Amantadine extended-release capsules for levodopa-induced dyskinesia in patients with Parkinson’s disease

Figures & data

Figure 1 Classic basal ganglia model representing (A) normal condition, (B) Parkinson’s disease, and (C) Parkinson’s disease with LID.

Notes: Normally dopaminergic input from SNc facilitates motor movement through excitatory response on direct pathways via D1 receptors and reduces motor movements through inhibitory response on indirect pathways via D2 receptors. Loss of dopaminergic input from SNc influences both direct and indirect pathways. There is underactivity of the direct pathway and overactivity of the indirect pathways, resulting in decreased glutamatergic output from the thalamus, causing hypokinetic movements. Chronic levodopa therapy overstimulates both D1 and D2 receptors, with opposite influence on direct and indirect pathways leading to increased thalamo-cortical glutamatergic output causing LID. Green arrows indicate inhibitory, GABA connections; red arrows, excitatory Glut (glutamatergic) connections.
Abbreviations: GABA, γ-aminobutyric acid; GPe, globus pallidus externa; GPi, globus pallidus interna; L-DOPA, levodopa; LID, levodopa-induced dyskinesia; PD, Parkinson’s disease; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.

Table 1 Summary of therapeutic trials for amantadine extended-release capsules

Study	Design	Dose ADS-5102 (amantadine HCL)	mITT population (n)	Duration	Outcomes
					Primary measure	Results – change from baseline LS mean	Secondary measures	Results – change from baseline LS mean
EASED^Citation32	Randomized, double-blind, placebo-controlled	209.5 mg (260 mg) 274 mg (340 mg) 338.5 mg (420 mg)	80	8 weeks	UDysRS total score change at 8 weeks	ADS-5102 −209.5 mg: −12.3 TD: −5.6, p=0.15 −274 mg: −17.9 TD: −11.3, p=0.005 −338 mg: −16.9 TD: −10, p=0.013 Placebo: −6.7	ON time w/o troublesome dyskinesia OFF time	TD: −209.5 mg: +3.3 hours, p=0.004 −274 mg: +3.0 hours, p=0.008 −338 mg: +2.7 hours, p=0.01 TD: −209.5 mg: −1.3 hours, p=0.07 −274 mg: −0.9 hours, p=0.19 −338 mg: −0.1 hours, p=0.93
EASE LID^Citation33	Randomized, double-blind, placebo-controlled	274 mg (340 mg)	121	25 weeks	UDysRS total score change at 12 weeks	ADS-5102: −15.9 Placebo: −8.0 TD: −7.9, p=0.0009	UDysRS total score at 24 weeks ON time w/o troublesome dyskinesia at 12 weeks OFF time at 12 weeks	ADS-5102: −15.6 Placebo: −6.3 TD: −9.3, p<0.001 ADS−5102: +3.6 hours Placebo: +0.9 hours TD: 2.8 hours, p<0.0001 ADS-5102: −0.6 hours Placebo: −0.3 TD: 0.9 hours, p=0.017
EASE LID-3^Citation34	Randomized, double-blind, placebo-controlled	274 mg (340 mg)	75	13 weeks	UDysRS total score change at 12 weeks	ADS-5102: −20.7 Placebo: −6.3 TD: −14.4, p<0.0001	ON time w/o troublesome dyskinesia at 12 weeks OFF time	ADS-5102: +4 hours Placebo: +2.1 hours TD: 1.9 hours, p=0.01 ADS-5102: −0.5 hours Placebo: +0.6 hours TD: −1.1 hours, p=0.01

Abbreviations: mITT, modified intention-to-treat; TD, treatment difference ADS-5102 vs placebo; UDysRS, Unified Dyskinesia Rating Scale; w/o, without; LS, least square mean.

Table 2 Summary of most common AEs for amantadine extended-release capsules

AEs % (n)	Study
	EASED^Citation32		EASE LID^Citation33		EASE LID-2^Citation36	EASE LID-3^Citation34
	ADS-5102 274 mg, n=21	Placebo n=22	ADS-5102 274 mg, n=63	Placebo n=60	ADS-5102 274 mg, n=223	ADS-5102 274 mg, n=37	Placebo n=38
Hallucinations	23.8 (5)	0	23.8 (15)	1.7 (1)	19.3 (43)	8.1 (3)	5.3 (2)
Constipation	23.8 (5)	9.1 (2)	15.9 (10)	5.0 (3)	12.6 (28)	8.1 (3)	0
Peripheral edema	<10	NR	23.8 (15)	0	13.0 (29)	<5	NR
Dizziness	28.6 (6)	4.5 (1)	22.2 (14)	0	6.7 (15)	10.8 (4)	NR
Dry mouth	19 (4)	0	17.5 (11)	0	7.2 (16)	13.5 (5)	2.6 (1)
Falls	14.3 (3)	13.6 (3)	15.9 (10)	8.3 (5)	25.1 (56)	8.1 (3)	5.3 (2)
Nausea	14.3 (3)	4.5 (1)	4.8% (3)	NR	8.1 (18)	13.5 (5)	2.6 (1)

Abbreviations: AEs, adverse events; NR, not reported.

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