Objective: Evaluate delayed release/extended release amantadine (AMT DR/ER) capsules for motor complications in patients meeting 5-2-1 criteria for device-aided therapies (DAT) in advanced Parkinson disease.

Background: The 5-2-1 criteria (≥5 levodopa doses, ≥2 hours OFF, and ≥1-hour dyskinesia per day) propose to identify patients uncontrolled on oral/transdermal therapies who may benefit from DATs, namely, DBS, levodopa/carbidopa intestinal gel (LCIG) or subcutaneous-apomorphine infusion (SCA).[1][2]
The bedtime-administered, AMT DR/ER capsule formulation is the only FDA-approved medication for both dyskinesia and/or OFF episodes in levodopa-treated patients.[3] AMT DR/ER significantly reduced OFF time and dyskinesia in 2 Phase 3 clinical trials;[4] effects persisted through a 2-year, open-label follow-on trial.[5]

Method: We identified AMT DR/ER pooled, phase 3 trial subjects (NCT02136914; NCT02136914) [3] who met 5-2-1 criteria at baseline. Week-12 treatment differences in GOOD ON time (ON without troublesome dyskinesia), other PD diary states, rating scale and safety outcomes were evaluated.

Results: At baseline, of 198 subjects, 104 (52.5%) used levodopa ≥5 times/day, 118 (59.6%) recorded ≥2 hours OFF time and 196 (99%) recorded ≥1-hour troublesome dyskinesia; n=64 (32.3%; n=28 placebo; n=36 AMT DR/ER) met all 3 criteria and composed the 5-2-1 subgroup.

The 5-2-1 subgroup (vs. overall Phase 3) was somewhat younger at diagnosis (53 vs. 56 years) and start of levodopa therapy (55 vs. 58 years), had dyskinesia longer (4.7 vs. 3.8 years), recorded more daily OFF time (4.0 vs 2.8 hours) and used higher levodopa doses (782 vs. 1032 mg).

At Week 12, LS mean (SE) GOOD ON time improved with AMT DR/ER (3.6 (0.63) h/day) vs. placebo (0.8 (0.72) h/day; treatment difference: 2.8(0.91) h/day; P=.003), with significant differences emerging at first assessment (Week 2). AMT DR/ER reduced OFF time (treatment difference: -1.4 (0.60) h/day; P=.02) and troublesome dyskinesia (-1.6 (0.76) h/day; P=.04). Improvements in CGI (P=.003), UDysRS: 9.2 (P=.006), and MDS-UPDRS Part II: -2.6 (P =.01) and Part IV: -1.5 (P=.02) scores suggest increased GOOD ON time was meaningful and accompanied by improved function. Adverse events included peripheral edema, falls, dizziness, dry mouth and hallucinations.

Conclusion: Findings suggest a trial of AMT DR/ER should be considered in appropriate patients eligible for DAT.

References: [1] Antonini A, Stoessl AJ, Kleinman LS, et al. Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson’s disease: a multi-country Delphi-panel approach. Curr Med Res Opin. 2018/12/02 2018;34(12):2063-2073. [2] Aldred J, Anca-Herschkovitsch M, Antonini A, et al. Application of the ‘5-2-1’ screening criteria in advanced Parkinson’s disease: interim analysis of DUOGLOBE. Neurodegener Dis Manag. Oct 2020;10(5):309-323. [3] Gocovri (amantadine) extended release capsules (prescribing information). Emeryville, CA: Adamas Pharma, LLC; 1/2020. [4] Elmer LW, Juncos JL, Singer C, et al. Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson’s Disease. CNS Drugs. Apr 2018;32(4):387-398. [5] Tanner CM, Pahwa R, Hauser RA, et al. EASE LID 2: A 2-Year Open-Label Trial of Gocovri (Amantadine) Extended Release for Dyskinesia in Parkinson’s Disease. J Parkinsons Dis. Jan 6 2020.

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