Parkinson Disease Treatment Advances

Parkinson disease (PD) is one of the most common neurologic disorders, projected to affect at least 12 million people worldwide by 2040.¹ With this emerging surge in PD prevalence, there is tremendous urgency for treatment advancements. Despite the obstacles created by the COVID-19 pandemic on the research community, in 2021 to 2022, there were 147 active clinical trials–62% of which were studying symptomatic treatments with the remaining investigating potential disease-modifying therapies (DMTs).² Since the 1960s, levodopa has remained the mainstay of PD treatment, with recent advances in novel delivery mechanisms including inhaled and continuous infusions of levodopa. In a review of PD clinical trials from 2021 to 2022, 42.2% of interventions were novel and 34% were repurposed agents.² This balance highlights the evolving spectrum of PD treatments, as we investigate different therapeutic approaches and attempts to impact the pathophysiology of disease.

Motor fluctuations and dyskinesias frequently affect persons living with PD as the disease progresses. The mean time to develop dyskinesia is 5.81 years from diagnosis,³ and a study suggests 95% of individuals with PD will experience motor fluctuations by 10 years.⁴ Consequently, there is a vast need for improved treatments to address these motor symptoms.⁵ In this review, we discuss new treatments for motor symptoms of PD that became available over the past 5 years (Table).

Pharmacologic Therapies

Inhaled Levodopa

Dopaminergic therapies are the first-line treatment options for motor symptoms in PD.⁶ These treatments include levo-dopa, monoamine oxidase inhibitors, dopamine agonists (DAs), or a combination of these. Levodopa has been available in oral formulations and enteral suspension. Recent studies have focused on new methods of drug delivery that bypass the gut to address motor fluctuations and potentially escape food-drug interactions that can compromise absorption.

In 2018, the Food and Drug Administration (FDA) approved inhaled levodopa powder for the treatment of OFF periods while using oral carbidopa/levodopa therapy. In a phase 3, randomized, multicenter, double-blind, placebo-controlled study, participants age 30 to 85 who were experiencing at least 2 hours of OFF time were treated with 60 or 84 mg inhaled levodopa or placebo.⁷ This study supported safety and efficacy of both doses and met the primary endpoint of improved Movement Disorder Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) motor scores 30 minutes postdose compared with predose. The 84-mg dose led to an approximate 4-point reduction in MDS-UPDRS scores compared with placebo. No significant change vs placebo was seen at 20 minutes, despite the hope for more rapid transition to ON state with pulmonary inhalation. Furthermore, there was no difference in total daily OFF time based on participant diaries. It was postulated that limiting use of the inhaler (average 2x/day) and not permitting use for the first dose of the day may have lessened the impact on OFF time. Adverse events included cough, upper respiratory infections, discolored sputum, and nausea. Inhaled levodopa may be a rescue strategy when individuals experience motor fluctuations.

Scored Levodopa Tablets

Considering precise medication dosing in PD is important, in 2021, a new scored tablet of carbidopa/levodopa became available. Each tablet has 4 segmented fractions that can be broken off and taken individually, with each segment containing carbidopa/levodopa 6.25/25 mg for precise dosing. The tablet is designed with deep scores to make it easier to divide it and to make accurate fine adjustments.

Sublingual Apomorphine

Apomorphine is a potent, nonergoline dopamine agonist that has been available as a subcutaneous injection since 2004 and is used as a rescue treatment for OFF episodes. The injection has some inherent challenges for use, including assembly of medication, the need for an injection, supervised dose titration requirement, side effects including nausea and hypotension, and injection site reactions. In a randomized, double-blind, placebo-controlled study of 109 participants at 32 sites, the difference in MDS-UPDRS part 3 motor scores from predose to 30 minutes postdose was significantly greater with apomorphine sublingual film vs placebo.⁸ A significant difference in motor scores was observed 15 minutes postdose and this difference persisted up to 90 minutes. Secondary endpoints including clinical global impression of change (CGIC) scales were also met. Most participants had symptom improvement within 10 to 20 minutes of dosing, and participant diaries revealed full ON response in nearly 80% of OFF episodes treated.⁸ Side effects occurred in 31% (17/54) of participants and most commonly were mild-to-moderate oropharyngeal events (eg, oral mucosal erythema, dry mouth, glossodynia, lip edema, oropharyngeal swelling, or throat irritation), which led to therapy discontinuation in 9 participants. In May 2020, the FDA approved sublingual apomorphine to quickly reverse “OFF” time,⁸ making another rescue therapy available.

Safinamide

Adjunctive treatments such as monoamine oxidase B (MAO-B) inhibitors with dopamine agonists or levodopa therapy can help manage motor fluctuations. Safinamide is an oral, selective, reversible MAO-B inhibitor taken once daily. The FDA approved safinamide for adjunctive treatment of motor fluctuations in 2017. In a parallel-group clinical trial, 669 participants with motor fluctuations being treated with stable regimens of levodopa and other PD pharmacotherapies were randomly assigned to receive safinamide 50 or 100 mg/day or placebo for 24 weeks.⁹ Safinamide significantly increased daily ON time without troublesome dyskinesia (1.37±2.745 hours and 1.36±2.625, respectively, with 50 or 100 mg/day vs 0.97 ± 2.375 hours with placebo).⁹ Significant reductions were observed with safinamide vs placebo in daily OFF time, OFF time after the first levodopa dose of the morning, and MDS-UPDRS part 3 scores during ON time.⁹ In an 18-month, placebo-controlled extension to the original study, there was a 31% and 27% decrease in the mean total dyskinesia rating scale scores with 50 or 100 mg/day safinamide, respectively; however, the least squares mean change was not significant. The benefits of 100 mg/day safinamide vs placebo remained significant as measured by ON time without troublesome dyskinesia, daily OFF time, MDS-UPDRS part 3 score, and some aspects of quality of life.¹⁰ Another double-blind, parallel-group, 24-week trial in 549 participants treated with stable doses of levodopa treated with 50 or 100 mg/day safinamide vs placebo also showed a benefit with safinamide vs placebo (increased ON time without dyskinesia, or “good ON time”) of 1.42 vs 0.57 hours, as measured with participant diaries.¹¹

Opicapone

Catechol-O-methyltransferase (COMT) inhibitors are used in conjunction with levodopa therapy to extend the duration of action of levodopa by preventing peripheral degradation. The COMT inhibitors tolcapone and entacapone have been available for some time, but tolcapone is no longer widely used because of the risk of severe and fatal hepatotoxicity. Entacapone is limited by the need to take it multiple times per day for a limited benefit of approximately 0.6 hours more ON time per day.¹² Opicapone was approved in 2020, has lower hepatotoxicity than tolcapone, and is taken orally once daily. In 2 randomized, double-blind, parallel group studies comparing opicapone to placebo and entacapone, respectively, improvement from baseline in absolute OFF-time was seen with 50 mg/day opicapone. The mean improvement from baseline in absolute OFF time was −60.8 minutes (95% CI: 97.2) with opicapone vs −24.4 minutes with placebo (P=.0015). Opicapone was noninferior to entacapone (−26.2 minutes OFF time, 95% CI: −63.8, 11.4; P=.0051).¹³ In another study, the least squares mean change in OFF time with 50 mg/day opicapone vs placebo was −118.8±13.8 minutes vs −64.5±14.4 minutes based on 24-hour participant diaries completed 3 days before scheduled visits.¹⁴ Reductions in OFF time were sustained throughout a 1-year open-label extension study.¹⁴

Extended-Release Amantadine

Amantadine is an N-methyl-D-aspartate receptor (NMDAR) antagonist approved for use in PD since 1973 for treatment of levodopa-induced dyskinesia. Immediate-release formulations require frequent dosing and have poor tolerability at higher doses. In 2017, a delayed-/extended-release (DR/ER) formulation of amantadine that is taken once daily (at bedtime) was approved. In 2 phase 3 randomized, double-blind, placebo-controlled 25-week and 12-week trials, 274 mg DR/ER amantadine vs placebo led to a mean improvement of 15.9±1.6 points vs 8.0±1.6 points on the Unified Dyskinesia Rating Scale (UDysRS) in 1 trial and 20.7±2.2 vs 6.3±2.1 points in the other.^15,16 In a pooled analysis, there was an overall placebo-adjusted, 1-hour reduction in OFF time compared with baseline.^17,18 These findings supported the approval of DR/ER amantadine as adjunctive treatment for OFF episodes. Another ER amantadine hydrochloride was approved in 2018 for levodopa-induced dyskinesias (Table).

Istradefylline

Istradefylline is an adenosine A2A receptor antagonist approved in 2019 for adjunctive treatment of PD to reduce motor fluctuations. There have been 8 randomized, double blind, placebo-controlled studies of istradefylline for PD. Pooled analysis of data from 2,719 participants showed those who received istradefylline (20 mg, n=848; 40 mg, n=879) vs placebo (n=992) had a statistically significant, although modest, decrease from baseline in daily OFF time of −0.38 and −0.45 hours, respectively, and a 0.40 and 0.33 hour increase in ON time without troublesome dyskinesia, respectively.¹⁹ Although istradefylline initially was not approved by the FDA based on a subset of these trials reviewed in 2008, additional trial data and analyses led to the eventual approval.^20-22

Procedural Treatments

Focused Ultrasound

Magnetic resonance-guided high-intensity focused ultrasound (FUS) targeting the thalamus was approved in 2018 for the treatment of tremor-dominant PD. FUS targeting the globus pallidus internus (GPi) for bradykinesia, rigidity, and dyskinesia was approved in 2021. There is a rich history of surgical treatment of these targets for PD. Currently, both procedures are approved for unilateral targeting only owing to safety concerns (eg, dysarthria or falls). The procedure is performed in a single session, during which high-intensity ultrasound waves are delivered across the skull to create a thermal lesion in the targeted structure. After unilateral FUS thalamotomy in tremor-predominant PD, 23 individuals had complete cessation of rest and action tremor and the remaining 3 participants had 90% tremor improvement.²³ Long-term results from 26 individuals treated with FUS thalamotomy who were followed for up to 5 years (median 36 months; 7 participants followed for 5 years) revealed persistent tremor improvement compared with baseline. However, 1 participant had complete tremor recurrence and 5 others had partial tremor return during this 5-year period.²² There was notable improvement in quality of life after 6 months and 1 year of treatment, although the authors of this study noted improvements in total PDQ39 scores—a measure of quality of life—were not statistically significant compared with baseline at later time points, potentially related to disease progression.²³ The preliminary results of the open-label safety and feasibility study of FUS pallidotomy revealed mostly mild and transient adverse events related to the procedure. On the UDysRS, there was improvement at 3 months and up to 12 months compared with baseline. Additionally, improvement was noted on the treated side as assessed with the MDS-UPDRS part 3 at 3 months and up to 1 year. FUS is appealing as it is incisionless, and no programming or battery changes are required. However, it does constitute creating a structural lesion, offers only unilateral symptom management, and lacks capacity to steer and modify therapy based on response.

Directional Deep Brain Stimulation

Recently developed directional leads for deep brain stimulation (DBS) consist of 2 middle rings segmented into thirds for a total of 8 contacts vs the 4 circumferential rings in conventional electrodes. Directional stimulation can be used to shape the electrical field away from regions where stimulation can cause unwanted effects.²⁴ In a recent study, 90% of participants treated with directional stimulation had a wider therapeutic window than those who had omnidirectional subthalamic nuclei (STN)-DBS, although motor outcomes in the 2 groups were similar.²⁵ The hope is that directional stimulation might offer more targeted programming to address specific symptoms, avoid stimulation of nearby structures, or reduce necessary amplitude to achieve a particular benefit.²⁵ Segmented electrodes provide a valuable alternative for programming when steering stimulation in the horizontal plane but provide limited benefit in suboptimally placed leads in the vertical axis. There are 3 manufacturers that offer directional DBS lead systems, 1 that allows remote programming and another that consists of a directional lead with novel sensing capabilities to detect brain signals that can correlate with symptoms and treatment. Sensing technology offers the hope of individualized stimulation based on an individual’s physiology in the future. Additionally, most DBS systems have a single current source shared by all contacts; however, newer technology in some allows for independent current control. With independent current control, more accurate delivery of stimulation between 2 or more active contacts is possible. Since the advent of DBS, advancements have also included novel programming strategies including closed-loop and adaptive programming, in which stimulation parameters are automatically altered based on the individual’s clinical state; however, these are used only in research at present. An ongoing international, multicenter clinical trial is currently being conducted for adaptive stimulation.^a

Future Directions

Innovations in advanced therapies for PD include novel formulations of levodopa for continuous delivery via subcutaneous infusion as an alternative to surgical enteral tube placement. Continuous subcutaneous delivery of foscarbidopa/foslevodopa (precursors of carbidopa/levodopa) has demonstrated an increase in ON time without troublesome dyskinesias compared with oral immediate-release carbidopa/levodopa in a phase 3 study. Similarly, continuous subcutaneous delivery of carbidopa/levodopa up to 720 mg of an individual’s total levodopa dose, over 16- or 24-hour periods daily, is being evaluated in a phase 3 trial.^b In a phase 3 trial, a novel oral ER levodopa formulation dosed a mean 3 times/day improved “good ON” time relative to immediate-release carbidopa/levodopa dosed a mean 5 times/day by 0.53 hours (P=.0194).²⁶ In a multicenter, double-blind, placebo-controlled trial of an apomorphine infusion pump,^c there was an average 2.47-hour reduction in daily OFF time with pump-delivered apomorphine vs a 0.58-hour reduction with pump-delivered placebo, supporting resubmission to the FDA in 2021 for possible approval.²⁷

Investigational therapies targeting the pathologic hallmark of α-synuclein accumulation have included small molecule inhibitors of α-synuclein accumulation, passive immunization with monoclonal antibodies, and active immunization with immunogenic peptides that induce antibodies to α-synuclein. C-Abelson kinase (c-Abl) inhibitors have been studied for potential neuroprotective effects, with some disappointing results for nilotinib attributed to poor penetration of the central nervous system, and newer candidates being explored.

Although many of these initially promising avenues have not found success in larger trials, each lesson learned brings us closer to unraveling the ultimate strategy that will lead to meaningful therapy and disease modification for PD. Anti-inflammatory approaches, the gut microbiome, and gene-specific therapies are additional areas of continued study. It is likely that in the future, our treatment armamentarium will continue to expand, and we will learn individual predictors for the best strategies to implement.