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

GLGi: Attention Deficit Hyperactivity Disorder (ADHD)

Louis Sanfilippo, MD January 22, 2008

Chicago

© 2007 Gerson Lehrman Group Inc., All Rights Reserved

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.


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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7

Diagnosis & Assessment of ADHDClinical 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

8

Prevalence of ADHD in the U.S. Population

0

1

2

3

4

5

6

7

8

9

10

Ages 4-17*** Ages 18+***0

1

2

3

4

5

6

7

8

9

10

Ages 4-17* Ages 18+**

Percent(%) Millions

* 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

Prevalence of ADHD (in percentages) Prevalence of ADHD (in millions)

9

ADHD: Trends in Medication Treatment

10

Overview: Medication Treatments for ADHD

FDA-Approved TreatmentsStimulants

Schedule II DrugsPotentiate dopamine/norepinephrine neurotransmission

Atomoxetine (Strattera; Eli Lilly) Non-stimulantNorepinephrine reuptake inhibitor

Off-Label TreatmentsModafanil (Provigil; Cephalon) – arousal-promotingGuanfacine - alpha-2 agonistClonidine - alpha-2 agonistBupropion (Wellbutrin family) – norepinephrine/dopamine reuptake inhibitorTricyclic Antidepressants

11

ADHD Prevalence vs. Medication Treatment, U.S.

0.00%

1.00%

2.00%

3.00%

4.00%

5.00%

6.00%

7.00%

8.00%

Ages 4-17* Ages 20+**

Prevalence

Rx Treated

*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.

12

ADHD Medication Treatment Trends, Ages 0-19 (2000-2005)*

2.80%

3.10%

3.40%

4.00%

4.40% 4.40%

2.00%

2.50%

3.00%

3.50%

4.00%

4.50%

2000 2001 2002 2003 2004 2005

Ages 0-19

% Children &

Adolescents Treated Late 2002, Strattera With Medication 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.

13

ADHD Medication Treatment Trends, Ages 20+ (2000-2005)*

0.40% 0.40%

0.50%

0.60%

0.70%

0.80%

0.20%

0.30%

0.40%

0.50%

0.60%

0.70%

0.80%

2000 2001 2002 2003 2004 2005

Ages 20+

% Adults Treated

with Medication Late 2002, Strattera introduced

ANNUAL GRWOTH RATE = 15.3% (2000-2005)

*Castle, L, et. al.; Trends in Medication Treatment for ADHD. Journal of Attention Disorders. 2007; 335-342.

14

Trends: ADHD Diagnosis & Medication Treatment

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 0-9Adults 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.

15

AN OVERVIEW:Clinical Decision-Making in ADHD Pharmacotherapy

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

16

The Stimulant Landscape: Drugs & CompaniesAmphetamine Line

Extended Release Formulations (up to 12 hours) –once daily

Vyvanse capsules (Shire) – lisdexamfetamine, d-amphetamine/L-lysine prodrug; approved 2/07, launched 2nd quarter 2007Adderall XR capsules (Shire) – mixed amphetamine salts of dextroamphetamine & racemic d/l-amphetamineDexedrine 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) -dextroamphetamineGeneric versions of Dexedrine

Methylphenidate Line

Extended Release Formulations (up to 12 hours) – once daily

Concerta tablets (McNeil Pediatrics) - methylphenidateFocalin XR capsules (Novartis) - dexmethylphenidateDaytrana 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 certificationMetadate CD Capsules (UCB) -methylphenidate +metadate ER

Intermediate-Release Formulations, First-Generation (3-6 hours) – 1-2x daily

Ritalin SR tablets (Novartis) & generic versions - methylphenidateMetadate ER tablets & generic versions – methylphenidate

Immediate Release Formulations (2-4 hours), 2-4x daily

Ritalin tablets (Novartis) & generic versions – methylphenidateFocalin tablets (Novartis) & generic versions (approved 2/07) - dexmethylphenidate

17

ADHD Pharmacotherapy: Choosing the Initial Type of Drug

Stimulants: 1st 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-toleratedHigh Effect Size

~60-70% respond favorably to stimulant medication initially and over timemore significant with stimulants (0.95 long-acting; 0.91 short-acting) than with atomoxetine (0.62)**

When might stimulants not be considered1st or 2nd Line?Comorbid Tic Disorders

StratteraStimulant, with alpha-agonist or atypical antipsychotic

Anxiety Disorders StratteraStimulant, with SSRI for anxiety

Substance Abuse DisordersStatteraLong-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 attention-deficit/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.

18

Practical Concepts in ADHD Stimulant Treatment

19

One Drug May Not Fit All …but are some better?

ADHD pharmacotherapy should be tailored to each patientDrug 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 formulationsoffer flexibility of dosing

achieve faster, higher peak levels; may optimize performance situations

help avoid “feeling on” all day

Clinicians have preferences

20

Stimulant Treatment Often Involves A Combination Drug Strategy

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 IR- methylphenidate 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?

21

Which Class: Methylphenidate or Amphetamine?

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 deliverySprinkles for food (able with Adderall XR; not with Concerta)

Patch (Daytrana) only with methylphenidate

Insurance Factors (covered later)

Dextroamphetamine & dexmethylphenidate much less commonly used

22

Which Form: Immediate, Intermediate, or Extended Release?

Extended-Release Formulations Generally Favored Easier, for parents and patientsNo need for in-school dosingStability of effect for most of dayImproved treatment adherenceLess abuse/misuse potentialBetter profile for patients at risk for subtance abuse

Short-ActingFor patient seeking flexible dosing optionsUseful as boostersHigher peak levels may be better for some patientsVery low dose titrations may be better for very young children

Intermediate-Acting

23

VYVANSE (LDX:lisdexamfetamine dimesylate)

24

OVERVIEW: How Does/Will VYVANSE Fit Into the Stimulant & ADHD Treatment Landscape?

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

25

VYVANSE: Efficacy Data for ADHDIt Works: Results from Phase II, III Studies, High Effect SizesStudy NRP-104-201 (Phase II)*

Vyvanse & Adderall XR vs. placeboChildren ages 6-12, n=52Significant 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=290Significant 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 studySignificant improvement (>60%) from baseline in the ADHD-RS at endpoint

Pivotal Adult Phase III ADHD Trial**** sNDA before FDAAdults 18-55, n=414“Significant reduction” in ADHD-RS-IV scores; 57-61% improved/very imprv (similar to MAS SR trials)

ConclusionsChildren: 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

26

VYVANSE:Distinguishing Clinical

Features

27

The Prodrug Concept

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 d-amphetamine form (unlike other stimulants)

Pharmacokinetic properties associated with the prodrug mechanism of action confer unique clinical and safety properties

First-in-class prodrug stimulant

28

Does Vyvanse offer efficacy soon enough in the day? How does it measure up with other long-acting stimulants?

VYVANSE: Distinguishing Clinical Features

29

VYVANSE: Time to Efficacy, Peak LevelsHow soon to work in the day? reach peak levels? (T-max = time to reach maximum drug concentration)

Likely fairly consistent given saturation kineticsSignificant 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 contentSignificant 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 PracticeGood. In the range of other ER formulationsBooster IR-amphetamine can be used in the am if an issue

Conclusions & ImplicationsVyvanse works soon enoughMay provide a more consistent T-max. More data neededT-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 46th 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.

30

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


31

VYVANSE: Duration of Action

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 trialVyvanse & Adderall XR both with significant effect on attention & deportment at 12 hoursChange 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 formsAvoidance of booster dosesMostly a positive Possibly a negative

some patients prefer flexibility of dosing with other formulationssleep


**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.

32

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


33

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 parametersLower numbers reflect less inter-patient variabilityT-max (Time to max. concentration)

Vyvanse - 15.33Adderall XR - 52.77

C-max (Max. observed concentration)Vyvanse - 20.34Aderrall XR - 43.96

Clinical Practice Implications

PatientsCliniciansMarketing


34

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?


35

VYVANSE: Safety Profile, Overdose Toxicity1, 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/kgLD-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

1Krishnan 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.

2Jasinski 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.

36

VYVANSE: Safety Profile, Misuse/Abuse Liabilities

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

37

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.

38

VYVANSE: Safety Profile, Side Effects

Cardiovascular Profile/Side EffectsHistorical Background

Canada, 2005: Adderall XR pulled from market ~ 6 mos based on 20 int’l reports of sudden deathUS 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, 12/0720% 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

VyvanseFDA and Agency for Health Research and Quality (AHRQ) Study

most comprehensive study to date of potential CV risks and ADHD medicationsCompletion ~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.

39

VYVANSE: Current Clinical Trials*Clinicaltrials.gov (as of 1/2/08)

9 registered clinical trialsmostly 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 2008Aim: 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”

40

Practice Patterns: What Am I Doing? Colleagues?

HistoryIR Formulations

Concerta vs. Adderall XR, Canada

Vyvanse

Initiating Stimulant TreatmentsFavoring 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

41

Other (Clinical & Non-Clinical) Factors that May Affect Stimulant Prescribing

Patterns

42

Generic Incursion: The Landscape AheadAdderall 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 2004Two parties have filed generic ANDAs, pending approval

Ritalin LA***November 2007, Barr Pharmaceuticals filed ANDA with Paragraph IV certifications for generic Ritalin LACelgene & Novartis filed suit30 month stay before FDA will accept ANDA

*Shire/Barr: excitement levels rise on Adderall deal. At http://www.pharmaceutical-business-review.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

43

How Will the Use of Vyvanse Be Affected by a Generic Adderall XR?

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?

44

VYVANSE: Insurance Coverage, Pricing Structure, & Positioning

for Formulary Coverage

45

3-Tiered Formulary Models

Three TiersTier 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 ModelIf step-therapy is not followed, then the drug claim may be rejected

Physician may bypass or override step-therapy by acquiring pre-certification (“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

46

2008 Aetna Preferred Drug Guide,3,4, & 5 Tier Open Formulary Plans*

DRUG Co-Pay Tier

Pre-Certificat

ion

Step-Therapy

ADDERALL

3

mixed amph salts

1

ADDERALL XR

2

VYVANSE 2

CONCERTA

3 YES

FOCALIN, FOCALIN XR 3

YESRITALIN, RITALIN LA, RITALIN SR 3

YESmethylphenidate, methylphenidate SR 1

DAYTRANA

2

* 2008 Aetna Preferred Drug Guide, 3,4 & 5 Tier Open Formulary Plans. At http://www.aetna.com/FSE/planType.do

47

VYVANSE: Insurance, Price Structure & Positioning

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

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PRICING: Vyvanse, Adderall XR, and Concerta

Chain Pharmacy in CT, December 2007

Vyvanse (#30 capsules/1 month supply)30 mg daily dose - $134.99

50 mg daily dose - $134.99


Adderall XR (#30 capsules/1 month supply)10 mg daily dose - $167.99



Concerta (#30/1 month supply)18 mg daily dose - $132.99




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PRICING: Adderall, Branded & Generic

Chain Pharmacy in CT, December 2007 (con’d)

Amphetamine Line/Immediate Release DrugsAdderall (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

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PRICING: Vyvanse, Adderall XR, & Concerta

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 - $ "





Concerta (#30/1 month supply)18 mg daily dose - $119.33




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PRICING: Adderall & Ritalin, Branded & Generics

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 - " ; #60 - $ " )20 mg tabs (#30 - " ; #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)

MethylphenidateRitalin

#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

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Yet Other Factors that May Influence Rx Patterns….

Clinician FactorsNew clinical data, observable benefit, and tolerability

The New-Drug-On-The-Market Phenomenon

Who’s treating the ADHD?

Patient FactorsPerception 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

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OVERVIEW: ADHD Drugs in The Pipeline

The Problem with New Treatments

Emerging Non-Stimulant ClassesAlpha-2 agonists

Neuronal Nicotinic Acetylcholine Receptor (NNR) agonists

CV Safety

The Adult ADHD Market

Failures

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ADHD Drugs in the Pipeline

“APPROVABLE”, now awaiting final FDA decisionsSPD-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 IIICLONICEL (Sciele Pharma/Addrenex)

First Phase III Trial, Children & Adolescents, initiated October 2007

Extended release clonidine

Non-stimulant, alpha-2 agonist

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ADHD Drugs in the PipelinePhase 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

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

Documents

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