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 non-purposeful movements of the head and neck, arms, legs or trunk. 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, long-acting formulation of amantadine HCl in development for the treatment
of central nervous system (CNS) disorders, including LID in Parkinson’s disease. Administered once-nightly at bedtime,
ADS-5102 provides a slow initial increase in amantadine plasma concentration, resulting in high plasma concentration
during daytime hours when LID can be troublesome and low concentration overnight. Adamas is investigating whether the
novel pharmacokinetic profile and low overnight amantadine plasma concentration may reduce the insomnia, sleep
disturbances, and vivid dreams occasionally associated with amantadine. ADS-5102 is being investigated in clinical
studies at once-nightly dose strengths 1.3 to 2.1 fold greater than the 100 mg twice-daily dose typically used with
Adamas has completed a Phase 2/3 clinical trial of ADS-5102 for the treatment of LID in Parkinson's disease patients.
The EASED study was a randomized, double-blind, placebo-controlled clinical trial that enrolled 83 Parkinson's disease
subjects at 31 study sites in the US. The study's primary efficacy analysis compared ADS-5102 to placebo for
reduction in LID over eight weeks as assessed by the Unified Dyskinesia Rating Scale (UDysRS). Secondary efficacy
outcome measures included changes in a standardized PD diary, including: ON time without troublesome dyskinesia;
overall PD clinical status as assessed by the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS); and fatigue
measured using the Fatigue Severity Scale. The EASED trial also included an assessment of dose response for
ADS-5102. The study enrolled male and female subjects aged 30 to 85 years who had Parkinson's disease and were
experiencing troublesome LID. Study participants were randomized to receive 260 mg, 340 mg, or 420 mg doses of
ADS-5102 or placebo once-nightly for eight weeks with a two-week safety follow-up. In order to participate in the
study, subjects had to have a score of at least 2 on Part IV, item 4.2 (functional impact of dyskinesia) of the
MDS-UPDRS at screening and Day 1, and be experiencing at least two 30 minute intervals of ON time with troublesome
dyskinesia between the hours of 9 am-4 pm. Safety measures included adverse events and routine safety laboratory
tests that were reviewed during the study by an independent data monitoring committee.
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 and at the 9th World Parkinson's Congress on Oct 2, 2013 in
Montreal, Canada. Press releases containing additional details of the study results can be seen here and 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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