Parkinson’s Disease: Clinical Update

Navigating The Rising Burden Of Parkinson’s
Disease: Global & Indian Data

According to the Global
Burden of Diseases Survey from 2019, 8.51 million people worldwide (95%
uncertainty interval: 7.29, 9.84) have Parkinson’s disease. More than 12
million individuals will be affected by Parkinson’s disease worldwide by the
year 2050, according to conservative forecasts. In the last ten years, the
prevalence and incidence of the condition have increased by more than 30%. (2)

A report indicated
that around 0.58 million people were living in India who had Parkinson’s
disease, and this number is predicted to rise significantly in the upcoming
years. Despite the high prevalence of Parkinson’s disease, little is known
about the underlying genetic and environmental risk factors that are unique to
the Indian population. (3)

India has the lowest
global overall incidence of Parkinson’s disease (70 per 100,000 normal
populations). Yet, Mumbai’s (a state in India) Parsi community has the highest
prevalence of Parkinson’s disease in the world [328 per 100,000 people]. (4)

Revisiting Medical Management of Parkinson’s
Disease

Given that the cause
of parkinsonism is unknown, current antiparkinsonian pharmacological treatments
target restoring the physiological stimulation of the striatal dopamine
receptors. Levodopa, among other antiparkinsonian medications, and
anticholinergic medications (muscarinic receptor antagonists) are some of the
most commonly used treatment agents (5)

Nevertheless,
long-term levodopa treatment adds motor problems in patients with advanced
nigrostriatal degeneration, such as motor fluctuations between “on”
and “off” levodopa states when symptoms come back before the next
dose is due and levodopa-induced dyskinesia. Amantadine treatment is the only partially effective
anti-dyskinetic pharmacological therapy; it may help shorten off-time in
levodopa-treated individuals. (5)

Glimpse of Amantadine’s Mechanism of Action in
Parkinson’s Disease:

Amantadine’s efficacy
in the symptomatic management of Parkinson’s disease patients was accidentally
discovered more than 50 years ago, and the medication is still routinely used
by neurologists today. Its unique combination of dopaminergic and glutamatergic
activity as part of its pharmacological actions accounts for its dual impact on
Parkinsonian symptoms and levodopa-induced dyskinesias. (6)

Amantadine continues
to be the medication with proven efficacy in reducing levodopa-induced
dyskinesias without worsening parkinsonism in patients with Parkinson’s
disease, with the potential of reducing motor fluctuations. (6)

Current Clinical Position of Amantadine in
Parkinson’s Disease

A recent post-hoc analysis of phase 3 clinical trials evaluated
the efficacy and safety of amantadine in 198 patients meeting 5-2-1 criteria
(≥5 levodopa doses/day, ≥2 h OFF/day, and ≥ 1-hour dyskinesia/day). The
analysis evaluated the Unified Dyskinesia Rating Scale (UDysRS) and Parkinson’s
disease motor states (patient diaries) during the 12th week of
amantadine and placebo treatment. The cohort was followed into a 2-year
open-label trial. The Movement Disorder Society- Unified Parkinson’s Disease
Rate Scale (MDS-UPDRS) Part IV scores were assessed relative to the
double-blind baseline. At the week-12 endpoint, amantadine significantly
improved Unified Dyskinesia Rating Scale 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 troublesome dyskinesia and OFF
time. Treatment benefit on MDS-UPDRS-Part IV was sustained through open-label,
follow-up. The findings suggest Amantadine should be considered an option for
people with Parkinson’s who meet the 5-2-1 criteria. (7)

Hauser RA et al.
evaluated OFF time reductions with amantadine in a pooled analysis of
two-phase III amantadine trials, followed by a 2-year open-label extension.
OFF outcomes were analysed for the modified intention to treat analysis (mITT)
population and stratified by baseline OFF time of ≥2.5 h/day or <2.5 h/day.
At Week 12, the mean placebo-subtracted treatment difference in OFF time was
−1.00 [−1.57, −0.44] h in the mITT population (n =
196), −1.2 [−2.08, −0.32] h in the ≥2.5 h subgroup (n =
102) and −0.77 [−1.49, −0.06] in the <2.5 h subgroup (n = 94). Amantadine-treated participants
showed reduced MDS-UPDRS Part IV motor fluctuation sub-scores by week 2 that
were maintained below the baseline to Week 100. These
analyses showed a robust effect of amantadine in reducing OFF time in patients
experiencing dyskinesia and at least 2.5 h of OFF time at baseline. (8)

ALLAY-LID Trials I and II: Double-blind,
placebo-controlled trials assessed the efficacy of levodopa induced dyskinesia
(LID) in 222 Parkinson’s disease patients ((N = 87 ALLAY-LID I, N
= 135 ALLAY-LID II). Participants were randomized to Amantadine 193 mg, 258 mg,
or placebo. A significant reduction in UDysRS scores versus placebo was
observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled
analysis, placebo-adjusted UDysRS score differences were -5.5 [-9.8, -1.2], p =
0.012 and -5.2 [-9.5, -0.9], p = 0.017, respectively. Amantadine 258 mg
significantly increased time spent ON without troublesome dyskinesia in
ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia
supported the primary outcome (i.e,UDysRS score change from baseline to Day
98). Amantadine significantly reduced LID in ALLAY-LID II; post-hoc pooled data
also indicated a positive treatment effect on LID. (9)

Clinical Key Takeaways:

The incidence of
Parkinson’s disease has been rising globally, and in the next few years, the
number of diagnoses is predicted to double. (1) The disease has a detrimental
effect on patients’ quality of life and imposes high healthcare costs. (1,2)
Despite advances in understanding the disease, the trade-offs between managing
OFF time and dyskinesia in current therapy algorithms are often challenging.
(8) Amantadine is the only medication FDA-approved for treating dyskinesia and
OFF episodes in levodopa-treated patients with Parkinson’s disease. (7)
Amantadine has a potential benefit that can be used for Parkinson’s disease
therapies.

References:

1. Leite
Silva ABR, Gonçalves de Oliveira RW, Diógenes GP, et al. Premotor, nonmotor and
motor symptoms of Parkinson’s Disease: A new clinical state of the art. Ageing Res Rev. 2023;84:101834.
doi:10.1016/j.arr.2022.101834

2. Singh A,
Hussain S, Akkala S, et al. Beta-adrenergic drugs and risk of Parkinson’s
disease: A systematic review and meta-analysis. Ageing Res Rev. 2022;80:101670. doi:10.1016/j.arr.2022.101670

3. Rajan R,
Divya KP, Kandadai RM, et al. Genetic Architecture of Parkinson’s Disease in
the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in
Parkinson’s Disease Research. Front
Neurol. 2020;11:524. Published 2020 Jun 18. doi:10.3389/fneur.2020.00524

4. Akhilesh Kumar Verma, Janak Raj, Vivek Sharma,
Tej Bali Singh, Shalabh Srivastava, Ragini Srivastava. Epidemiology and
associated risk factors of Parkinson’s disease among the north Indian
population. Clinical Epidemiology and Global Health. Volume 5, Issue 1,2017.
doi.org/10.1016/j.cegh.2016.07.003.

5. Paz RM,
Murer MG. Mechanisms of Antiparkinsonian Anticholinergic Therapy
Revisited. Neuroscience.
2021;467:201-217. doi:10.1016/j.neuroscience.2021.05.026

6. Rascol O,
Fabbri M, Poewe W. Amantadine in the treatment of Parkinson’s disease and other
movement disorders. Lancet Neurol.
2021;20(12):1048-1056. doi:10.1016/S1474-4422(21)00249-0

7. Hauser
RA, Goud S, Formella AE. Potential utility of amantadine DR/ER in persons with
Parkinson’s disease meeting 5-2-1 criteria for device-aided therapy. Clin Park Relat Disord. 2021;6:100123.
Published 2021 Dec 8. doi:10.1016/j.prdoa.2021.100123

8. Hauser
RA, Lytle J, Formella AE, Tanner CM. Amantadine delayed-release/extended-release
capsules significantly reduce OFF time in Parkinson’s disease. NPJ Parkinsons Dis. 2022;8(1):29.
Published 2022 Mar 18. doi:10.1038/s41531-022-00291-1

9. Rascol O,
Tönges L, deVries T, et al. Immediate-release/extended-release amantadine
(OS320) to treat Parkinson’s disease with levodopa-induced dyskinesia: Analysis
of the randomized, controlled ALLAY-LID studies. Parkinsonism Relat Disord. 2022;96:65-73.
doi:10.1016/j.parkreldis.2022.01.022