
• Co-morbidity ODD, Anxiety, Depression

16
Pharmacological Treatment for Children with ADHD

• Clinicians should recommend pharmacotherapy to
  improve target outcomes in children with ADHD2
• Stimulant medication is a first-line treatment
  for ADHD1
• Methylphenidate (MPH) reduces core symptoms of
  ADHD3
• Any individual stimulant effective in 70 of
  ADHD patients
• Many who fail to respond to one may respond to
  another3,4
• Stimulants generally safe and well tolerated4
• Therapeutic goal for stimulants in ADHD is to
  provide optimal efficacy with manageable side
  effects

17
References

• 14.1 Jensen PS. Ritalin Theory and Practice, 2nd
  ed. Larchmont, NY Mary Ann Liebert, Inc.
  19991-3
• 14.2 Barbaresi WJ, Katusic SK, Colligan RC,
  Pankratz VS, et al. How common is
  attention-deficit/hyperactivity disorder?
  Incidence in a population-based birth cohort in
  Rochester, Minn. Arch Pediatr Adolesc Med. 2002
  Mar156(3)217-24
• 14.3 US Department of Health and Human Services,
  1999
• 14.4 Scott-Levin Inc., Physician Drug and
  Diagnosis Audit (PDDA), 2001
• 14.5 The MTA Cooperative Group, A 14-month
  randomized clinical trial of treatment strategies
  for attention-deficit/hyperactivity disorder. The
  MTA Cooperative Group. Multimodal Treatment Study
  of Children with ADHD. Arch Gen Psychiatry. 1999
  Dec56(12)1073-86
• 14.6 Mannuzza S, Klein RG, Bessler A, Malloy P,
  LaPadula M. Adult psychiatric status of
  hyperactive boys grown up. Am J Psychiatry. 1998
  Apr155(4)493-8
• 14.7 Barkley RA, Fischer M, Edelbrock CS,
  Smallish L. The adolescent outcome of hyperactive
  children diagnosed by research criteria I. An
  8-year prospective follow-up study. J Am Acad
  Child Adolesc Psychiatry. 1990 Jul29(4)546-57
• 14.8 Gittelman R, Mannuzza S, Shenker R, Bonagura
  N. Hyperactive boys almost grown up. I.
  Psychiatric status. Arch Gen Psychiatry. 1985
  Oct42(10)937-47
• 15.1 Barkley RA. Major life activity and health
  outcomes associated with attention-deficit/hyperac
  tivity disorder. J Clin Psychiatry. 200263 Suppl
  1210-5.
• 15.2 Fischer M, Barkley RA, Edelbrock CS,
  Smallish L. The adolescent outcome of hyperactive
  children diagnosed by research criteria II.
  Academic, attentional, and neuropsychological
  status. J Consult Clin Psychol. 1990
  Oct58(5)580-8
• 15.3 Hechtman L, Weiss G. Long-term outcome of
  hyperactive children. Am J Orthopsychiatry. 1983
  Jul53(3)532-41
• 15.4 Faraone SV, Biederman J, Lehman BK, et al.
  Intellectual performance and school failure in
  children with attention deficit hyperactivity
  disorder and in their siblings. J Abnorm Psychol.
  1993 Nov102(4)616-23
• 15.5 Biederman J, Monuteaux MC, Doyle AE, et al.
  Impact of executive function deficits and
  attention-deficit/hyperactivity disorder (ADHD)
  on academic outcomes in children. J Consult Clin
  Psychol. 2004 Oct72(5)757-66
• 15.6 Wilens TE, Dodson WA clinical perspective of
  attention-deficit/hyperactivity disorder into
  adulthood. J Clin Psychiatry. 2004
  Oct65(10)1301-13
• 15.7 Barkley RA, Fischer M, Smallish L, et alThe
  persistence of attention-deficit/hyperactivity
  disorder into young adulthood as a function of
  reporting source and definition of disorder. J
  Abnorm Psychol. 2002 May111(2)279-89
• 15.8 Barkley RA, Fischer M, Smallish L, et al.
  Young adult follow-up of hyperactive children
  antisocial activities and drug use. J Child
  Psychol Psychiatry. 2004 Feb45(2)195-211
• 15.9 Eakin L, Minde K. Hechtman L. The marital
  and family functioning of adults with ADHD and
  their spouses. J Atten Disord. 2004 Aug8(1)1-10
• 15.10 Biederman J. Impact of comorbidity in
  adults with attention-deficit/hyperactivity
  disorder. J Clin Psychiatry. 200465 Suppl 33-7
• 16.1 American Academy of Pediatrics. Subcommittee
  on Attention-Deficit/Hyperactivity Disorder and
  Committee on Quality Improvement. Clinical
  practice guideline treatment of the school-aged
  child with attention-deficit/hyperactivity
  disorder. Pediatrics. 2001 Oct108(4)1033-44

18
AAP Treatment Guidelines for ADHDPEDIATRICS Vol.
108 No. 4 October 2001, pp. 1033-1044

• Stimulants are generally considered safe
  medications, with few contraindications to their
  use
• Side effects occur early in treatment and tend to
  be mild and short-lived
• The most common side effects are decreased
  appetite, stomachache or headache, delayed sleep
  onset, jitteriness, or social withdrawal
• Most side effects can be successfully managed
  through adjustments of dosage or schedule

19
AAP Treatment Guidelines for ADHDPEDIATRICS Vol.
108 No. 4 October 2001, pp. 1033-1044

• Children who fail to show positive effects or who
  experience intolerable side effects on one
  stimulant medication should be tried on another
• Children who fail 2 stimulant medications can be
  tried on a third type or formulation of stimulant
  medication
• 15 to 30 of children experience motor tics,
  most of which are transient, while on stimulant
  medications
• The presence of tics before or during medical
  management of ADHD is not an absolute
  contraindication to the use of stimulant
  medications

20
Gaps with Available ADHD Treatments

• Provide clinicians with greater flexibility for
  ADHD treatment
• Provide families with the opportunity to
  individualize the childs treatment to meet the
  needs of the day
• Options to support the childs functioning early
  in the day
• Ability to shorten PM medication impact
• Reduction in multiple prescriptions co-pays

21
Physicians should be alert for problems with
adherence

• Hippocrates, 200 B.C.

22
Issues Related to Treatment Compliance in
Children with ADHD

• Doesnt like the taste
• Doesnt like taking medications
• Refuses to take the medication
• Gags when taking medication
• Parent gives up due to stress

23
Conclusions

• ADHD is a significant, impairing disorder with
  potential long-term implications
• MPH is a first-line treatment for ADHD
• Some patients respond preferentially to one ADHD
  treatment over another, AND
• Different treatments offer different advantages
• There is a group of patients that is not
  receiving optimal therapyFamilies need
  additional therapeutic options

24
Clinical Efficacy of MTS in Children with ADHD

• Liza Squires, MDSenior Director, Global Clinical
  Medicine
• Shire Pharmaceuticals

25
MTS Clinical Development Program Efficacy
Objectives

• Establish efficacy with a 9-hour wear time
• Study 201 Laboratory Classroom Study
• Onset and duration
• Study 302 Outpatient Study
• Efficacy in an outpatient setting

26
Study 101

• Identify clinically optimal wear time based upon
  PK profile
• Four arm, single-dose, crossover, PK study
• MTS 25cm2, 6-, 8-, and 10-hour patch wear time
  and Concerta? 36 mg
• 24 children with ADHD age 6-12 years

27
Study 101 Plasma Concentration of d-MPH
25
MTS 25cm2 (6 hours)
MTS 25cm2 (8 hours)
MTS 25cm2 (10 hours)
20
Concerta 36 mg
15
d-MPH (ng/mL)
10
5
0
0
5
10
15
20
25
30
35
Hour
n 24 for Concerta n 23 for MTS
Treatments MTS06, MTS08 and MTS10 represent wear
times before patch removal at 6, 8 and 10 hours,
respectively
28
Study 201MTS Laboratory Classroom Study

• Assess efficacy and time course of treatment
  effect, tolerability and safety of MTS
• SKAMP Deportment scale (SKAMP-D) scores
• PERMP (Math Productivity) Scores
• Multiple time points during 2 classroom days
• Double-blind, multi-center, placebo-controlled,
  crossover design laboratory classroom study
• Pediatric patients age 6-12 years diagnosed with
  ADHD by DSM-IV-TR criteria

29
Study 201 Design
Randomization Practice classroom
Screening
Follow-up or open label study
Baseline
Laboratory Classroom
27 mg (37.5 cm2 )
20 mg (25 cm2 )
16 mg (18.75 cm2 )
10 mg (12.5 cm2)
MTS
MTS
Randomization at Week 5
1 Wk
1 Wk
PTS
PTS
30
Laboratory Classroom StudyDaily Schedule

• 615 Arrival, Pre-dose Evaluation
• 700 Class 0, PERMP, SKAMP
• 730 MTS Dosing
• 740 Breakfast / Free-time
• 915 Vital signs / Bloods
• 930 Class 1, PERMP, SKAMP
• 1000 Snack
• 1015 Vital signs / Bloods
• 1030 Class 2, PERMP, SKAMP
• 1100 Free-time / Bloods
• 1200 Class 3, PERMP, SKAMP
• 1230 Lunch / AE Assessment
• 1315 Vital signs / Bloods
• 1330 Class 4, PERMP, SKAMP

• 1400 Free-time / Physical / ECG
• 1445 Vital signs / Bloods
• 1500 Class 5, PERMP, SKAMP
• 1530 Snack / Free-time / AE Assessment
• 1615 Vital signs / Bloods / MTS Removal
• 1630 Class 6, PERMP, SKAMP
• 1700 Free-time
• 1745 Vital signs / Bloods
• 1800 Class 7, PERMP, SKAMP
• 1830 Dinner / Free-time / AE Assessment
• 1915 Vital signs / Bloods
• 1930 Class 8, PERMP, SKAMP
• 2000 Dismissal

31
Study 201 Primary AnalysisSKAMP Deportment Score
(0-9 Hours)
MTS PTS
N79 N79
Mean (SD) 3.2 ? 3.6 8.0 ? 6.3
Median 2.2 7.3
Range 0 to 17 0 to 29
LS Mean (SE) 3.2 ? 0.6 8.0 ? 0.6
Difference and 95 CI of LS Mean (MTS-PTS) -4.8 95 CI -5.9 to -3.6 -4.8 95 CI -5.9 to -3.6
p-value lt0.0001 lt0.0001
32
Study 201 SKAMP-D Onset Duration
33
Study 201 PERMP Number Attempted Correct
34
Study 201Secondary Efficacy Endpoints
Scale p-value MTS-PTS Difference 95 CI
SKAMP (Total) plt0.0001 -8.5 -10.2 to -6.8
ADHD-RS-IV (Total) plt0.0001 -16.5 -19.8 to -13.1
CPRS (Total) plt0.0001 -15.1 -20.5 to -9.7
PGA plt0.0001 Improved (1 or 2) 65-76
CGI plt0.0001 Improved (1 or 2) 78-80
35
Study 201Efficacy Summary

• Overall efficacy of MTS in reducing ADHD symptoms
  apparent to trained observers, clinicians and
  parents
• Statistically significant improvement in all
  primary and secondary efficacy endpoints
• 9-hour target wear time
• Onset of effect within 2 hours of application
• Duration of effect through 12 hours

36
Study 302 Design

• Evaluate the safety and efficacy of
  methylphenidate transdermal system (MTS) compared
  to placebo with reference to Concerta
• A phase III, randomized, double-blind,
  multi-center, parallel-group, placebo-controlled,
  dose-optimization study
• 38 study centers in the US 274 subjects
• Pediatric patients age 6-12 years with ADHD by
  DSM-IV-TR criteria

37
Study 302 Design
38
Study 302 Clinical Outcome Measures

• Primary Outcome
• Clinician-rated ADHD-RS-IV
• Secondary Outcomes
• Conners Teacher Rating Scale Revised SF
  (CTRS-R)
• Conners Parent Rating Scale Revised SF (CPRS-R)
• Clinical Global Impressions (CGI-I)
• Parent Global Assessment (PGA)

39
Study 302Subject Demographics ITT
Characteristic MTSN96 Concerta N89 Placebo N85 OverallN270
Mean age in yrs (SD) 8.8(1.91) 8.8(1.93) 8.5(1.90) 8.7(1.91)
Sex Male () 60 66 74 67
Race () Caucasian African-American Asian Other 791227 801407 731908 771417
40
Study 302 ADHD-RS-IV Change from Baseline to
Endpoint
MTSN96 ConcertaN89 PlaceboN85
ADHD-RS-IVBaseline Score 43.0?7.5 43.8?6.7 41.9?7.4
Change From Baseline (LOCF) Change From Baseline (LOCF) Change From Baseline (LOCF)
LS Mean ? SE -24.2?1.5 -21.6?1.5 -10.3?1.5
Difference Active Placebo95 CI -13.9-18.06 to -9.7 -11.3-15.6 to -7.06
plt0.0001 plt0.0001

Reference only not a primary comparison
41
Study 302 ADHD-RS-IV Change from Baseline to
Endpoint
plt0.05 MTS vs placebo
42
Study 302Secondary Efficacy Endpoints
Active Placebo Difference 95 CI Active Placebo Difference 95 CI
P-value MTS Concerta
Teacher (CTRS-R) Total lt0.0001 -10.2 -15.0 to -5.4 -12.4 -17.4 to -7.5
ADHD Index lt0.0001 -5.8 -8.4 to -3.2 -7.2 -9.8 to -4.6
Oppositional 0.0345 -0.8 -1.5 to -0.1 -1.0 -1.7 to -0.2
Hyperactivity lt0.0001 -2.7 -4.2 to -1.3 -3.4 -4.8 to -1.9
Cognitive problems 0.0040 -1.4 -2.4 to -0.5 -1.8 -2.8 to -0.8

Parent (CPRS-R) Total
1100 hrs lt0.0001 -12.7 -18.8 to -6.6 -9.3 -15.4 to -3.1
1500 hrs lt0.0001 -12.4 -18.6 to -6.2 -7.0 -13.3 to -0.7
Average daily total lt0.0001 -13.4 -19.4 to -7.4 -8.5 -14.6 to -2.6

Clinician (CGI 1 or 2) lt0.0001 71.9 vs 23.5 66.3 vs 23.5
Parent (PGA 1 or 2) lt0.0001 67.8 vs 24.7 60.7 vs 24.7
MTS vs Placebo only MTS vs Placebo only MTS vs Placebo only MTS vs Placebo only
43
Study 302 Efficacy Summary

• MTS, worn for 9 hours, reduces symptoms of ADHD
  based on assessments by
• clinicians
• teachers
• parents
• Statistically significant improvement in all
  primary and secondary efficacy endpoints

44
MTS Clinical Development Program Efficacy
Conclusions

• MTS with a 9-hour target wear time demonstrated
  significant efficacy in laboratory classroom and
  outpatient settings
• Improvements in behavior are present within 2
  hours of patch application and persist for 3
  hours after patch removal
• Improvements ADHD symptoms and behavior reported
  by
• Trained observers
• Teachers
• Parents
• Clinicians

45
MTS Safety Evaluations

• Raymond D. Pratt, MD
• Vice President, Clinical Development
• Shire Pharmaceuticals

46
Safety Evaluations MTS Program

• Spontaneous and Elicited AEs
• No Deaths
• Clinical Laboratory Evaluations
• No Clinically Relevant Lab Abnormalities
• Physical Examinations, Vital Signs, ECGs
• No Clinically Relevant Abnormalities
• AE pattern similar in studies 201 and 302
• MPH-related
• Study 302- double-blind, placebo controlled with
  reference to Concerta
• Long-term study N-021
• Growth Effects

47
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI
• Headache
• Tics
• Appetite AEs
• Weight and Growth
• Sleep Effects
• Dermal Evaluations

48
AEs in 12-Hour MTS Studies
Study 010 Study 010 Study 018 Study 018 Total 12-Hour Total 12-Hour
COSTART MTS N101 () PTS N109 () MTS N106 () PTS N105 () MTS N207 () PTS N214 ()
Anorexia 17 2 50 2 34 2
Decreased appetite NR NR NR NR NR NR
Weight decreased 1 0 10 1 6 0
Insomnia 17 3 29 5 23 4
Nausea 1 4 3 2 2 3
Vomiting 3 7 8 4 5 6
Tic/twitching 3 0 7 0 5 0
Headache 14 6 17 12 15 8
49
AEs in 12-Hour MTS Studies
Study 010 Study 010 Study 018 Study 018 Total 12-Hour Total 12-Hour
MedDRA MTS N101 () PTS N109 () MTS N106 () PTS N105 () MTS N207 () PTS N214 ()
Anorexia 3 1 15 0 9 1
Decreased appetite 14 1 36 2 25 2
Weight decreased 1 0 10 1 6 0
Insomnia 17 3 29 5 23 4
Nausea 1 4 3 2 2 3
Vomiting 3 7 8 4 5 6
Tic 3 0 7 0 5 0
Headache 14 6 17 12 15 8
50
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI
• Headache
• Tics
• Appetite AEs
• Weight and Growth
• Sleep Effects
• Dermal Evaluations

51
Most Commonly Reported Treatment-Emergent AEs
(5 and 2x Placebo)
Adverse Event (Preferred Term) MedDRA 7.0 Percent of subjects reporting AEs Percent of subjects reporting AEs Percent of subjects reporting AEs Percent of subjects reporting AEs
Adverse Event (Preferred Term) MedDRA 7.0 MTS N98 MTS N98 Concerta? N91 Placebo N85
of subjects with any AE 75 69 58
Decreased appetite 26 19 5
Insomnia 13 8 5
Nausea 12 8 2
Vomiting 10 10 5
Weight decreased 9 8 0
Tic 7 1 0
Affect lability 6 3 0
Nasal congestion 6 3 1
Anorexia 5 3 1
Nasopharyngitis 5 4 2
52
Study 302 Discontinuations
Reason MTSn () Concertan () Placebon ()
Adverse event 7 (7.1) 3 (3.2) 1 (1.1)
Protocol violation 1 (1.0) 1 (1.1) 3 (3.4)
Withdrew consent 3 (3.1) 5 (5.3) 6 (6.8)
Lost to follow-up 2 (2.0) 0 2 (2.3)
Elected OL Study 12 (12.0) 17 (18.7) 32 (37.6)
Other 3 (3.1) 1 (1.1) 11 (12.5)
Sponsor decision 2 (2.0) 1 (1.1) 2 (2.3)
53
Study 302Discontinuation AEs
Treatment Gender /Age/Race Dose Adverse Event
MTS F/6/H 18.75 cm2 Viral infection
MTS F/7/W 12.5 cm2 Infectious mononucleosis
MTS M/9/W 37.5 cm2 Application site reaction
MTS F/9/W 25 cm2 Application site erythema
MTS M/7/W 25 cm2 Headaches
MTS M/10/W 25 cm2 Irritability, Crying
MTS M/6/W 25 cm2 Facial tics
Concerta M/11/W 18 mg Syncope
Concerta M/12/W 18 mg Abdominal pain
Concerta M/6/W 18 mg Aggression, Anger, Headache
Placebo M/9/W Worsening ADHD symptoms
54
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI and Headache
• Tics
• Appetite AEs
• Weight and Growth
• Sleep Effects
• Dermal Evaluations

55
Study 302 GI-Related AEs
MTS N98 Concerta N91 Placebo N85
Abdominal Pain Subjects (N) 7 9 5
Events (N) 10 11 8
Ongoing (N) 3 1 0
Duration (days) 5?4 4?7 3?4
Vomiting Subjects (N) 10 9 4
Events (N) 14 9 4
Ongoing (N) 0 0 0
Duration (days) 1?1 1?1 2?1
Nausea Subjects (N) 12 7 2
Events (N) 18 7 2
Ongoing (N) 1 0 0
Duration (days) 5?8 6?7 3
56
Study 302 CNS-Related AEs
MTS N98 Concerta N91 Placebo N85
Headache Subjects (N) 15 18 10
Events (N) 24 26 14
Ongoing (N) 1 2 1
Duration (days) 3?6 3?4 4?8
Affect Lability Subjects (N) 6 3 0
Events (N) 6 3 0
Ongoing (N) 2 2 0
Duration (days) 1112 29.0
57
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI and Headache
• Tics
• Appetite AEs
• Weight and Growth, short and long term
• Sleep Effects
• Dermal Evaluations

58
Study 302 MedDRA Coding for Tic
Misc. Mouth Movements Misc. Mouth Movements Onset Dose Verbatim term Outcome
MTS M/7/W 25 cm2 Repetitive tongue movements Resolved, 9 days dose Reduced
MTS M/10/W 12.5 cm2 Tongue rotation Ongoing no changes
Compulsion or Stereotypy Compulsion or Stereotypy
MTS M/11/W 18.75 cm2 Chewing Resolved, 8 days
MTS M/9/AF 25 cm2 Biting Lip Ongoing no changes
MTS M/7/W 12.5 cm2 Tongue biting Resolved, 1 day
59
Study 302 MedDRA Coding for Tic
Tic Onset Dose Verbatim term Outcome
MTS M/6/W 25 cm2 Tic D/C Ongoing _at_ 30 days
MTS M/8/W 25 cm2 Tongue Facial Tic Resolved, 9 day

Concerta M/12/W 54 mg Tongue Tic Ongoing no changes
60
Tic in Controlled MPH Studies
Rate Difference
Citation
Year
MPH
Placebo
-0.50
-0.25
0.00
0.25
0.50
Barkley
1990
16 / 66
16 / 66
Firestone
1998
4 / 32
1 / 32
Kooij
2004
3 / 45
1 / 45
Law
1999
10 / 51
2 / 12
MTS
2005
7 / 98
0 / 85
MTS OROS
2005
1 / 91
0 / 85
Palumbo
2004
9 / 224
8 / 219
Palumbo OROS
2004
5 / 216
8 / 219
Pelham
1990
1 / 22
1 / 22
Pelham
1991
2 / 22
1 / 22
Pelham
1999
1 / 25
1 / 25
Pelham
2001
4 / 70
0 / 70
Pelham OROS
2001
0 / 70
0 / 70
Plizka
2000
0 / 20
1 / 18
Stein
2003
1 / 47
0 / 47
Combined (15)
64 / 1099
40 / 1037
Placebo
MPH
61
Tic in Open-Label Studies
Study Events (N) Total (N) Events ()
Concerta PI Study 1 39 432 8.0
Concerta PI Study 2 9 682 1.3
Wilens 2005 Concerta 40 408 9.8
MTS N-021 2 191 1.0
MTS 303 5 255 2.0
62
Study 302AEs Coded as Tics

• Most MTS events were transient
• 4 of 7 resolved with continuing MTS
• Only 1 discontinuation
• Symptoms mild, do not interfere with activity
• Verbatim descriptions not all tics
• Abnormal tongue and mouth movements
• Compulsions and stereotypy are common in ADHD
• Overall frequency of tics in MTS studies
  consistent with published data with stimulants
• Tic not a contraindication to stimulant Rx

63
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI and Headache
• Tics
• Appetite AEs
• Weight and Growth, short and long term
• Sleep Effects
• Dermal Evaluations

64
Study 302 Appetite-Related AEs
MTS N98 Concerta N91 Placebo N85
Anorexia Subjects (N) 5 3 0
Events (N) 6 3 1
Ongoing (N) 2 2 0
Duration (days) 1414 7 3
Decreased Appetite Subjects (N) 25 17 4
Decreased Appetite Events (N) 27 19 4
Decreased Appetite Ongoing (N) 12 11 0
Decreased Appetite Duration (days) 1611 2010 85
Weight Loss Subjects (N) 9 7 0
Events (N) 9 7 0
Ongoing (N) 5 4 0
Duration (days) 1913 1718
65
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI and Headache
• Tics
• Appetite AEs
• Weight and Growth, short and long term
• Sleep Effects
• Dermal Evaluations

66
Study 302 Weight Loss
67
Study 302 Weight Changes
68
AnorexiaControlled MPH Studies
69
Decreased AppetiteControlled MPH Studies
70
Study 302 Appetite and Weight

• MTS higher observed N of appetite-related AEs
• Most are transient and mild
• Number of ongoing AEs similar in both MPH groups
• Actual weight loss similar in MPH groups
• Effects are typical for oral MPH products

71
Growth Effects Long-Term Evaluation

• Study N-021
• 191 patients, followed for up to 3 years
• 12-hour target wear time
• Includes 50 cm2 patch
• Important to assess effects of continuous use of
  MTS on growth parameters

72
Long-Term Growth Effects 12-Hour Wear Time

• Subjects treated with MTS continue to grow during
  treatment
• Growth deficits (observed/expected) in weight and
  height present with MTS (12 hour wear time)
• Deficits are small after 3 years
• Short-term, weight deficits related to dose
• Prior stimulant therapy predicts smaller deficits
  
• Results similar to those reported for other
  stimulants

73
Actual Growth Indices
Height (cm)
Weight (kg)
Body Mass Index
74
Growth Velocity as Z-Score
75
Comparison to Other StimulantsHeight
76
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI and Headache
• Tics
• Appetite AEs
• Weight and Growth, short and long term
• Sleep Effects
• Dermal Evaluations

77
Study 302Sleep-Related AEs
MTS N98 Concerta N91 Placebo N85
Insomnia Subjects (N) 13 7 4
Events (N) 18 12 4
Ongoing (N) 5 6 1
Duration (days) 1310 118 1614
78
InsomniaControlled MPH Studies
Rate Difference
Citation
Year
MPH
Placebo
-0.50
-0.25
0.00
0.25
0.50
Ahmann
1993
116 / 206
75 / 206
Barkley
1990
28 / 82
18 / 82
Biederman
2003
2 / 65
0 / 71
Connors
1980
13 / 20
5 / 20
Firestone
1998
17 / 32
19 / 32
Greenhill
2002
11 / 155
4 / 161
Kooij
2004
15 / 45
10 / 45
302 MTS
2005
13 / 98
4 / 85
302 OROS
2005
7 / 91
4 / 85
Pelham
1999
7 / 25
3 / 25
Pelham
1991
4 / 22
1 / 22
Pelham
1990
2 / 22
1 / 22
Pelham
2005
9 / 36
3 / 36
Spencer
2005
25 / 104
7 / 42
Stein
2003
32 / 47
21 / 47
Combined (15)
175 / 981
301 / 1050
Placebo
MPH
79
Childrens Sleep Habits Questionnaire (CSHQ)

• CSHQ for children aged 4-12 years
• Parents assess the previous week
• Assesses quality, latency, duration, habitual
  efficiency, disturbances and daytime dysfunction
• 33 questions Scored as 1 to 3
• 1 (rarely occurring never or 1 time in the week)
• 2 (sometimes occurring 2 to 4 times in the week)
• 3 (usually occurring 5 or more times in the
  week)
• Asks if the behavior is considered a specific
  problem

80
Study 302CSHQ Scores
CSHQ Total Score
81
Study 302Sleep-Related Events

• Insomnia associated with MPH
• Observed incidence higher in MTS group
• Most events resolve on continuing treatment
• Transient and mild in severity
• No discontinuations or dose changes
• MTS and Concerta have little effect on sleep
  habits

82
MTS Safety

• Overview of AEs in 12 hour wear time studies
• Overview of AEs in 9 hour wear time study
• GI and Headache
• Tics
• Appetite AEs
• Weight and Growth, short and long term
• Sleep Effects
• Dermal Evaluations

83
Dermal Evaluations

• Subjects evaluated for dermal reactions at all
  post-baseline visits
• Adhesion Scale
• Adhesion performance of transdermal system
• Dermal Response Scale
• Primary skin reactions and evidence of skin
  irritation
• Dermal Discomfort Scale
• Experience of discomfort and pruritus

84
Week 7 Transdermal System Adhesion
Adhesion Scale (surface attached) 0 ? 90 1
? 75 but lt 90 2 ? 50 but lt 75 3 lt50
4 MTS/PTS detached
85
Week 7 Dermal Response Evaluation
Dermal Response Scale 0 no evidence of
irritation 1 minimal erythema 2 definite
erythema 3 erythema and papules 4 definite
edema 5 erythema, edema, papules 6
vesicular eruption 7 strong reaction beyond
site
86
Week 7Experience of Discomfort
Discomfort Scale 0 no discomfort 1 mild 2
moderate but tolerable 3 severe intolerable
87
Study 302Dermal Assessment

• MTS typically associated with slight to minimal
  erythema
• MPH a mild irritant
• Most subjects experienced no discomfort
• Few cases of mild discomfort, typically itching
• Excellent adhesion
• Few discontinuations due to application site
  reactions

88
MTS Safety Conclusions

• Generally well tolerated
• No related serious AEs
• Few discontinuations due to AEs
• Common AEs related to stimulant effects
• Mild, transient and resolve on continued
  treatment
• Persisting AE incidence similar to Concerta
• Target wear time of 9 hours reduced the incidence
  of anorexia and insomnia
• Skin reactions are mild
• Short and Long-term growth effects are similar to
  all stimulants
• Results consistent with other approved MPH
  products

89
MTSClinical Perspective

• Sharon B. Wigal, PhDAssociate Clinical Professor
  of Pediatrics
• University of California, Irvine

90
MTSPatients in Clinical Trials

• an investigational medicinal patch to treat
  ADHD
• Treatment-naïve children
• Children with prior stimulant exposure

91
MTS Experience inLaboratory School Setting

• Ease in administration
• Ease of removal
• Level of patient/family satisfaction

92
MTSParent Comments School

• Teacher reports the change is like night and
  day
• His teacher noticed a big difference like a
  different kid
• much more focused and accomplishes work

93
MTSParent Comments Home

• Everybody comments on her improvement
• my child listens, follows through on
  directions
• I can tell when the meds wear off because
  child pesters her brother

94
MTSParents Comments Long-term Use

• The three side effects that I have noted (loss
  of appetite, sleeplessness and skin irritation)
  have all been acceptable trade offs... After
  several weeks, his appetite returned in the
  evening either by acclimation or by modifying our
  removal time to 330 PM the earlier removal time
  also assisted in eradicating sleeplessness at
  bedtime. Lastly, I have noticed far less
  reddening of skin (barely any) as time has passed
  and have not had any complaints of skin
  irritation for some time.

95
MTSClinical Utility Conclusions

• MTS was a viable treatment option for children
  with ADHD
• Ease of use
• Compliance to treatment
• Positive parent perception
• Flexibility of treatment period
• Manageable side effects

96
Benefit / Risk Summary

• Raymond D. Pratt, MD

97
Benefits of MTS

• Once-daily application
• Behavioral response within 2 hours
• Clinical benefits persist for at least 3 hours
  after patch removal
• Transdermal
• No oral dosing
• Excellent adhesion minimal irritation
• 9-hour MPH exposure similar to oral MPH products
• Exposure controlled by patch size and wear time
• Drug delivery stops on patch removal
• Decreased risk of accidental ingestion or overdose

98
Risks of MTS

• Adverse events with MTS are same as oral MPH
• MTS wear times gt 9-hours might lead to a higher
  incidence of anorexia and insomnia
• Longer-term effects with MTS on growth parameters
  are similar to other psychostimulants
• Potential for sensitization and irritation with
  MTS
• CII substance potential for abuse and/or
  diversion

99
Conclusions

• MTS is a new effective delivery system for
  once-daily treatment of ADHD with MPH
• Onset of effect within 2 hours of application
• Duration of effect covers the school day
• Potential for customized treatment
• Positive benefit-risk balance
• Incidence of AEs similar to other MPH products

100

101
Summary of Psychiatric AEs By Treatment All
Studies
Study Treatment N Psychosis/mania events (n) Suicidal events (n) Aggression events (n)
021 MTS 191 3 1 3
102 Crossover RxMTS 34 0 0 0
102 Crossover Rx Concerta 33 1 0 0
201 Titration Crossover Rx MTS 93 0 0 3
201 Crossover Rx Placebo 79 0 0 0
302 MTS 98 0 0 3
302 Concerta 91 1 0 1
102
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103
302 Summary of Patch Wear Time by Visit Safety
Population
104
Structures of Methylphenidate and Its
threo-Isomers
Methylphenidate
The 2 asymmetric carbon atoms are denoted with
asterisks.
d-threo (2R2?R)
l-threo (2S2?S)
105
Differences in the Exposure to l-threo-Methylpheni
date after Oral or Transdermal Administration of
Parent Racemate
dl-threo-methylphenidate (dl-threo-MPH)
MTS transdermal patch (12.5 37.5 cm
patch/9hr) d-threo-MPHl-threo-MPH SPD485-10
2 1.6 1.0d SPD485-201 1.6 1.0d SPD485-302
1.9 1.0d
Oral route Plasma C max
d-threo-MPHl-threo-MPH Ritalin IR 5.0
1.0a Ritalin SR 10.0 1.0b Concerta 40.0
1.0c
aSrinivas et al (1997) bHubbard et al (1989)
cModi et al (2000) dSponsors data obtained in
paediatric patients
106
Catecholamine Mechanisms Efficacy vs Side-Effects
Methylphenidate and its isomers
Atomoxetine
Bupropion
Norepinephrine
Mixed profile
Dopamine
Efficacy in ADHD Cognitive function
? Attentiveness ? Distractibility
? Hyperactivity ? Behavioural ? disruption
Side-effects Insomnia ? BP/HR ? Abdominal
cramps ? Tics ? Appetite ? Body
weight ? Growth rate ?
107
Monoamine Reuptake Inhibition Profiles of the
Enantiomers of threo-Methylphenidate
Data for inhibition of tritiated uptake into rat
synaptosomes taken from aRichelson Pfenning
(1984) bAndersen (1989) cDeutsch et al
(1996)/Schweri et al (2002) dFerris et al
(1972) ePatrick et al (1987)
108
Intracerebral Microdialysis Experiments in
Freely-Moving Rats Confirms the Reuptake
Inhibition Profiles of Methylphenidates
Enantiomers
Norepinephrine, Frontal cortex
Dopamine, striatum
109
The Behavioural Effects of the Isomers of
Methylphenidate Mirror Their Neurochemical
Profiles
d-Methylphenidate (10 mg/kg ip)
d-Methylphenidate (1 mg/kg ip)
l-Methylphenidate (10 mg/kg ip)
Saline (ip)
110
Clinical Studies

• Srinivas et al (1992) placebo-controlled,
  cross-over study in children with ADHD.
• d-MPH (5 mg) as efficacious as dl-MPH (10 mg)
• l-MPH (5 mg) was inactive
• Wigal et al (2004) placebo-controlled,
  dose-titration trial in children with ADHD.
• d-MPH delivered efficacy and side-effects
  equivalent to dl-MPH at approximately half the
  dose (18.2 versus 32.1 mg/day)

111
Summary and Conclusions

• d-Threo-methylphenidate (d-MPH) 10x potent than
  the l-isomer (l-MPH)
• d-MPH is the predominant driver of efficacy and
  side-effects
• The lower potency and plasma concentrations of
  l-MPH dictate that it contributes at most 5-10
  of the efficacy and side-effects of dl-MPH in the
  MTS patch
• Clinical data support the hypothesis that whilst
  l-MPH delivers no discernable clinical benefit,
  its presence in racemic MPH preparations does not
  adversely impact on the side-effect liability of
  such products

112
Dosing Diary
113
Mean Plasma d-MPH Concentration vs Time Plots for
Caucasians
JMV Colors need to be changed
25
MTS06 25cm2
MTS08 25cm2
MTS10 25cm2
20
Concerta 36 mg
15
d-MPH (ng/mL)
10
5
0
0
5
10
15
20
25
30
35
Time after dosing (hours)
Study 101 n9 MTS n 10 Concerta
114
Irritation Analysis (Study N17-020)
Parameter Irritation Analysis Irritation Analysis Irritation Analysis Irritation Analysis
Parameter MTS Placebo PTS MTS Negative Control-Saline
Mean 2.06 1.62 2.06 0.78
Std Dev 0.56 0.65 0.56 0.57
N 145 145 145 145
Adjusted Difference 0.03 0.03 1.08 1.08
95 Upper Confidence 0.1536 0.1536 1.2047 1.2047
MTS is equivalent to the comparator (placebo or control) if 95 upper confidence bound is less than or equal to zero. MTS is more irritating than the placebo and the control. MTS is equivalent to the comparator (placebo or control) if 95 upper confidence bound is less than or equal to zero. MTS is more irritating than the placebo and the control. MTS is equivalent to the comparator (placebo or control) if 95 upper confidence bound is less than or equal to zero. MTS is more irritating than the placebo and the control. MTS is equivalent to the comparator (placebo or control) if 95 upper confidence bound is less than or equal to zero. MTS is more irritating than the placebo and the control. MTS is equivalent to the comparator (placebo or control) if 95 upper confidence bound is less than or equal to zero. MTS is more irritating than the placebo and the control.
115
Number of Subjects Who Underwent Challenge and
Rechallenge Reactions (Study N17-020)
Category N
Participating in Challenge Period 133
Participating in Rechallenge Period 36
With Irritation at Rechallenge Period 16
With Sensitization based on Challenge and Rechallenge Periods 17
With Sensitization based on Challenge Alone 1
With Potential Sensitization to MTS, but Rechallenge Needed 8
With Sensitization based on Incomplete Challenge Period 1
One subject (No. 331) only had a 48-hour evaluation One subject (No. 331) only had a 48-hour evaluation
116
Treatment-Emergent Adverse Events in ?5 of All
Subjects Long-Term Pediatric Population by Time
Body System COSTART Term Time of Event Onset in Days Time of Event Onset in Days Time of Event Onset in Days Time of Event Onset in Days Time of Event Onset in Days Time of Event Onset in Days Time of Event Onset in Days
Body System COSTART Term 1-29 (n322) 30-59 (n286) 60-89 (n255) 90-119 (n171) 120-149 (n143) 150-179 (n128) 180-209 (n117)
Any Adverse Event 288 (89) 209 (73) 194 (76) 127 (74) 82 (57) 50 (39) 36 (31)
Headache 35 (11) 13 (5) 9 (4) 10 (6) 8 (6) 5 (4) 3 (3)
Abdominal Pain 26 (8) 9 (3) 4 (2) 5 (3) 0 2 (2) 2 (2)
Anorexia 66 (20) 13 (5) 12 (5) 5 (3) 3 (2) 2 (2) 1 (1)
Vomiting 16 (5) 4 (1) 6 (2) 3 (2) 1 (1) 2 (2) 0
Weight Loss 25 (8) 4 (1) 2 (1) 3 (2) 0 0 0
Insomnia 54 (17) 10 (3) 5 (2) 0 1 (1) 0 1 (1)
Nervousness 19 (6) 5 (2) 2 (1) 2 (1) 0 2 (2) 0
Application Site Reaction 255 (79) 174 (61) 165 (65) 109 (64) 66 (46) 32 (25) 18 (15)
COSTART Version 5, 1995, was used to code the
reported AEs by Body System and COSTART Term
117
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