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Review
. 2021 Dec 8:6:100123.
doi: 10.1016/j.prdoa.2021.100123. eCollection 2022.

Potential utility of amantadine DR/ER in persons with Parkinson's disease meeting 5-2-1 criteria for device aided therapy

Robert A Hauser  1 , Santosh Goud  2 , Andrea E Formella  2
Affiliations
Review

Potential utility of amantadine DR/ER in persons with Parkinson's disease meeting 5-2-1 criteria for device aided therapy

Robert A Hauser et al. Clin Park Relat Disord. .

Abstract

Background: The 5-2-1 criteria (≥5 levodopa doses/day, ≥2 h OFF/day, and ≥ 1-hour dyskinesia/day) propose to identify people with Parkinson's disease (PD) who are poorly controlled on oral therapies and who may therefore benefit from device-aided therapies. Amantadine-DR/ER is the only medication FDA-approved for both dyskinesia and OFF episodes in levodopa-treated patients. In this post-hoc analysis of phase 3 clinical trials, we evaluated the efficacy and safety of amantadine-DR/ER in patients meeting 5-2-1 criteria.

Methods: Week-12 treatment differences (Amantadine-DR/ER - placebo) in the Unified Dyskinesia Rating Scale (UDysRS) and PD motor states (patient diaries) were evaluated in pooled, phase-3, double-blind trial participants meeting 5-2-1 criteria at baseline. This 5-2-1 cohort was followed into a 2-year open-label trial, where Movement Disorder Society - Unified Parkinson's Disease Rate Scale (MDS-UPDRS) Part IV scores were assessed relative to double-blind baseline.

Results: Of 198 enrolled participants in the phase 3 trials, 65 (33%; n = 29 placebo; n = 36 amantadine-DR/ER) comprised the 5-2-1 cohort. At Week-12 endpoint, amantadine-DR/ER significantly improved UDysRS scores (treatment difference of 9.57 ± 3.15 points, p = 0.004) and ON time without troublesome dyskinesia ('good ON', treatment difference of 2.9 ± 0.90 h/day, p = 0.002). Improvements in good ON time resulted from significant reductions in both troublesome dyskinesia and OFF time. Treatment benefit on MDS-UPDRS-Part IV was sustained through open-label, follow-up. The most common adverse events in patients who met 5-2-1 criteria and were treated with amantadine-DR/ER included falls and peripheral edema.

Conclusions: Findings suggest Amantadine-DR/ER should be considered as an option for people with PD who meet 5-2-1 criteria.

Keywords: 5-2-1 criteria; Amantadine; Dyskinesia; OFF time; ON time; Parkinson’s disease; Treatment.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert A Hauser is supported in part by a Center of Excellence grant from the National Parkinson Foundation and is employed by the University of South Florida (Florida). He received payment from Adamas Pharmaceuticals, Inc. for participating as a Steering Committee member and reports receiving personal fees from Abbvie, Acorda, Adamas, Alterity, Amneal, Cerevance, Curium Pharma, Enterin, Global Kinetics Corp., Inhibikase, Jazz Pharmaceuticals, Kyowa Kirin, Merck, Merz, Neurocrine, NeuroDerm, Orion, Pharmather Inc., Sage Therapeutics, Scion, Sio Gene Therapies, Sunovion, Supernus, Tolmar, and Vivifi Biotech. Santosh Goud and Andrea E. Formella are employed by and own stock in Adamas Pharmaceuticals Inc.

Figures

Fig. 1
Fig. 1
LS Mean Change from baseline in efficacy parameters during double-blind treatment for patients meeting all three 5–2-1 criteria (a) Unified Dyskinesia Rating Scale (UDysRS), (b) Changes good ON time versus OFF time + ON time with troublesome dyskinesia, based on PD diaries (c) Clinician’s Global Impression of Change (CGI-C) in overall Parkinson’s disease symptoms ratings by Treatment Group. *p < 0.05, **p < 0.01 versus placebo, analysed using MMRM for UDysRS and PD Diary measures and CMH for CGI-C. Good ON is defined as ON time without troublesome dyskinesia. AMT DR/ER: amantadine DR/ER. ONTD: ON with troublesome dyskinesia.
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