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 12^th 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