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22
Glycopyrrolate
Larry Dillaha, M.D.Executive Vice President
Chief Medical Officer
for the treatment of chronic moderate-severe drooling in pediatric patients
33
Cerebral Palsy (CP) Cerebral Palsy (CP) Definition:
A group of motor impairments manifested as various physical and mental disorders caused by injury to the brain.
Common symptoms:Uncontrolled reflex movementsSpasticity affecting different parts of the bodyMental retardationSeizure disordersVision impairmentsAuditory impairmentsDrooling
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Impact of CPImpact of CP
800,000 patients in US
$920,0001 total lifetime cost of care
Patients need around-the-clock care
Frequent doctor and hospital visits
Shortened life expectancy
1: United CP
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DroolingDroolingDefinition - unintentional loss of saliva from the mouth
Sialorrhea - increase in salivary flow
Anatomy - 3 pairs of major salivary glandsParotid Submandibular – 70%Sublingual
Oral PhaseInability to close the mouthPoor head controlAbnormal tongue controlReduced intra-oral sensation
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Pediatric DroolingPediatric Drooling
Drooling is normal in growing children, up to the age of 18 months
Drooling beyond the age of 4 is considered abnormal
Drooling frequently persists in children with CP
Parents of more than 1400 patients with CP stated:– Drooling is sometimes a problem 'requiring a bib' (34%)
– Drooling is often a problem 'requiring daily clothing changes' (16%)1
1:Bachrach SJ, et al. Use of glycopyrrolate and other anticholinergic medications for sialorrhea in children with cerebral palsy. Clin. Pediatr. (Phila)
1998;37:485-90.
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Complications of Severe DroolingComplications of Severe Drooling
Chronically irritated, chapped, or macerated skin cheilitis 67%
Pooling of saliva in mouthLeaking of saliva into the hypopharynx– Congested breathing– Loud rattle in the throat
Unrecognized aspirationRecurrent silent pneumoniaAnxiety and refusal to swallow
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Limited Success with Current Drooling TreatmentsLimited Success with Current Drooling Treatments
Oral motor training
Behavioral therapy
Radiotherapy
Surgical Therapy
Pharmacological therapy
1010
Orphan Drug DesignationOrphan Drug Designation
Granted by the FDA in June 2006– Pediatric patients with chronic moderate-
to-severe drooling
7 years marketing exclusivity after product launchTax credits for development
1111
Development of Orphan Drug IndicationDevelopment of Orphan Drug Indication
Development of new liquid formulation
Created a caregiver manual
Dose titration study
Generate safety data for NDA filing
1212
Glycopyrrolate HistoryGlycopyrrolate HistoryApproved in U.S. for more than 40 years
Anticholinergic agentglycopyrrolate inhibits the action of acetylcholine
Adjunctive therapy in treatment of peptic ulcersOnly Approved Indication in U.S.
Available only in tablets and injectable liquid
1313
Many Other Current UsesMany Other Current Uses
Gastrointestinal
Hyperhidrosis
Meniere’s Disease
Dermal Conditions
Anesthesia
1414
Day - 8 to 0
Visit 3Day 1 Visit 4
Week 2
Visit 5Week 4
Visit 6Week 6
Visit 7Week 8
Efficacy Study Design Efficacy Study Design Screening
Visit 1Day - 21 to
Day -9
Baseline
TreatmentDose Titration
Randomized, DB, Placebo controlled
Post Titration
1515
Efficacy AssessmentsEfficacy AssessmentsEfficacy will be assessed by:
Modified Teacher’s Drooling Scale (mTDS)
Visual analog scale (VAS) performed at the end of the day on thesame days as the mTDS
Rate today’s overall extent of drooling by placing a mark on the line below:
Normal Extremely wet
Global assessment by parent/caregiver and Investigator
1616
Safety Study DesignSafety Study DesignTwenty-four week, multi-center (26 sites), open-label
100 patients complete 24 weeks of oral Glycopyrrolate Liquid treatment
Patient population: – 3 - 18 years of age– Cerebral Palsy – MR– Other neurological conditions
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6 Month Safety Study6 Month Safety Study
Visit 8EXIT VISITWeek 24
Visit 2Day 1 Visit 3
Week 4 Visit 4Week 8 Visit 5
Week 12 Visit 6Week 16 Visit 7
Week 20
Screening
Day -14 to Day -3
Baseline
Day -2 and -1
TreatmentDose Titration
1818
Safety AssessmentsSafety Assessments
Description and tabulation of all AEs;
Physical examinations (PEs) at screening and Week 24;
ECGs
Clinical laboratory evaluations
Behavioral and safety-related data recorded by parents/caregivers
– Twice weekly for the first month of the study
– Once a week from Week 4 to the end of study (Week 24)
1919
Glycopyrrolate Clinical TimelineGlycopyrrolate Clinical TimelineApr
il 200
7Oct
2007
Completed pivotal phase III patient enrollment
Began patient pivotal phase III enrollment
File with NDA
Mid 20
08
1st ha
lf 200
8
Final Results