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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.
© 2007 Gerson Lehrman Group Inc., All Rights Reserved
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
© 2007 Gerson Lehrman Group Inc., All Rights Reserved
About GLG Institute
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Gerson Lehrman Group Contacts
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© 2007 Gerson Lehrman Group Inc., All Rights Reserved
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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?
VYVANSE: Distinguishing Clinical Features
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). 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.
32
Does Vyvanse offer more stable, consistent drug delivery than other (ER) stimulants? Implications for patients? Implications for clinicians?
VYVANSE: Distinguishing Clinical Features
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
*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.
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?
VYVANSE: Distinguishing Clinical Features
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
48
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
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
49
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
50
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 - $ "
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
51
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
52
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
53
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
54
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
55
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