ADS-5102 (amantadine HCl ER)
Adamas Pharmaceuticals is developing ADS-5102 for the treatment of central nervous system (CNS) disorders, including
levodopa-induced dyskinesia (LID) in Parkinson’s disease patients. LID is a disabling condition characterized by
involuntary hyperkinetic movements. There are currently no medications approved for the treatment of LID.
Amantadine, the active component of ADS-5102, is an NMDA receptor antagonist and mild dopamine agonist. Approved
in the US for use in parkinsonism, amantadine has also shown efficacy in small clinical studies in LID and other
neurological conditions, but its use is limited by a lack of controlled efficacy studies and increased adverse
events at doses above 200 mg/day.1,2
ADS-5102 is a proprietary, investigational, extended-release formulation of amantadine HCl. Designed for once-nightly
administration, ADS-5102's unique “chronotherapeutic” pharmacokinetic profile is characterized by a slow increase
in amantadine plasma concentrations, high plasma concentrations during the daytime hours when LID can be troublesome
and low plasma concentrations overnight. Adamas is investigating whether the low overnight amantadine plasma
concentration may reduce the insomnia, sleep disturbances, and vivid dreams occasionally associated with amantadine.
Due to its altered pharmacokinetic profile, ADS-5102 is being investigated in clinical studies at daily dose strengths
1.3 to 2.1 fold greater than the 100 mg twice-daily dose typically used with immediate-release amantadine.
Adamas has completed a Phase 2/3 clinical trial of ADS-5102 for the treatment of LID in Parkinson's disease
patients. The EASED™ (Extended Release Amantadine Safety and Efficacy Study in
Levodopa-Induced Dyskinesia) clinical trial was a randomized, double-blind, placebo-controlled study that
enrolled 83 Parkinson's disease subjects at 31 sites in the US (NCT 01397422). Subjects were
randomized in a 1:1:1:1 ratio to the four treatment groups: placebo, 260 mg ADS-5102, 340 mg ADS-5102 and 420 mg
ADS-5102. The EASED study of ADS-5102 met its primary endpoint; both the 340 mg and 420 mg ADS-5102 dose levels
significantly reduced LID as measured by the change in Unified Dyskinesia Rating Scale (UDysRS) Total Score over
eight weeks versus placebo. Consistent with the changes observed in the UDysRS, ADS-5102 also demonstrated
statistically significant functional improvement in dyskinesia as assessed by the MDS-Unified Parkinson's Disease
Rating Scale (MDS-UPDRS, item 4.2), a measure of the degree of impact that dyskinesia has on the patient's daily
function in terms of activities and social interactions. In addition, subjects reported a statistically significant
increase of approximately three hours in “ON Time without troublesome dyskinesia” compared to placebo at week 8
across all dose levels.
The adverse events (AEs) reported in this study were consistent with Parkinson's disease and the known amantadine
safety profile. Treatment emergent AEs were common in all treatment groups, and most were mild to moderate in
Results from the EASED trial were presented at the 17th International Congress of Parkinson's Disease and
Movement Disorders on June 18, 2013 in Sydney, Australia. A press release detailing results of the EASED study
can be seen here.
Additional Indications under Investigation
In addition to Parkinson's disease, amantadine has been used by physicians to treat a variety of CNS indications,
including multiple sclerosis fatigue,3-5 ADHD,6 chronic and acute traumatic brain
injury7,8 and antipsychotic-induced weight gain.9 The mechanistic explanations for
amantadine's activity are as varied as these indications, including NMDAr antagonism,10 dopamine
release,11 norepinephrine release,12 serotonin release,13 BDNF upregulation14
and anti-cholinergic activity.15
What these indications have in common is that amantadine, a drug first approved for influenza A, has shown
promising results in several small pilot studies. Adamas is currently investigating the mechanisms and activities
of amantadine in preclinical models and anticipates conducting studies in up to two additional indications. In
the longer term, Adamas expects to develop additional combination products based upon ADS-5102.
1 Hayden et al., AAC, 1983, P. 458-464
2 Jackson et al., Bull. Pan American Health Org, 1967, 595
3 Martinez-Martin P, et al., “Impact of fatigue in Parkinson's disease: the Fatigue Impact Scale for
Daily Use (D-FIS).” Qual Life Res, 2006. May;15(4):597-606.
4 Pucci, E., P. Branas, et al., "Amantadine for fatigue in multiple sclerosis." Cochrane Database
Syst, 2007. Rev(1): CD002818.
5 Putzki, N., et al., “Prevalence and severity of multiple-sclerosis-associated fatigue in treated
and untreated patients.” Eur Neurol, 2008. 59(3-4): p. 136-42.
6 Donfrancesco R, Calderoni D, Vitiello B., “Open-label amantadine in children with attention-deficit/
hyperactivity disorder.” J Child Adolesc Psychopharmacol. 2007 Oct;17(5):657-64.
7 Hammond F., “Use of Amantadine Hydrochloride in the Treatment Irritability and Aggression in Chronic
Traumatic Brain Injury: A Randomized, Controlled Trial.” American Neuropsychiatric Association Annual Conference,
March 18, 2010, Tampa, FL 2010.
8 Giacino, J., White, J., et al., “Placebo-controlled trial of amantadine for severe traumatic brian
injury”, NJEM, 2012, 369:819-26.
9 Graham, K.A., Gu, H., et al., “Double-blind, placebo-controlled, investigation of amantadine for weight
loss in subjects who gained weigh on olanzapine.” Am J Psychiatry, 2005, 162:1744-6.
10 Blanpied, T.A., Boekman, E., et al., “Amantadine inhibits NMDA receptors by accelerating channel
closure during channel block.” J Neurosci, 2005, 25:3312-22.
11 Scatton, B., Cheramy, A., et al., “Increased synthesis and release of dopamine in the striatum of
the rat after amantadine treatment.” Eur J Pharmacol, 1970, 13:131-3.
12 Sommerauer, C., Rebernik, P., et al., “The noradrenaline transporter is the site of action for the
anti-Parkinson drug amantadine.” Neuropharmacology, 2012, 62: 1708-16.
13 Wesemann, W., Dette-Wildenhahn, G., et al., “Effects of 1-aminoadamantanes on adenine nucleotide and
serotonin storage in blood platelets.” Eur J Cell Biol, 1981, 26:158-67.
14 Rogoz, Z., Skuza, G., et al., “Repeated co-treatment with fluoxetine and amantadine induces brain-derived
neurotrophic factor gene expression in rats.” Pharmacol Rep, 2008, 60:817-26.
15 Matsubayashi, H., Swanson, K. L., and Albuquerque, E.X., “Amantadine inhibits nicotinic acetylcholine
receptor function in hippocampal neurons.” J Pharmacol Exp Ther, 1997, 281:834-44.
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