GLGi: Attention Deficit Hyperactivity Disorder (ADHD)
Louis Sanfilippo, MD
January 22, 2008
Chicago

Council Member Biography
Louis Sanfilippo, MD , is an Assistant Clinical Professor of Psychiatry at Yale School of Medicine and is also in private practice. He is a
Managing Partner of Cenestra Health, a biotech company focused on developing empirically validated nutraceutical products. Dr. Sanfilippo teaches on Psychopharmacology to Yale Psychiatry residents with a focus on antidepressants, mood stabilizers, antipsychotics, and psychostimulants. His clinical expertise is in the treatment of anxiety, depression, ADHD, and bipolar disorder in adults, college students, athletes and executives. Dr. Sanfilippo has published articles, chapters, and books across a wide range of topics, including psychotic disorders, principles of psychopharmacology in young adults, mood disorders and suicide, forensic and ethical issues in psychiatry, the philosophy of mind, as well as a review of psychiatry for medical students. He has presented on sports psychiatry and has been a fellow with American
Psychoanalytic Association.
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Topics
► Recent developments in the treatment protocol for attention deficit hyperactivity disorder (ADHD)
► Prescribing patterns, reimbursement, and generic competition for stimulants
► Novel therapeutics in clinical development
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Clinical Diagnosis of ADHD
Inattention Symptoms (at least 6 of 9 symptoms) or
Hyperactivity/Impulsivity Symptoms (at least 6 of 9)
Symptoms present for 6 months
Some symptoms before 7 years of age
Symptoms cause impairment in 2 or more settings
Spectrum of Severity
Collateral History
Neuropsychological Testing
Assessment of Comorbid Disorders (Different for Children &
Adults)
Learning/Communication
Oppositional Defiant
Anxiety
Mood (Depression & Bipolar)
Substance Abuse Disorders
7

10
9
8
7
6
5
4
3
2
1
Prevalence of ADHD (in percentages) Prevalence of ADHD (in millions)
0
Percent(%)
Ages 4-17* Ages 18+**
5
4
3
2
1
0
Millions
10
9
8
7
6
Ages 4-17*** Ages 18+***
* Mental health in the United States: Prevalence of diagnosis and medication treatment for attention-deficit hyperactivity disorder, United States, 2003. MMWR,
September 2, 2005; 54(34):842-847.
** Kessler RC, et. al. The prevalence and correlates of adult ADHD in the United States from the National Comorbidity Survey Replication. Am J Psychiatry.
2006; 163:716-723.
*** US Census Bureau, Statistical Abstract of the United States, 2006. Numbers derived from 2004 data. At http://www.census.gov/prod/2005pubs/06statab/pop.pdf
8

9

FDA-Approved Treatments
Stimulants
Schedule II Drugs
Potentiate dopamine/norepinephrine neurotransmission
Atomoxetine (Strattera; Eli Lilly)
Non-stimulant
Norepinephrine reuptake inhibitor
Off-Label Treatments
Modafanil (Provigil; Cephalon) – arousal-promoting
Guanfacine - alpha-2 agonist
Clonidine - alpha-2 agonist
Bupropion (Wellbutrin family) – norepinephrine/dopamine reuptake inhibitor
Tricyclic Antidepressants
10

8.00%
7.00%
6.00%
5.00%
4.00%
3.00%
Prevalence
Rx Treated
2.00%
1.00%
0.00%
Ages 4-17* Ages 20+**
* Kessler RC, et. al.; The prevalence and correlates of adult ADHD in the United States from the National Comorbidity Survey Replication.
Am J Psychiatry. 2006; 163:716.723.
**Castle, L, et. al.; Trends in Medication Treatment for ADHD. Journal of Attention Disorders. 2007; 335-342.
11

ADHD Medication Treatment Trends, Ages 0-19 (2000-2005)*
4.50%
4.40% 4.40%
4.00%
4.00%
3.50%
3.00%
2.80%
3.10%
3.40%
2.50%
Ages 0-19
2.00%
% Children &
Adolescents Treated
With Medication
2000 2001 2002 2003 2004 2005
Late 2002, Strattera introduced
ANNUAL GROWTH RATE = 9.5% (2000-2005)
*Castle, L, et. al.; Trends in Medication Treatment for ADHD. Journal of Attention Disorders. 2007; 335-342.
12

ADHD Medication Treatment Trends, Ages 20+ (2000-2005)*
0.80%
0.80%
0.70%
0.60%
0.50%
0.40%
0.40% 0.40%
0.50%
0.60%
0.70%
Ages 20+
0.30%
0.20%
% Adults Treated
2000 2001 2002 2003 with Medication Late 2002, Strattera introduced
2004 2005
ANNUAL GRWOTH RATE = 15.3% (2000-2005)
*Castle, L, et. al.; Trends in Medication Treatment for ADHD. Journal of Attention Disorders. 2007; 335-342.
13

Up to 65% children with ADHD will continue to have symptoms into adulthood *
Pharmacologic treatment of Adult ADHD doubled between 2000-2005**
Marketing New Drug Treatments May Increase Public & Clinician
Awareness
Most Rapid Rate of Growth in Pharmacologic Treatment (2000-2005)**
Children ages 0-9
Adults ages 20-64
Medication Patterns (in 2005)**
Children & Adolescents (Extended Release Formulations account for
68.3%)
Amphetamine mix, 32.4% (does not include dextroamphetamine products)
Methylphenidate, 46.9% (does not include dexmethylphenidate products)
Atomoxetine, 16.7%
Adults (Extended Release Formulations account for 43.7%)
Amphetamine mix, 43.4%
Methylphenidate, 34.5%
Atomoxetine, 13.7%
*American Academy of Child & Adolescent Psychiatry. Practice Parameters for the assesment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder, J Am Acad Child Adolesc Psychiatr. 1997; 36
(10 Suppl); 85S-121S.
**Castle, L, et. al.; Trends in Medication Treatment for ADHD. Journal of Attention Disorders . 2007; 335-342.
14

The Stimulant Landscape: Drugs & Companies
Pharmacotherapy Approaches
:
Choosing the Initial
Type of Drug
Stimulant vs. Non-Stimulant
Comorbidities
Treatment with Stimulants: Which One to Choose?
Practical Concepts in ADHD Medication Treatment
Which Class: Amphetamine or Methylphenidate?
Which Form: Immediate-Release, Intermediate-Release, or
Extended Release?
VYVANSE (lisdexamfetamine)
Clinical Practice
15

Amphetamine Line
Extended Release Formulations (up to 12 hours) –once daily
Vyvanse capsules (Shire) – lisdexamfetamine, d-amphetamine/L-lysine prodrug; approved
2/07, launched 2 nd quarter 2007
Adderall XR capsules (Shire) – mixed amphetamine salts of dextroamphetamine & racemic d/l-amphetamine
Dexedrine SR spansules (GlaxoSmithKline) & generic versions of Dexedrine SR dextroamphetamine
Immediate Release Formulations (3-6 hours) – 2-3 times daily
Adderall tablets (Barr/Duramed-Shire Deal)
Generic versions of Adderall (ie, “mixed amphetamine salts”)
Dexedrine tablets (GlaxoSmithKline) dextroamphetamine
Generic versions of Dexedrine
Methylphenidate Line
Extended Release Formulations (up to 12 hours) – once daily
Concerta tablets (McNeil Pediatrics) methylphenidate
Focalin XR capsules (Novartis) dexmethylphenidate
Daytrana Transdermal Patch (Shire) methylphenidate
Intermediate-Release Formulations,
Second-Generation (6-8 hours) – 1-2x daily
Ritalin LA capsules (Novartis; Celgene);
ANDA filed for generics 11/2007 with
Paragraph IV certification
Metadate CD Capsules (UCB) methylphenidate +metadate ER
Intermediate-Release Formulations, First-
Generation (3-6 hours) – 1-2x daily
Ritalin SR tablets (Novartis) & generic versions - methylphenidate
Metadate ER tablets & generic versions – methylphenidate
16
Immediate Release Formulations (2-4 hours), 2-4x daily
Ritalin tablets (Novartis) & generic versions – methylphenidate
Focalin tablets (Novartis) & generic versions
(approved 2/07) - dexmethylphenidate

Stimulants: 1 st Line Treatments for ADHD (without comorbidities)*
Texas Algorithm for Children: if one stimulant trial fails, use drug from alternative stimulant class (ie, if amphetamine first, then try methylphenidate product)*
Efficacious and generally well-tolerated
High Effect Size
~60-70% respond favorably to stimulant medication initially and over time more significant with stimulants (0.95 long-acting; 0.91 short-acting) than with atomoxetine
(0.62)**
When might stimulants not be considered1 st or 2 nd Line?
Comorbid Tic Disorders
Strattera
Stimulant, with alpha-agonist or atypical antipsychotic
Anxiety Disorders
Strattera
Stimulant, with SSRI for anxiety
Substance Abuse Disorders
Stattera
Long-Acting Stimulant
Other clinical conditions in which most severe comorbidity should be treated first (ie, depression, aggression)
*Pliska SR, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006; 45:642-657.
**Farone SV, Biederman J, et al. Comparing the efficacy of medications for ADHD using metaanalysis. MedGenMed.
2006;8:4 .
17

18

ADHD pharmacotherapy should be tailored to each patient
Drug dose-response curves are unique for each patient
Patients may respond better to one drug class than another
Other clinical factors (ie, lifestyle, comorbidities, abuse liabilities)
Be clinically rational, accept trial & error
Patients/parents have preferences
Extended-release formulations are easy with once daily dosing offer continuous effect through much of the day decrease concern medication will wear off too early or at an important time
Immediate-release formulations offer flexibility of dosing achieve faster, higher peak levels; may optimize performance situations help avoid “feeling on” all day
Clinicians have preferences
19

Combining different formulations may help optimize efficacy and is common practice
ER form in the morning, IR form (“booster”) in the afternoon
Concerta in the am, IR-methylphenidate in mid-late afternoon
Adderall XR in the am, Adderall in late afternoon
Concerta + IR-methylphenidate booster in the am, with IRmethylphenidate in afternoon
Other variations on the theme
Combination Rx is typically within the same drug class (ie, amphetamine: Adderall XR with its IR form) but not always
Vyvanse: ER form in the am + IR form in the pm, all-in-one?
20

More important than the class of stimulant is which time-release formulation is chosen and its associated properties
Patient and/or clinician factors that may influence the use of one class of stimulant over the other
Family history (ie, positive or negative response)
Patient preference/bias
Clinician preference/bias
Clinical relevance of the type of encapsulation or delivery
Sprinkles for food (able with Adderall XR; not with Concerta)
Patch (Daytrana) only with methylphenidate
Insurance Factors (covered later)
Dextroamphetamine & dexmethylphenidate much less commonly used
21

Which Form: Immediate, Intermediate, or Extended Release?
Extended-Release Formulations Generally Favored
Easier, for parents and patients
No need for in-school dosing
Stability of effect for most of day
Improved treatment adherence
Less abuse/misuse potential
Better profile for patients at risk for subtance abuse
Short-Acting
For patient seeking flexible dosing options
Useful as boosters
Higher peak levels may be better for some patients
Very low dose titrations may be better for very young children
Intermediate-Acting
22

23

Efficacy Data
Distinguishing Clinical Features
Current Clinical Trials
Practice Patterns: What Am I Doing? What Are
Colleagues Doing?
Other (Clinical & Non-Clinical) Factors That May
Affect Prescribing Patterns
24

It Works: Results from Phase II, III Studies, High Effect Sizes
Study NRP-104-201 (Phase II)*
Vyvanse & Adderall XR vs. placebo
Children ages 6-12, n=52
Significant results vs. placebo on primary efficacy measure: SKAMP-DS Rating Scale
(attention/deportment), analog classroom (p<0.001)
Significant results vs. placebo on secondary measures: PERMP, Clinical Global Impression (p<0.001)
Study NRP-104-301 (Phase III)**
Children ages 6-12, n=290
Significant results vs. placebo on primary efficacy measure ADHD-RS-IV (50-59% decrease in ADHD-
RS scores vs. 15% decrease for placebo, p<0.001)
Study NRP-104-302***
Long-term open-label study
Significant improvement (>60%) from baseline in the ADHD-RS at endpoint
Pivotal Adult Phase III ADHD Trial**** sNDA before FDA
Adults 18-55, n=414
“Significant reduction” in ADHD-RS-IV scores; 57-61% improved/very imprv (similar to MAS SR trials)
Conclusions
Children: Effect Sizes very high, dose-related (? better than other stimulants)
Adults: looks efficacious
*Biederman J et al (2007). Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry 62:970-976.
**Biederman J et. al (2007). Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a Phase
III, multi-center, randomized, double-blind, forced-dose, parallel-group study. Clin Therapeutics 29: 450-463.
***Findling RL, el al. Long-term efficacy and safety of lisdexamfetamine in school-age children with attention-deficit/hyperactivity disorder. Poser presented at the annual meeting of the American Pscyhiatric Association; 2007 May 23; San Diego, CA.
****From Press Release, Results of VYVANSE pivotal trial in adult ADHD presented at major scientific meeting. At http://www.shire.com/shire/uploads/press/shire/LDX1238.pdf
25

26

Lisdexamfetamine dimesylate is a therapeutically inactive prodrug
The active ingredient d-amphetamine is covalently linked to the amino acid l-lyine
The active ingredient d-amphetamine is released during the enzymatic breakdown of the prodrug in the gut and liver
Saturation kinetics govern the breakdown into the active damphetamine form (unlike other stimulants)
Pharmacokinetic properties associated with the prodrug mechanism of action confer unique clinical and safety properties
First-in-class prodrug stimulant
27

Does Vyvanse offer efficacy soon enough in the day? How does it measure up with other longacting stimulants?
28

How soon to work in the day? reach peak levels? (T-max = time to reach maximum drug concentration)
Likely fairly consistent given saturation kinetics
Significant improvement SKAMP-DS at 2 hours**
Mean T-max=3.7 hours*
Mean T-max=4.5 hours; Range of T-max=4.5-6 hours** (n=8 Vyvanse; 70 mg)
How does this compare to Adderall XR?
Adderall XR carries higher variability; influenced by stomach pH/food content
Significant improvement of SKAMP-DS at 3 hours**
Mean T-max=6 hours; Range of T-max=3.00-12 hours** (n=9 Adderall XR; 30 mg)
How might this compare to Concerta?
Mean T-max=6.8 hours***
Clinical Practice
Good. In the range of other ER formulations
Booster IR-amphetamine can be used in the am if an issue
Conclusions & Implications
Vyvanse works soon enough
May provide a more consistent T-max. More data needed
T-max may be between Adderall-IR and Adderall XR
*Krishnan S (2006): A multiple-dose single-arm pharmacokinetics study of oral lisdexamfetamine dimesylate (LDX; NRP-104) in healthy adult volunteers. Abstract presented at the New Clinical Drug Evaluation Unit 46 th Annual Meeting; June 12-15, 2006; Boca Raton, Florida.
**Biederman J, et al (2007). Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry 62:970-976.
***Concerta Package Insert. At: http://www.concerta.net/concerta/pages/full.jsp
.
29

What is Vyvanse’s duration of effect in a given day? How does this compare to other ER stimulants? Implications, Pros & Cons?
30

Duration of Action
Efficacy on attention and deportment at 12 hours*
Efficacy on inattention and hyperactivity at 6 pm (dosed b/w 7:30-8:00 am)**
Comparison to Adderall XR**
Small trial; not an active comparison trial
Vyvanse & Adderall XR both with significant effect on attention & deportment at 12 hours
Change in math scores (PERMP) most favorable for Vyvanse (49 for LDX;
22 for Adderall XR; -24 for placebo)
Clinical Practice
Conclusions & Implications
May offer greater efficacy in late afternoon/evening than other ER forms
Avoidance of booster doses
Mostly a positive
Possibly a negative some patients prefer flexibility of dosing with other formulations sleep
*Biederman J et al (2007). Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry 62:970-976.
**Biederman J et. al (2007). Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a Phase III, multi-center, randomized, double-blind, forced-dose, parallel-group study. Clin Therapeutics 29: 450-463.
31

Does Vyvanse offer more stable, consistent drug delivery than other (ER) stimulants? Implications for patients? Implications for clinicians?
32

VYVANSE: A More Consistent Drug Delivery System?
Phase II Trial with Vyvanse, Adderall XR, and placebo arms
(n=52)*
Coefficient of variance (%CV)
Measure of inter-patient variability of pharmacokinetic parameters
Lower numbers reflect less inter-patient variability
T-max (Time to max. concentration)
Vyvanse - 15.33
Adderall XR - 52.77
C-max (Max. observed concentration)
Vyvanse 20.34
Aderrall XR - 43.96
Clinical Practice
Implications
Patients
Clinicians
Marketing
*Biederman J et al (2007). Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry
62:970-976.
33

Does Vyvanse offer a better safety profile among stimulants? Better alternative for patients at risk, or with a prior history of substance abuse? Other safety or side effect issues? How significant?
34

1, 2
LD-50
Amount of drug expected to cause death of 50% of the animal population (ie, rats)
LD-50 of Vyvanse greater than 1000 mg/kg
LD-50 of amphetamine about 100 mg/kg
Vyvanse carries significantly reduced toxicity compared with amphetamine
Higher doses of Vyvanse lead to attenuated plasma concentrations (saturation kinetics) compared with amphetamine
1 Krishnan S, et al. Determination of the acute oral toxicity of lisdexamfetamine dimesylate in rats [poster]. Presented at the
2007 Society of Biological Psychiatry; May 17-19, 2007; San Diego, California.
2 Jasinski D, et al. Pharamacokinetics of oral lisdexamfetamine (LDXl NRP104) vs. d-amphetamine in healthy adults with a history of stimulant abuse [poster]. Presented at the 2006 U.S. Psychiatric & Mental Health Congress; November 17,
2006; New Orleans, LA.
35

Schedule II: High Abuse Potential, Severe Dependence Liability
Decreased Misuse/Abuse Liability?
IR formulations: greatest risk, recreational use/misuse on college campuses
ER formulations: less risk, can be crushed
Vyvanse oral ingestion required; no crushing, sniffing, etc….
Shire study: Vyvanse vs. amphetamine in patients with a history of drug abuse
Drug-liking events (DLE) significantly less than amphetamine
Implications
Clinical Practice
Marketing
36

VYVANSE: Safety Profile, Substance Abuse Comorbidities
Comorbidity of ADHD & Substance Use Disorders (SUD)
Complicated & Extremely Signficant Clinical Area
30% adults: ADHD-SUD comorbidity*
Stimulant treatment of ADHD reduces risk of SUD in adolescents**
(contrary to what many may think)
Clinical Practice
A role for Vyvanse? When?
“Wear-off” effects, drug re-enforcing behavior
Clinical Trials
Pilot study of Vyvanse in ADHD Adolescents at Risk for Substance
Abuse (at clinicaltrials.gov)
Sponsored by Columbia University; study start date January 2008
*Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 2005; 57:1215-1220.\
**Biederman J, et al. Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk of substance abuse disorder. Pediatrics
1999; 104:e20.
37

Cardiovascular Profile/Side Effects
Historical Background
Canada, 2005: Adderall XR pulled from market ~ 6 mos based on 20 int’l reports of sudden death
US FDA, 2006: Drug Safety/Risk Mgmt Comt. rec’d black box on CV risk;
Pediatric Advisory Comt. against
Stimulants in General*
Retrospective cohort study (n=55,383; children/adolescents), Pediatrics, 12/07
20% increased hazard of cardiac ED/office visits, use v. non-use (low overall)
Rates of serious or fatal manifestations of heart disease small and comparable to national background rates
Vyvanse
FDA and Agency for Health Research and Quality (AHRQ) Study most comprehensive study to date of potential CV risks and ADHD medications
Completion ~2009/2010, n=500,000 children and adults
Other Side Effects/Issues
Distinctions from other ER stimulants
*Winterstein AD, el al. Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics . 2007;
120; 1494-1501.
38

Clinicaltrials.gov (as of 1/2/08)
9 registered clinical trials mostly for trials completed, or nearing completion, as basis of Shire’s
FDA drug applications (children and adults)
Shire sponsored trials (at clinicaltrials.gov)
Classroom study to assess time of onset in children ages 6-12 with ADHD (study completed December 2007)
Dose-optimization study in children ages 6-12 with ADHD study estimated close to completion dosing beginning with 20 mg, and up to 70 mg
Columbia Study: Pilot Study of Vyvanse in ADHD Adolescents at Risk for
Substance Abuse
Open-label feasibility study, estimated start January 2008
Aim: develop method to approach and treat high risk youth before they develop substance abuse
Safety Studies Across ADHD Drug Treatments (AHRQ Study)
Implications
*A listing currently registered Vyvanse clinical trials can be found at:http://clinicaltrials.gov by searching the term “Vyvanse”
39

History
IR Formulations
Concerta vs. Adderall XR, Canada
Vyvanse
Initiating Stimulant Treatments
Favoring ER formulations
When Vyvanse? When Concerta or Adderall XR?
Switching Stimulant Treatments
“if it ain’t broke, don’t fix it”, changing views?
Switching to Vyvanse
Switching off Vyvanse
Future
40

41

Adderall XR*
Shire Pharmaceuticals/Barr Laboratories patent litigation settled
Deal to allow Barr’s launch of generic Adderall XR as early as April
1, 2009, followed by 180 days market exclusivity of the generic
Time delays?
Concerta**
Concerta patent expired 2004
Two parties have filed generic ANDAs, pending approval
Ritalin LA***
November 2007, Barr Pharmaceuticals filed ANDA with Paragraph
IV certifications for generic Ritalin LA
Celgene & Novartis filed suit
30 month stay before FDA will accept ANDA
*Shire/Barr: excitement levels rise on Adderall deal. At http://www.pharmaceutical-businessreview.com/article_feature.asp?guid=28EC938C-683A-4E5F-90BC-770D38F4D471
**Johnson & Johnson 10-Q quarterly report, August 2007. At http://64.233.169.104/search?q=cache:-
Q_PMr2NaFcJ:biz.yahoo.com/e/070808/jnj10-q.html+10-
+and+Johnson+and+anda+and+concerta&hl=en&ct=clnk&cd=1&gl=us&ie=UTF-8
***Barr sued over Ritalin LA patent challenge. FDA-News. At http://fdanews.com/newsletter/article?issueId=10988&articleId=100965
42

Adderall XR & its generic equivalent(s) will NOT be the generic equivalent of Vyvanse
Continuing Vyvanse Prescriptions.
Clinically (and in my view, from a managed care quality of care standpoint) it will be problematic for patients taking Vyvanse to be pressured to take a “non-generic ‘generic’ alternative” of Vyvanse
Initiating or Switching to Vyvanse Prescriptions.
Formularies may revise their step-therapy protocols for initiating or switching to new Vyvanse prescriptions once a generic version of Adderall
XR or Concerta is out
Step-therapy may be bypassed by pre-certification
How willing would clinicians be to take on pre-certs, other advocacy roles?
Will Vyvanse be compelling enough clinically if such measures are required?
When could a generic form of Vyvanse be available?
43

44

Three Tiers
Tier 1 - Generics, least expensive co-pay
Tier 2 - Preferred brand, middle co-pay
Tier 3 - Non-preferred brand or generic, highest co-pay
(Tiers 4, 5) – For self-injectables
Step-Therapy Model
If step-therapy is not followed, then the drug claim may be rejected
Physician may bypass or override step-therapy by acquiring precertification (“medical exception”) for the drug
Assessed on a case-by-case basis
Typically can be done prior to or after the prescription is filled
Formularies are dynamically evolving based on economic and medical factors
45

DRUG
ADDERALL mixed amph salts
ADDERALL XR
VYVANSE
CONCERTA
FOCALIN, FOCALIN XR
RITALIN, RITALIN LA,
RITALIN SR methylphenidate, methylphenidate SR
DAYTRANA
Co-Pay Tier Pre-Certification Step-Therapy
3
1
2
3
3
2
3 YES
YES
YES
1
2
* 2008 Aetna Preferred Drug Guide, 3,4 & 5 Tier Open Formulary Plans. At http://www.aetna.com/FSE/planType.do
46

Where does Vyvanse stand in other prescription formularies/plans?
Anthem
Medco
Others
How will Shire’s pricing structure of Vyvanse (vs.
Adderall XR, Concerta) position it for inclusion and coverage?
Assumptions (wholesale, retail pricing)
Selected retail data
47

Chain Pharmacy in CT, December 2007
Vyvanse (#30 capsules/1 month supply)
30 mg daily dose - $134.99
50 mg daily dose - $134.99
70 mg daily dose - $134.99
Adderall XR (#30 capsules/1 month supply)
10 mg daily dose - $167.99
20 mg daily dose - $167.99
30 mg daily dose - $167.99
Concerta (#30/1 month supply)
18 mg daily dose - $132.99
27 mg daily dose - $140.99
36 mg daily dose - $138.99
54 mg daily dose - $157.99
48

Chain Pharmacy in CT, December 2007 ( con’d )
Amphetamine Line/Immediate Release Drugs
Adderall (Branded Version) - #60 tabs
5 mg tabs - $86.99
10 mg tabs - $77.99
20 mg tabs - $77.99
Generic mixed amphetamine combo - #60 tabs
5 mg tabs - $25.39
10 mg tabs - $32.39
20 mg tabs - $39.59
49

HMO Pharmacy in CT, December 2007
Vyvanse (#30 capsules/1 month supply)
30 mg daily dose - $125.63
50 mg daily dose "
70 mg daily dose "
Adderall XR (#30 capsules/1 month supply)
5 mg daily dose - $125.63
10 mg daily dose - $ "
15 mg daily dose - $ "
20 mg daily dose - $ "
25 mg daily dose - $ "
30 mg daily dose - $ "
Concerta (#30/1 month supply)
18 mg daily dose - $119.33
27 mg daily dose - $121.68
36 mg daily dose - $124.69
54 mg daily dose - $142.38
50

HMO Pharmacy in CT, December 2007 (con’d)
Amphetamine
Adderall (Branded Version)
5 mg tabs (#30 - $90.27; #60 - $163.53)
10 mg tabs (#30 -
20 mg tabs (#30 -
" ; #60 - $ " )
" ; #60 - $ " )
Generic mixed amphetamine combo
5 mg tabs (#30 - $19.93; #60 - $24.41)
10 mg tabs (#30 - $24.69; #60 - $31.59)
20 mg tabs (#30 - $19.93; #60 - $24.21)
Methylphenidate
Ritalin
#30 10 mg tabs - $33.88
#30 20 mg tabs - $47.33
Generic methylphenidate
#30 10 mg tabs - $10.99
#30 20 mg tabs - $14.83
51

Clinician Factors
New clinical data, observable benefit, and tolerability
The New-Drug-On-The-Market Phenomenon
Who’s treating the ADHD?
Patient Factors
Perception of the drug
Marketing & Public Awareness (ADHD, Vyvanse, Rx treatments)
Adult ADHD Indication
Greater Dosing Flexibility
Will Novartis chose to market Focalin XR?
New ADHD Drugs on the Market
52

The Problem with New Treatments
Emerging Non-Stimulant Classes
Alpha-2 agonists
Neuronal Nicotinic Acetylcholine Receptor (NNR) agonists
CV Safety
The Adult ADHD Market
Failures
53

“APPROVABLE”, now awaiting final FDA decisions
SPD-465 (Shire)
“ Extended-release Adderall XR”, up to 16 hr effect
Shire’s plans
INTUNIV (Shire)
Extended release guanfacine
Non-stimulant, alpha-2 agonist
Efficacy data & side effect profile
Phase III
CLONICEL (Sciele Pharma/Addrenex)
First Phase III Trial, Children & Adolescents, initiated October 2007
Extended release clonidine
Non-stimulant, alpha-2 agonist
54

Phase II
ABT-089 (Abbott Labs)
Children & Adults, ADHD
Neuronal Nicotinic Acetylcholine Receptor (NNR) partial agonist (alpha4beta2)
Published clinical data (n=11)
ABT-894 (Abbott Labs/Neurosearch)
Adult ADHD, initiated March 2007
Neuronal Nicotinic Acetylcholine Receptor (NNR) agonist (alpha4beta2)
MK0249 (Merck)
Adult ADHD, study start date July 2007
GTS21 (CoMentis)
Adult ADHD
? Status (per CoMentis website, Phase II expected Q4 2007; per clinicaltrials.gov,
Phase II/I “not yet open”, last updated January 2007)
Neuronal Nicotinic Acetylcholine Receptor (NNR) agonist (alpha7)
PF-03654746 (Pfizer)
Adult ADHD (not yet enrolling, clinicaltrials.gov)
? Novel Mechanism of Action (in a decongestant study)
JNJ-31001074 (Alza)
Adult ADHD (not yet open for recruitment)
Info last updated Dec 2007, clinicaltrials.gov
Phase I & Pre-Clinical
55