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GOCOVRI was studied in a comprehensive clinical program in PD patients on levodopa therapy experiencing dyskinesia1

Study 11,2
N = 121 (EASE LID)

Phase 3, randomized
2-arm, placebo-controlled 25-week duration

Study 21,3
N = 75 (EASE LID 3)

Phase 3, randomized
2-arm, placebo-controlled 13-week duration

Study 1 and Study 2 measured CHANGES FROM BASELINE TO Week 121

Primary outcome measure: Unified Dyskinesia Rating Scale (UDysRS) total score*

Key secondary outcome measures1:

  • ON time without troublesome dyskinesia (functional time)
  • OFF time

Other secondary outcome measures2,3:

  • ON time with troublesome dyskinesia

Patients completing Study 1 or Study 2 could continue to receive GOCOVRI in a 2-year, open-label safety study4

OPEN-LABEL SAFETY STUDY
N = 223 (EASE LID 2)

Open-label
ongoing, up to 2-year duration

ADDITIONAL PHASE 2/3 DOSE-FINDING CLINICAL STUDY5

DOSE-FINDING STUDY
N = 80 (EASED)

Phase 2/3, randomized
4-arm, placebo-controlled 8-week duration

*UDysRS is a 4-part rating scale incorporating patient and clinician evaluation of the presence, duration, and severity of dyskinesia.6

GOCOVRI PIVOTAL STUDIES

GOCOVRI™ (amantadine) extended release capsules was studied in 2 pivotal Phase 3, randomized, placebo-controlled studies in nearly 200 PD patients experiencing dyskinesia1

Study 1 and Study 2  trial schematics

Subjects randomized to active treatment received GOCOVRI 137 mg QHS for 1 week, which was titrated to 274 mg QHS (340 mg amantadine HCl) thereafter.

QHS, once daily at bedtime.

LEVODOPA-BASED THERAPY AND ALL OTHER PD MEDICATIONS WERE TO BE HELD CONSTANT THROUGHOUT BOTH STUDY 1 AND STUDY 21

UNIFIED DYSKINESIA RATING SCALE (UDysRS)6

The UDysRS is a 4-part scale. Total scores range from 0 to 104, with higher scores indicating more severe dyskinesia.

PATIENT OR CAREGIVER REPORTED

Part I

Historical Disability of Dyskinesia

  • 11 items; patient/caregiver perceptions of duration and severity
  • Score range 0 to 44

Part II

Historical Disability of OFF-Dystonia

  • 4 items; patient/caregiver perceptions of duration and severity
  • Score range 0 to 16

PHYSICIAN RATED

Part III

Objective Impairment of Dyskinesia

  • Clinician-rated degree of impairment due to dyskinesia based on 4 standardized physical activities
  • Impairment rated in 7 different parts of the body
  • Score range 0 to 28

Part IV

Objective Disability of Dyskinesia

  • Clinician-rated degree of disability based on 4 standardized physical activities
  • Score range 0 to 16

Pooled baseline characteristics2,3,7

Study 1 and Study 2 included a range of younger and older patients (34 to 82 years) as well as patients with a broad duration of dyskinesia (0.1 to 14 years)

  • Baseline characteristics were well-matched between treatment arms in both studies

Baseline characteristicsa

ALL SUBJECTS
N = 196

Range
(MINIMUM TO MAXIMUM)

Age (years)

64.7

34 to 82

Age <65 years (%)

45

N/A

Male (%)

56

N/A

Age (years) at PD diagnosis

55.5

29 to 75

Duration of levodopa treatment (years)

7.7

1.1 to 20.3

Duration of levodopa-induced dyskinesia (years)

3.8

0.1 to 14

UDysRS total score

40.1

8 to 76

ON time without troublesome dyskinesia (hours)

8.4

0.0 to 15.3

ON time with troublesome dyskinesia (hours)b

4.9

0.0 to 13.3

OFF time (hours)

2.8

0.0 to 9.5

Levodopa total daily dose (mg)

782.0

130 to 3100

Levodopa dose adjustment was not allowed during the course of either trial
aValues represent the least squares (LS) mean for each parameter (except for age and gender).
bOne patient had a protocol deviation of zero hours of ON time with troublesome dyskinesia at baseline in Study 2.

KEY ENTRY CRITERIA FOR GOCOVRI PIVOTAL STUDIES2,3

INCLUSION CRITERIA

EXCLUSION CRITERIA

  • Age: 30 to 85 years
  • Patients diagnosed with PD taking levodopa
    • Levodopa preparations administered at least 3 times daily
    • All PD medications unchanged for ≥30 days before screening and during study participation
  • Stable with levodopa therapy experiencing
    • 2 or more half-hour periods between 9 am and 4 pm of ON time with troublesome dyskinesia
    • At least mild functional impact due to dyskinesia
  • History of deep brain stimulation
  • History of exclusively diphasic, off state, myoclonic, dystonic or akathetic dyskinesia without peak dose dyskinesia
  • Presence of cognitive impairment, as evidenced by a MMSE of less than 24
  • History of clinically significant hallucinations (any type) due to PD medications, underlying PD or other/unknown cause, within prior year
  • Estimated GFR <50 mL/min/1.73m2
  • Use of amantadine within prior 30 days
MMSE, Mini-Mental State Examination.
GFR, glomerular filtration rate.

IN A DOSE-FINDING STUDY, A 274 MG (340 MG HCL) DOSE PROVIDED THE OPTIMAL BALANCE BETWEEN EFFICACY AND SAFETY5

The approved dose of GOCOVRI (amantadine) extended release capsules is 274 mg

GOCOVRI doses of 210 mg, 274 mg, and 338 mg are equivalent to 260 mg, 340 mg, and 420 mg amantadine HCl, respectively.

Primary efficacy analysis compared 274 mg dose level with placebo. Study medication administered as 3 capsules, once daily at bedtime, for 8 weeks.

GOCOVRI DEMONSTRATED significant and clinically relevant reductions in dyskinesia THROUGH Week 12 in 2 pivotal studies, without any adjustments to patients’ levodopa dose1,7,8

GOCOVRI achieved a 7.9 and 14.4 placebo-adjusted reduction in UDysRS total score through Week 12 in Study 1 and Study 2, respectively (primary endpoint)*

STUDY 1: UDysRS TOTAL SCORE (MEAN BL, 39.7)

GOCOVRI (amantadine) ER vs placebo reductions from baseline to Week 12 in UdysRS total score in Study 1

ReductionS WeRE SUSTAINED THROUGH WEEK 242

  • *UDysRS is a 4-part rating scale incorporating patient and clinician evaluation of the presence, duration, and severity of dyskinesia.6

STUDY 2: UDysRS TOTAL SCORE (MEAN BL, 40.7)

GOCOVRI (amantadine) ER vs placebo reductions from baseline to Week 12 in UdysRS total score in Study 2
  • *UDysRS is a 4-part rating scale incorporating patient and clinician evaluation of the presence, duration, and severity of dyskinesia.6

GOCOVRI significantly decreased OFF time by ~1 hour vs placebo1,7

GOCOVRI provided a placebo-adjusted decrease of ~1 hour in OFF time through Week 12 in Study 1 and Study 2 (key secondary endpoint)*

STUDY 1: OFF time (Mean BL, 3.1 hOUrs)

GOCOVRI (amantadine) ER vs placebo reductions from baseline to Week 12 in OFF time in Study 1

ReductionS WeRE SUSTAINED THROUGH WEEK 242

*Derived from PD home diary data.

STUDY 2: OFF time (Mean BL, 2.3 hOUrs)

GOCOVRI (amantadine) ER vs placebo reductions from baseline to Week 12 in OFF time in Study 2
  • *Derived from PD home diary data.

Patients treated with GOCOVRI gained up to 4 hours of functional time1,7

GOCOVRI provided gains of 3.6 and 4.0 hours in functional time (defined as ON time without troublesome dyskinesia) from BL through Week 12 in Study 1 and Study 2, respectively (secondary endpoint)*

STUDY 1: ON TIME WITHOUT TROUBLESOME DYSKINESIA (Mean BL, 8.4 hrs)

Improvements from baseline to Week 12 in ON time without troublesome dyskinesia in Study 1

Improvements WeRE SUSTAINED THROUGH WEEK 242

*Derived from PD home diary data.

STUDY 2: ON TIME WITHOUT TROUBLESOME DYSKINESIA (Mean BL, 8.3 hrs)

Improvements from baseline to Week 12 in ON time without troublesome dyskinesia in Study 2
  • *Derived from PD home diary.

In Study 1

GOCOVRI increased functional time by decreasing troublesome dyskinesia and OFF time (SECONDARY ENDPOINT)2,7

ON time without troublesome dyskinesia, ON time with troublesome dyskinesia and OFF time at baseline and week 12 in Study 1
  • Patients treated for PD have reported falling asleep during ADLs. In controlled clinical trials, somnolence and fatigue were reported as adverse reactions in 4% of GOCOVRI patients vs 1% of placebo patients (pooled data)1
  • Insomnia was reported as an adverse reaction in 7% of GOCOVRI patients vs 2% of placebo patients (pooled data)1

In Study 2

GOCOVRI increased functional time by decreasing troublesome dyskinesia and OFF time (SECONDARY ENDPOINT)3,7

ON time without troublesome dyskinesia, ON time with troublesome dyskinesia and OFF time at baseline and week 12 in Study 2
  • Patients treated for PD have reported falling asleep during ADLs. In controlled clinical trials, somnolence and fatigue were reported as adverse reactions in 4% of GOCOVRI patients vs 1% of placebo patients (pooled data)1
  • Insomnia was reported as an adverse reaction in 7% of GOCOVRI patients vs 2% of placebo patients (pooled data)1

Physicians reported a marked improvement in PD symptoms for patients on GOCOVRI vs placebo2,3,7

Clinician’s Global Impression of Change (CGI-C) scores at Week 12 (secondary endpoint)

 Clinician's Global impression of Change (CGI-C) scores at Week 12 in Study 1 and Study 2 for GOCOVRI (amantadine) ER vs placebo

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Important Safety Information

Indication

GOCOVRI™ (amantadine) extended release capsules is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

Contraindications

GOCOVRI™ (amantadine) is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2.

Warnings and Precautions

Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases.

Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose.

Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation of GOCOVRI.

Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges. Consider dose reduction or stopping medications.

Adverse Reactions

The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.

Drug Interactions

Other Anticholinergic Drugs: The dose of GOCOVRI should be reduced if atropine-like effects are observed.

Drugs Affecting Urinary pH: The pH of the urine has been reported to influence the excretion rate of amantadine. Monitor for efficacy or adverse reactions under conditions that alter the urine pH.

Alcohol: Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension.

Indication

GOCOVRI™ (amantadine) extended release capsules is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

References: 1. GOCOVRITM (amantadine) [Prescribing Information]. Emeryville, CA: Adamas Pharma LLC; 2017. 2. Pahwa R, Tanner CM, Hauser RA, et al. ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID Study) a randomized clinical trial. JAMA Neurol. 2017;74(8):941-949. 3. Oertel W, Eggert K, Pahwa R, et al. Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov Disord. 2017;32(12):1701-1709. 4. Hauser R, Pahwa R, Tanner CM, et al. ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 2 study): interim results of an open-label safety study. J Parkinsons Dis. 2017(7):511-522. 5. Pahwa R, Tanner CM, Hauser RA, et al. Amantadine extended release for levodopa-induced dyskinesia in Parkinson’s disease (EASED Study). Mov Disord. 2015;30(6):788-795. 6. Goetz CG, Nutt JG, Stebbins GT. The Unified Dyskinesia Rating Scale: presentation and clinimetric profile. Mov Disord. 2008;23(16):2398-2403. 7. Data On File. Adamas Pharma LLC, Emeryville, CA. 8. Pahwa R, Tanner CM, Hauser RA, et al. Poster presented at: 2017 Annual Meeting of the American Neurological Association; October 15-17, 2017; San Diego, CA.