Parkinson's disease drug therapies in the clinical trial pipeline: 2015

Abstract

Background

There is an urgent need to find more effective treatments for motor and non-motor symptoms of Parkinson's disease (PD) and to ultimately discover therapies to slow, stop or reverse the condition.

Objective

To provide an overview of PD drug therapies in Phase 1–3 clinical trials between 2015–2024 in order to highlight research findings and trends, identify opportunities for further research and funding, and provide a common ground for discussion among the patient, research and funding communities.

Methods

A dataset of PD drug clinical trials registered on ClinicalTrials.gov between 2015–2024 was analyzed and classified by trial focus (symptomatic therapy or disease-modifying therapy), trial phase, therapeutic category and drug novelty.

Results

The dataset included 444 trials, of which 42% were in Phase 1, 46% in Phase 2 and 12% in Phase 3. 63% of the trials were evaluating symptomatic therapies (ST) and 37% were testing disease-modifying therapies (DMT). 52% of the trials were exploring novel treatments, a third were testing repurposed compounds and the remainder were evaluating reformulations of existing PD drugs. 281 drug interventions were evaluated across the 444 trials.

Conclusion

The pipeline of clinical trials evaluating PD drug therapies between 2015–2024 contained a diverse set of novel, repurposed and reformulated compounds across a variety of biological pathways. While additional symptomatic treatments received regulatory approval, there are still no treatments to modify the course of the disease.

Plain language summary

Parkinson's disease drug therapies in the clinical trial pipeline: 2015-2024

The development of new drugs for Parkinson's disease (PD) is crucial for improving the quality of life for those diagnosed with the condition. This report provides a review of clinical trials evaluating drug therapies for PD between 2015–2024. Trial data were obtained from ClinicalTrials.gov, a publicly available website maintained by the U.S. National Institutes of Health, which provides information on clinical trials conducted worldwide. The analysis showed that 444 clinical drug trials were initiated during the 10-year period, of which 133 were still ongoing at the end of 2024. 42% of the trials were in Phase 1, while 46% were in Phase 2 testing. Only 12% of the trials were in Phase 3, the final step in clinical testing. The overall analysis looked at the breakdown of trials evaluating treatments to manage symptoms (63%) and those aiming to slow the progression of the disease (37%). Trials testing therapies to treat symptoms targeted an array of motor and non-motor symptoms, with existing treatments for non-motor symptoms recognized as a significant unmet need. The 444 trials tested 281 drug interventions, as many were tested in multiple trials. 52% of the trials were evaluating new drugs, 33% were testing drugs approved for other conditions and had potential to treat PD, and the remainder were exploring reformulations of existing PD drugs (different delivery methods). The analysis also explored how the therapies work by categorizing them based on their mechanism of action and biological targets. Fourteen drugs in the analysis were approved to treat PD symptoms, but there are still no treatments to modify the course of the disease.

Keywords

Parkinson's clinical trials studies disease modification neuroprotection symptomatic immunotherapy inflammation cell therapy repurposed

Introduction

Parkinson's disease (PD) is a chronic, progressive neurological condition characterized by a range of motor and non-motor symptoms. The cardinal motor symptoms are tremor, rigidity, bradykinesia, and postural instability, while common non-motor symptoms include hyposmia, constipation, REM sleep behavior disorder, fatigue, dystonia, depression, anxiety and cognitive issues.^1,2 There is currently no cure or disease-modifying therapy (DMT) that slows down the progression of the condition, but there are treatments to help alleviate symptoms and improve quality of life. The gold standard symptomatic therapy (ST) for addressing PD motor symptoms is carbidopa/levodopa, a dopamine (DA) replacement therapy first approved by the FDA in 1975.³ Since then, additional dopaminergic and other primarily neurotransmitter-based treatments have become available for managing symptoms. Beyond medication, deep brain stimulation and magnetic resonance-guided focused ultrasound procedures are also options for treating symptoms when drugs have become less effective and patients experience motor fluctuations (OFF time) and troublesome dyskinesias.⁴ Additionally, lifestyle interventions such as exercise, diet and stress reduction can be helpful adjunctive approaches for controlling symptoms.⁵

In order to enhance understanding of recent clinical research into new drug therapies for PD, this paper provides a longitudinal view of PD drug agents in Phase 1–3 clinical trials that were registered on ClinicalTrials.gov between 2015–2024. The trials investigated agents across a broad range of therapeutic approaches, offering the potential for symptomatic relief and disease modification. This review is an extension of the five annual reports entitled “Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline”, published between 2020–2024, each of which provided a snapshot of PD drug trials active at the beginning of the year.^6–10 This more comprehensive view of the pipeline over time, highlighting both trials that completed and remained active at the end of the period, can further help underscore what has been learned from research efforts around the world and identify opportunities and directions for further research and funding. Importantly, it is hoped the analysis provided here will provide a common ground for discussion and inquiry in future collaborations between the research, funding, and patient communities.

Methods

The data collection, screening and classification method used to generate the dataset for the 10-year pipeline analysis is described below and illustrated in Figure 1.

Figure 1.

Schematic for data collection, screening, and classification.

Data collection

ClinicalTrials.gov is the largest database of privately and publicly funded clinical studies conducted around the world and is maintained by the National Library of Medicine at the National Institutes of Health (NIH).¹¹ Trial data on the site is submitted directly by each study's sponsor or principal investigator. To generate the dataset of PD drug trials for the 2015–2024 pipeline analysis, a search of ClinicalTrials.gov was conducted on January 16, 2025 using the parameters:

Condition: Parkinson disease

Study type: Interventional

Phase: Early Phase 1, Phase 1, Phase 2, Phase 3

First Posted: January 1, 2015 - December 31, 2024

The “First Posted” date for a trial is the date its record was first available on ClinicalTrials.gov after undergoing a quality control review by the National Library of Medicine (NLM).¹² In this report, we use the term “registration date” to refer to a trial's “First Posted” date.

Screening

Our search yielded 610 trials, which were downloaded and screened to determine eligibility for inclusion in the analysis. The screening process identified and excluded trials that were non-drug related, including those evaluating devices, biomarkers, or behavioral interventions. In addition, trials that were retroactively registered after 2014, but had start dates before 2015, were also excluded as they were outside of our analysis window. Finally, trials that were either withdrawn (i.e., halted before their start date), did not have supporting information available to allow classification, were observational studies or were not evaluating a PD treatment were also excluded. In total, the filters eliminated 166 trials, leaving the remaining 444 trials as the dataset of drug trials for analysis (Supplemental File 1). For the purposes of our analysis, early Phase 1 trials and Phase 1/Phase 2 trials were grouped with Phase 1 trials and Phase 2/Phase 3 trials were grouped with Phase 2 trials. Trials whose ClinicalTrials.gov “status” parameter was “Recruiting”, “Not yet recruiting” “Active, not recruiting”, or ‘Enrolling by invitation” were classified as “Active” trials within our analysis.

Classification

Trials in the dataset were classified in three ways based on the nature of the agents being evaluated. Agent names were based on information provided in the “Interventions” field of ClinicalTrials.gov trial records.

The classifications were:

ST vs. DMT: Each trial was classified as evaluating either a symptomatic therapy (ST) or disease-modifying therapy (DMT) based on the trial's description on ClinicalTrials.gov or through an online literature search of the trial agent. If a trial was classified as ST, the symptom(s) targeted in the trial were obtained from the study title and study description, and if not specified, were based on the trial's primary and secondary outcome measures and an online search of publicly available information about the trial drug.

Therapy category: Each trial was assigned to a therapy category based on the mechanism of action (MOA) or target of the agent being evaluated. Agent MOA and target characteristics were determined from information in the trial description on ClinicalTrials.gov and from other publicly available information, such as journal publications and company press releases. The therapy categories are consistent with those described in the aforementioned annual reports entitled “Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline”, 2020–2024,^6–10 with the exception of additional MOA/target sub-categories. The therapy categories are:

Anti-inflammatory: agents seeking to reduce inflammatory processes.

Antioxidants: agents focused on reducing oxidative stress.

Cell therapy: trials including either intracerebral cell transplantation or peripheral delivery of cells.

DMT Other: DMT agents whose MOA or target did not match another category. Each trial in this grouping includes a subcategory with its MOA or target.

Dopaminergic symptom relief therapies: ST agents that either restore, replace or mimic the neurotransmitter DA. This grouping includes the subcategories DA agonist; Levodopa (LD) reformulation; COMT inhibitor; MAOB inhibitor; DA Other.

Energy and mitochondria: agents seeking to stimulate improvements in mitochondrial function.

GBA: agents focused on enhancing the activity of glucocerebrosidase (GCase).

GLP-1R agonists: a specific class of drugs activating the glucagon-like peptide-1 receptor.

Kinase inhibitor: agents blocking specific kinase activity, excluding those inhibiting LRRK2 activity, which were placed in the LRRK2 category.

LRRK2: agents seeking to reduce or inhibit the activity of LRRK2.

Microbiome/GIT): agents specifically targeting the activity of the gastrointestinal tract (GIT).

Neurotrophic factors: therapies involving the delivery of growth factors such as GDNF or CDNF.

Non-dopaminergic neurotransmitter symptom relief therapies: ST agents that target neurotransmitter systems other than DA. This includes the subcategories Adenosine A2A receptor antagonist; Adrenergic; Cannabinoid; Cholinergic; GABAergic; Glutamatergic; and Serotonergic.

ST Other: ST agents whose MOA or target did not match another category. Each trial in this grouping includes a subcategory with its MOA or target.

Targeting alpha-synuclein: molecules specifically focused on preventing alpha-synuclein aggregation, or disaggregation of existing complexes.

Agent novelty: Based on information in trial descriptions on ClinicalTrials.gov and other publicly available information, trial agents were classified as either:

Novel: not approved by a regulatory agency for the treatment of any disease.

Repurposed: a) already approved as a treatment for a disease or condition other than PD and now being evaluated for PD, b) already approved to treat PD symptom(s) and now being tested to treat an additional PD symptom, c) not approved, but in common use (e.g., a probiotic or supplement) and being explored for PD.

Reformulated: already approved as a treatment for PD, but now being tested with an alternate dosing or delivery method.

Results

Overview

Our screening criteria resulted in a dataset of 444 PD drug trials registered between 2015–2024, of which 42% were in Phase 1, 46% were in Phase 2 and 12% were in Phase 3. Based on our categorization, most trials (279/444; 63%) were testing agents for potential ST outcomes, with the remaining proportion (165/444; 37%) focused on DMT. (Table 1).

Table 1.

Number of PD drug trials registered on ClinicalTrials.gov between 2015–2024 by phase and ST/DMT.

	Phase 1	Phase 2	Phase 3	Total	% Total
ST	106	127	46	279	63%
DMT	80	76	9	165	37%
Total	186	203	55	444
% Total	42%	46%	12%		100%

Bold numbers reflect totals.

Annual trials by phase

The annual number of trial registrations over the 10-year period showed a steady increase in trials registered between 2017 (38 trials) and 2020 (57 trials), driven by increases across Phase 1, Phase 2, and Phase 3 registrations (Figure 2). Registrations for each trial phase declined in 2021, resulting in a significant annual drop-off in total registered trials that year (36), coinciding with the onset of the COVID-19 pandemic. While annual Phase 1 trial registrations doubled between 2021–2024, Phase 2 registrations remained below their pre-2020 levels and Phase 3 registrations dropped to just two in 2023 and in 2024. As a result, total annual trial registrations after 2020 were less than the peak levels seen a few years earlier, but had begun to slowly ramp up.

Figure 2.

Annual number of PD drug trials registered on ClinicalTrials.gov between 2015–2024 by trial phase.

Annual trials by ST/DMT

The annual number of ST and DMT trial registrations over the 10-year period indicates that the majority of newly registered trials each year through 2022 were ST (Figure 3). However, the number of DMT trials increased over time, representing over 50% of all new registrations between 2022 and 2024. As previously noted for each of the Phase 1 to Phase 3 registrations, trial registrations for both ST and DMT declined noticeably after 2020, but have partially rebounded in subsequent years.

Figure 3.

Annual number of PD drug trials registered on ClinicalTrials.gov between 2015–2024 by ST and DMT.

Trials by novelty and ST/DMT

Among the 279 ST trials, 46% were evaluating novel agents, 29% were testing repurposed compounds, and one fourth were testing reformulations of existing symptomatic treatments. For the 165 DMT trials, 62% were evaluating novel agents and 38% were testing repurposed compounds (Table 2).

Table 2.

Number of PD drug trials registered on ClinicalTrials.gov between 2015–2024 by novelty and ST/DMT.

	# ST trials	% ST trials	# DMT trials	% DMT trials	Total trials	% Total trials
Novel	128	46%	102	62%	230	52%
Repurposed	82	29%	63	38%	145	33%
Reformulation	69	25%			69	16%
Total	279	100%	165	100%	444	100%

Annual trials by novelty

Year by year analysis of trials categorized by the therapeutic novelty of their agents (Figure 4) shows a drop-off in the number of registered trials of reformulated agents after 2020. Newly registered trials with novel agents ranged from a low of 19 in 2016 to a high of 30 in 2019, with an annual average of 23. Annual levels of repurposed trials ranged from a low of 8 in 2018 to a high of 22 the following year, averaging 14.5 per year during the time period.

Figure 4.

Annual number of PD drug trials registered on ClinicalTrials.gov between 2015–2024 by therapeutic novelty.

Trials by therapy category

Trials testing agents targeting dopaminergic and non-dopaminergic neurotransmitter systems make up nearly half (209/444; 47%) of all trial activity and were also key drivers of trial activity at each phase (Phase 1: 76/186; 41%; Phase 2: 90/203; 44%; Phase 3: 43/55; 78%). Within DMT trials, sponsors explored a broad range of mechanisms, with clear interest (46/444; 10%) in mechanisms linked to PD genetic and protein pathology pathways: alpha-synuclein, LRRK2, and GBA. Interestingly, cell-based therapy trials were also a notable presence in overall trial activity (34/444; 8%), with 15 cell therapy trials exploring symptomatic treatments and 19 focused on DMT (Table 3).

Table 3.

Number of PD drug trials registered on ClinicalTrials.gov between 2015–2024 by therapy category, phase and ST/DMT.

	Phase 1			Phase 2			Phase 3			Total
Therapy category	ST	DMT	Total	ST	DMT	Total	ST	DMT	Total	ST	DMT	Total	% Total
Dopaminergic	60	-	60	29	-	29	30	-	30	119	-	119	27%
Non-DA NT	16	-	16	61	-	61	13	-	13	90	-	90	20%
ST Other	7	-	7	29	-	29	1	-	1	37	-	37	8%
Cell therapy	15	13	28	-	6	6	-	-	-	15	19	34	8%
DMT Other	-	15	15	-	16	16	-	-	-	-	31	31	7%
Targeting aSyn	1	17	18	2	9	11	-	2	2	3	28	31	7%
Microbiome/GIT	4	4	8	6	-	6	1	1	2	11	5	16	4%
Energy & Mitochondria	1	2	3	-	10	10	-	2	2	1	14	15	3%
Anti-inflammatory	-	9	9	-	4	4	-	-	-	-	13	13	3%
GBA	-	4	4	-	6	6	-	1	1	-	11	11	2%
Kinase inhibitor	1	4	5	-	6	6	-	-	-	1	10	11	2%
Neurotrophic factors	-	7	7	-	4	4	-	-	-	-	11	11	2%
Antioxidant	1	-	1	-	6	6	1	1	2	2	7	9	2%
GLP-1R agonist	-	2	2	-	6	6	-	1	1	-	9	9	2%
LRRK2	-	3	3	-	3	3	-	1	1	-	7	7	2%
Total	106	80	186	127	76	203	46	9	55	279	165	444	100%

Bold numbers reflect totals.

Annual trials by therapy category

Analysis of trials by therapy category and year of registration (Table 4) highlights a temporal evolution of therapeutic focus over the 10-year period. The first six years (2015–2020) were dominated by studies of dopaminergic agents (96 trials) and other neurotransmitter-targeting agents (63 trials), accounting for 55% of the 289 trials registered in those years. After 2020, there was a marked drop-off in annual trial registrations, falling from 57 in 2020 to 36 in 2021, with the biggest decline seen in dopaminergic trial registrations, which continued through 2024. The decrease in dopaminergic trial registrations after 2020 was concurrent with the drop in new trials of reformulated compounds (Figure 4), all of which were dopaminergic-based. The extent to which the COVID pandemic may have played a role in this or whether opportunities for dopaminergic strategies are being exhausted is unclear. By 2024, only 23% of new trial starts (10/44) involved dopaminergic or other neurotransmitter mechanisms of action.

Table 4.

Number of PD drug trials registered on ClinicalTrials.gov between 2015–2024 by therapy category and year.

Therapy category	2015	2016	2017	2018	2019	2020	2021	2022	2023	2024	Total
Dopaminergic	20	12	16	15	13	20	10	4	4	5	119
Non-dopaminergic NT	11	13	5	12	13	9	9	8	5	5	90
ST Other	4	5	4	4	3	3	2	5	4	3	37
Cell therapy	3	1	2	2	2	2	5	3	6	8	34
DMT Other		3	4	4	3	4			6	7	31
Targeting aSN	3		4	3	4	7	3	4	1	2	31
Microbiome/GIT	1			3	3	2	2	4		1	16
Energy & mitochondria	3	1		1	3	2	1	2		2	15
Anti-inflammatory					2	1	1		6	3	13
GBA		3			1			2	3	2	11
Kinase inhibitor		2	1	2	1	2		1	2		11
Neurotrophic factors	1		1	1	1		2		2	3	11
Antioxidant		2	1	1	1	2	1	1			9
GLP-1R agonist		1		3	1	3				1	9
LRRK2				1	2			2		2	7
Total	46	43	38	52	53	57	36	36	39	44	444

Bold numbers reflect totals.

Beyond neurotransmitter-based strategies focused on STs, new trial registrations during the study period explored a wide range of approaches that primarily targeted disease modification.

Agent analysis

Most trials in our dataset were evaluating a single compound, with the remainder either testing a combination therapy (fixed dose combination or co-administered therapy) or comparing different therapies. In our agent analysis, we refer to each of these interventions (single compound, combination, comparative) as an agent.

A total of 281 agents were evaluated across the 444 trials in the dataset, with 165 agents tested in 279 ST trials and 116 agents tested in 165 DMT trials (Table 5) Overall, 50% of the agents were novel (140/281), 39% were repurposed (109/281), and 11% were reformulations (32/281). Among DMT agents only, 57% were novel (66/116) and 43% were repurposed (50/116). Among ST agents, 45% were novel (74/165), 36% were repurposed (59/165) and 19% were reformulations (32/165), with reformulations driven largely by numerous levodopa and DA agonist reformulations. Three treatments were evaluated in both ST and DMT trials (Rifaximin, Rasagiline (TVP-1012, Azilect), and N-acetylcysteine) and are included in both the ST and DMT agent counts. Two drugs, istradefylline and opicapone, were tested as both novel and repurposed agents and appear in both the novel and repurposed ST agent counts.

Table 5.

Number of agents in PD drug trials registered on ClinicalTrials.gov between 2015–2024 by therapy category, novelty, and ST/DMT.

	Novel			Repurposed			Reformulation			Total
Therapy category	ST	DMT	Total	ST	DMT	Total	ST	DMT	Total	ST	DMT	Total	% Total
Dopaminergic	20	-	20	3	-	3	32	-	32	55	-	55	20%
Non-DA NT	26	-	26	27	-	27	-	-	-	53	-	53	19%
ST Other	11	-	11	20	-	20	-	-	-	31	-	31	11%
Cell therapy	12	14	26	-	-		-	-	-	12	14	26	9%
DMT Other	-	5	5	-	18	18	-	-	-	-	23	23	8%
Targeting aSyn	1	12	13	-	4	4	-	-	-	1	16	17	6%
Microbiome/GIT	3	1	4	6	4	10	-	-	-	9	5	14	5%
Anti-inflammatory	-	8	8	-	4	4	-	-	-	-	12	12	4%
Energy & Mitochondria	-	4	4	1	6	7	-	-	-	1	10	11	4%
Antioxidant	-	2	2	2	4	6	-	-	-	2	6	8	3%
GLP-1R agonist	-	2	2	-	5	5	-	-	-	-	7	7	2%
Kinase inhibitor	1	4	5	-	3	3	-	-	-	1	7	8	3%
Neurotrophic factors	-	6	6	-	1	1	-	-	-	-	7	7	2%
GBA	-	4	4	-	1	1	-	-	-	-	5	5	2%
LRRK2	-	4	4	-	-	-	-	-	-	-	4	4	1%
Total	74	66	140	59	50	109	32	-	32	165	116	281	100%

Bold numbers reflect totals.

Symptom analysis

Within our cohort of 279 ST trials, the majority were targeting motor symptoms, including motor fluctuations (OFF time), dyskinesia, and gait and balance issues. Treatments targeting general motor symptoms included reformulations of LD and DA agonists, as well as novel cell therapy and AADC gene therapy approaches. Treatments for motor fluctuations (OFF) were primarily reformulations of LD and DA agonists. Treatments to alleviate dyskinesia included glutamatergic and serotonergic therapies, while treatments for gait and balance issues (including freezing and fall prevention) were mainly cholinergic, serotonergic and adrenergic approaches.

There was a wide range of non-motor symptoms for which trials were evaluating possible treatments. The symptoms, with number of agents tested for each symptom, were: cognition/MCI (8), constipation (8), depression (6), ICD (5), dementia (4), psychosis (4), anxiety (3), hallucinations (3), pain (3), sleepiness (3), nOH (2), sleep (2), urinary (2), apathy (1), dysphasia (1), foot dystonia (1), neuropsychiatric (1), nocturia (1), RBD (1), sialorrhea (1), and smell (1). The limited number of agents being tested for common and debilitating non-motor symptoms reinforces the need for additional focus on therapies to relieve these symptoms.

Trial status analysis

As of January 16, 2025, over half of the 444 trials in the dataset had ended (50% completed, 7% terminated, or 1% suspended), with the remainder either active (30%) or of unknown status (12%) (Figure 5). Trials have an unknown status designation on ClinicalTrials.gov if they are still listed as active, but are past their completion date and their status has not been verified by their sponsor within the past two years.¹² The 53 trials with an unknown status represent a substantial proportion of studies for which registry information is out-of-date, limiting potentially valuable data for the Parkinson's community.

Figure 5.

Status of 444 Phase 1-3 PD drug trials registered on ClinicalTrials.gov between 2015–2024, as of January 16, 2025.

Among the 224 completed trials in the dataset, only 76 (34%) had reported their results on ClinicalTrials.gov as of January 16, 2025. Of the remaining 148 completed trials, 128 were past their due date for reporting results, which is within one-year of the trial's primary completion date.¹³ The reporting of trial results is critical for ensuring valuable scientific data generated through clinical trials is recorded for the public benefit.

Of the 133 trials in the dataset that were still active as of January 16, 2025, 48 were in Phase 1, 69 in Phase 2 and 16 in Phase 3, with 70 testing DMTs and 63 evaluating STs. A chart depicting the agents in active trials is available in Supplemental File 2.

Among the 31 trials in the dataset that were terminated, reasons for termination included business decisions, lack of efficacy, data reported from affiliated studies, the COVID-19 pandemic, and insufficient enrollment. The rationale for a trial's termination is provided by sponsors on ClinicalTrials.gov, and we have included this info for these 31 trials in Supplemental File 2. Of the three suspended studies, one was put on hold to conduct an interim study, one was postponed while waiting for another trial to start, and one resumed in 2025.

Enrollment

Total enrollment for the Phase 1–3 drug trials in our analysis was over 39,000 participants (Table 6). Enrollment numbers reflect actual participants for trials that were completed, terminated or suspended and represent target levels for trials that were active or whose status was unknown at the end of the time period. Enrollment for Phase 1 trials was 6151 (16% of the total for all phases), with an average of 33 participants per trial. Enrollment for Phase 2 trials was 18,256 (47% of the total), with an average of 89 participants. Lastly, Phase 3 trial enrollment was 14,831 (38% of the total), with an average of 270 participants per trial. It is clear that advancing the PD drug pipeline requires the participation of large numbers of people with the disease who generously contribute their time, energy and willingness to assume a certain level of risk in order to further the common good. For this, the PD community is deeply thankful and extends a debt of gratitude.

Table 6.

Enrollment by phase for PD drug trials registered on ClinicalTrials.gov between 2015–2024.

Trials are completed, active, suspended, terminated or status unknown, as of January 16, 2025
	Number of trials	Target enrollment	Average per trial	Median	Min	Max
Phase 1	185	6151	33	24	1	128
Phase 2	204	18,256	89	60	2	640
Phase 3	55	14,831	270	244	7	992
Total	444	39,238	88	45	1	992

Discussion

The period between 2015 to 2024 was a time of significant activity within the PD clinical trial pipeline. Our analysis found an evolving landscape with therapies targeting a diverse range of biology, an increasing proportion of which hold disease-modifying potential. We saw the emergence of novel therapeutic modalities for PD including immunotherapies, stem cell-based treatments, and some of the first RNA-directed therapies. By many measures, we see a robust and healthy PD clinical trial pipeline.

Symptomatic therapies

As it has since the approval of the first levodopa-based formulations, therapies targeting dopaminergic signaling pathways dominated the PD pipeline over the last ten years. Much of the clinical trial activity reflected innovation across three types of approaches: optimized levodopa (or apomorphine) formulation and delivery, improved DA receptor agonists and modulators, and a resurgence of DA cell replacement. This is perhaps not surprising given the clear therapeutic benefits agents targeting DA signaling pathways still provide to people with PD and a continued desire to extend these benefits (while reducing potential side effects and complications) for as long as possible over the course of an individual's lifetime. Indeed, this intense focus on DA fueled most of the new FDA approvals for PD during this period (Table 7), with more likely on the way, such as tavapadon from AbbVie,¹⁴ who recently submitted a new drug application based on positive trial results. If approved, tavapadon may represent a new wave of optimized DA receptor agonists, possibly with fewer complications.¹⁵ The reworking of continuous levodopa delivery systems, such as Vyalev/Produodopa (foscarbidopa/foslevodopa) and ND0612, has been tested in advanced PD, but may eventually be oriented towards earlier stages of the disease, hopefully reducing the issue of levodopa-induced complications.

Table 7.

PD therapies approved by the FDA between January 1, 2015 and December 31, 2024, listed in descending order of approval date.

Approval year	Therapy	Indication
2024	Vyalev (foscarbidopa/foslevodopa)	PD motor fluctuations
2024	Crexont (carbidopa/levodopa)	PD motor fluctuations
2021	Dhivy (carbidopa/levodopa)	PD motor symptoms
2021	Gocovri (amantadine)	Second FDA approval: PD motor fluctuations
2020	Kynmobi (apomorphine) withdrawn 2023	OFF periods in PD/motor fluctuations
2020	Ongentys (opicapone)	OFF periods in PD/motor fluctuations
2019	Nourianz (istradefylline)	OFF periods in PD/motor fluctuations
2019	Myobloc (rimabotulinumtoxinB)*	Chronic sialorrhea
2018	Inbrija (levodopa inhalation powder)	OFF periods in PD/motor fluctuations
2018	Xeomin (incobotulinumtoxinA)*	Chronic sialorrhea
2018	Osmolex ER (amantadine) withdrawn 2024	Levodopa-induced dyskinesia
2017	Gocovri (amantadine)	First FDA approval: Levodopa-induced dyskinesia
2017	Xadago (safinamide mesylate)	OFF periods in PD/motor fluctuations
2016	Nuplazid (pimavanserin)	Hallucinations and delusions; PD psychosis
2015	Duopa (carbidopa/levodopa intestinal gel)	PD motor fluctuations
2015	Rytary (carbidopa/levodopa)	PD motor symptoms

*therapy not specifically approved for PD, but approved for a common non-motor symptom associated with PD.

To view more information about these drugs and their path through clinical trial phases leading to approval, see Supplemental File 2.

The initiation of clinical trials testing stem cell-derived DA cell replacement for improving PD motor symptoms offers a renewed chance for a long-held hope of restoring lost brain function. In the 1980s, trials of early tissue-derived transplant methods suggested potential promise, but subsequent larger trials revealed inconsistent outcomes and intolerable side effects like graft-induced dyskinesias, leading investigators to largely move toward stem cell-based approaches which offered greater scalability and consistency.¹⁶ While it took many years to perfect the cell culturing protocols, based on recently published data from several clinical stage stem cell-derived DA replacement cell programs,^17,18 these earlier challenges may now no longer be as significant a barrier. However, cell replacement, if eventually approved for PD, will enter a market saturated with a range of optimized DA-directed therapy (in addition to advanced neuromodulation and other surgical approaches). Whether cell replacement can differentiate its advantages over these other therapeutic options is yet to be determined.

Sponsors also explored therapies targeting a variety of other neurotransmitter and neurochemical systems with the hope of meeting under-addressed needs associated with motor and non-motor aspects of PD. Adenosinergic therapy offers an interesting case study. Based on early links between caffeine and PD risk and subsequent laboratory research, drug makers became interested in investigating antagonists of adenosine receptor 2A, caffeine's physiological target, for possible anti-parkinsonian motor benefits.¹⁹ Multiple antagonists have been developed and tested, three of which (istradefylline, tozadenant and sipagladenant) had clinical trial activity captured in our ten-year analysis. Of these, only istradefylline received FDA approval in 2019 (having already been approved in Japan in 2013,²⁰ but still not available in Europe²¹), although its path to regulatory acceptance and market uptake has been challenging, possibly due to its modest benefits, competitive market and cost.²²

As a weak, non-competitive antagonist of the NMDA receptor, which increases dopamine release and prevents dopamine reuptake, amantadine represents one of the more successful non-dopaminergic approaches in the treatment of PD. Reformulations of amantadine were developed and approved in 2017, 2018 and 2021 for motor/dyskinesia and PD motor fluctuations. Other non-dopaminergic approaches also advanced in the PD pipeline over the last ten years, many of which explored methods to target motor complications or non-motor symptoms. Important examples included pimavanserin, which targets serotonergic systems and was approved for PD psychosis in 2016. During our analysis period, sponsors also explored pimavanserin for impulse control disorders and depression.²³ We also saw an expansion of interest in psychedelics as putative treatments for PD, including ketamine and psilocybin for PD-associated depression.

Disease-modifying therapies

There was significant growth in investigational interventions directed against targets believed to be involved in the underlying disease biology of PD, which if successful would offer the best chance of truly modifying and slowing PD. Some of these studies include programs modulating biological pathways related to genetic variants associated with increased risk of PD. Chief among these were agents targeting alpha-synuclein pathology, which made up almost 14% of the DMT trials. Despite numerous studies with a variety of modalities targeting alpha-synuclein, there has been limited positive trial data to date, although passive immunotherapies have been shown to be active in cerebrospinal fluid, and post hoc analyses and extended treatment arms have generated some encouraging results worthy of further exploration.^24–29

The number of trials focused on LRRK2 or GBA1-related biology grew across the timeframe of our analysis, representing additional developments around genetic-based biological targets. Phase 1 data for LRRK2 inhibitors have provided compelling evidence of target engagement,^30–32 and over the next 18 months, we will have the first measures of efficacy with the results of the Phase 2 LUMA and NEULARK studies. Initial attempts to address GBA1 biology found that glucosylceramide synthase inhibition was not the correct target to address and actually worsened PD progression. Attention has remained focused, however, on improving lysosomal function with enhancers of GCase. In addition to a basket of studies proposing the repurposing of ambroxol, there are also a number of trials testing new chemical entities that enhance GCase activity. Preliminary data from these efforts have indicated good safety, tolerability and pharmacokinetics data,^33–35 and initial efficacy data from Bial's ACTIVATE study will be available later this year.

Anti-inflammation was another category in which we observed recent growth in the number of trials. Thirteen studies designated as targeting inflammation were registered in the last 6 years of the dataset, compared to none for the first 4 years. Favorable early safety/tolerability data has been reported from a Phase 1 trial with selnoflast³⁶ (NLRP3 inhibitor) and a Phase 2a trial with NE3107³⁷ (NF-kB inhibitor), and other studies are ongoing. Another area of interest driving trial activity in the last ten years was agents targeting mitochondrial function. Both the liver and gallbladder treatment, UDCA and the prostate/hypertension medication terazosin have been tested in pilot studies exploring mitochondrial function in PD with encouraging results,^38–41 and these agents will be advancing to Phase 3 testing in the next 12 months.⁴² Additional categories of DMTs that have garnered attention within our data set include antioxidants, kinase inhibitors, and manipulation of the gut microbiome. Little positive data is available to date in these areas, but numerous trials are ongoing and these will be areas to watch as results become available.

Similar to cell replacement, there has been a resurgence in efforts to deliver neurotrophic factors. Although early attempts in the 1990s and 2000s with GDNF and subsequently neurturin were unsuccessful in clinical trials,^43–45 the idea of neurotrophic approaches has remained compelling as a possible way to protect and revitalize remaining DA neurons if initial challenges can be overcome.⁴⁶ Over the period of our analysis, we saw continued emphasis on a number of neurotrophic factors (e.g., GDNF, CDNF) leveraging both protein infusion as well as gene therapy approaches. In addition, there were many cell-based therapies in our dataset using mesenchymal and other cell types believed to offer possible neurotrophic (or possibly other immunomodulatory and protective) factors. We observed a range of such approaches, although outcomes have been difficult to interpret. Importantly, given differing regulations across jurisdictions, these approaches are often offered through clinics directly to customers, often with limited data on their effectiveness. This remains a major challenge in educating the community about the potential dangers of such un-approved therapies, leading several major groups to offer guidelines for patients.^47,48

With the global impact of GLP-1-directed therapies for diabetes and weight loss, there has also been strong interest in exploring this class of therapy for CNS disorders, including neurodegenerative diseases like PD.⁴⁹ Over our ten-year analysis, there were five therapies explored in PD cohorts in this category, although outcomes from these trials were inconsistent, with a Phase 2 study of lixisenatide indicating motor stabilization,⁵⁰ but a large Phase 3 trial of exenatide showing no benefit.⁵¹ More recently, the announcement of top-line results from testing of oral semaglutide in AD revealed no benefit in slowing cognitive decline.⁵² Despite the setbacks, there was evidence within our dataset that this field is still evolving and developing, with Kariya Pharmaceuticals initiating clinical testing of their CNS penetrant, dual GLP-1/GIP receptor agonist, KP405. Any future developments of the GLP-1-directed therapies for PD (and other neurodegenerative disorders), however, will have to incorporate the learnings from the previous trial results.

Looking ahead

While it was encouraging to see an increase in the number of DMT trials initiated during the 10-year period, only nine were in Phase 3, the pivotal stage of clinical testing. A greater understanding of the underlying mechanisms associated with PD progression, development of improved biomarkers, and improved ability to observe changes in the rate of disease progression will be essential for bringing more therapies into Phase 3 trials.⁵³ Genetic analyses and molecular biology have pointed towards particular pathways which are now being clinically modulated. Initiatives such as Aligning Science Across Parkinson's support of key programs (Collaborative Research Network, Global Parkinson's Genetics Program, Parkinson's Progression Markers Initiative),⁵⁴ as well as The Michael J. Fox Foundation's Targets to Therapies Initiative⁵⁵ are laying the groundwork for new biology discovery and translation. In addition, multi-arm, multi-stage platforms, such as the Australian Parkinson's Mission,⁵⁶ Edmond J Safra Accelerating Clinical Trials in PD (EJS ACT-PD)⁵⁷ and NS-PARK's Master Trial in France^58,59 are designed to accelerate clinical testing of late-stage agents by enabling simultaneous early stage trials that can more seamlessly move from one phase to another as biological understanding evolves. Trial designs incorporating stratification of participants at baseline, along with greater use of digital biomarkers that measure meaningful benefits to patients, can also increase the likelihood of trials moving forward in the pipeline. Finally, given the heterogeneity of the PD population and the many potential causes for the underlying pathology, the use of combination therapies aiming at more than one target may well hold greater promise for slowing disease progression.⁶⁰

Caveats and considerations

While we have attempted to provide a clear view of trends in the PD clinical trial pipeline over the last decade, we appreciate there are many challenges in such an analysis. Our classification of agents and trials was based on available information and our authors’ knowledge, but we appreciate others, including study sponsors, might classify agents or trials differently. However, we think our classification largely captures the meaningful nature and direction of the PD clinical development pipeline and offers a useful resource to the community. In addition, while comprehensive, ClinicalTrials.gov does not capture all relevant trials globally, as some trials are listed on other trial registries. Since ClinicalTrials.gov relies critically on trial sponsors and principal investigators to submit data and regularly update records, information may not always be accurate or current. Also, sponsors may not always enter early clinical testing with PD as the focus. Therefore, we know we may have missed some relevant trial activity in our analysis, but think we capture most of the critical trials. Finally, while we highlight outcomes for a number of completed trials in the dataset, providing a list of published results for all of the trials is beyond the scope of this paper. However, we provide a supplementary Discussion file that captures additional trial results not noted in the body of the paper (Supplementary File 3).

Conclusion

Our 10-year analysis of the PD clinical trial pipeline captured 444 trials of drug therapies intended to treat or modify the course of the disease. Most of the ST trials evaluated treatments for motor symptoms, with potential approaches for addressing non-motor symptoms remaining an unmet need. The study period saw the initiation of many trials of agents with disease modification potential, targeting a variety of emerging biological pathways with both novel and repurposed agents. We highlight the ongoing efforts across academia, government, industry, and funding entities to better understand disease biology, develop more targeted therapies, and improve trial designs through implementation of multi-arm, multi-stage trial platforms. We hope this review will be a springboard for further commentary to help drive collaboration and meaningful progress toward better treatments and a cure.

Supplemental Material

sj-xlsx-1-pkn-10.1177_1877718X261454154 - Supplemental material for Parkinson's disease drug therapies in the clinical trial pipeline: 2015–2024

Supplemental material, sj-xlsx-1-pkn-10.1177_1877718X261454154 for Parkinson's disease drug therapies in the clinical trial pipeline: 2015–2024 by Susan Buff, Aleksandra Pilcicka, Kenneth Pitzer, Brian Fiske, Simon RW Stott and Kevin McFarthing in Journal of Parkinson's Disease

Supplemental Material

sj-xlsx-2-pkn-10.1177_1877718X261454154 - Supplemental material for Parkinson's disease drug therapies in the clinical trial pipeline: 2015–2024

Supplemental material, sj-xlsx-2-pkn-10.1177_1877718X261454154 for Parkinson's disease drug therapies in the clinical trial pipeline: 2015–2024 by Susan Buff, Aleksandra Pilcicka, Kenneth Pitzer, Brian Fiske, Simon RW Stott and Kevin McFarthing in Journal of Parkinson's Disease

Supplemental Material

sj-docx-3-pkn-10.1177_1877718X261454154 - Supplemental material for Parkinson's disease drug therapies in the clinical trial pipeline: 2015–2024

Supplemental material, sj-docx-3-pkn-10.1177_1877718X261454154 for Parkinson's disease drug therapies in the clinical trial pipeline: 2015–2024 by Susan Buff, Aleksandra Pilcicka, Kenneth Pitzer, Brian Fiske, Simon RW Stott and Kevin McFarthing in Journal of Parkinson's Disease

Footnotes

Abbreviations

Acknowledgements

We thank Katelyn Beissert of Cure Parkinson's for creating the active trial chart in Supplemental File 2. We also thank Parkinson's research advocate, Gary Rafaloff, for reviewing and providing constructive feedback on the manuscript. Finally, we would like to thank trial participants, their families, and the research community for their invaluable contributions in the pursuit of improved treatments and a cure for PD.

ORCID iDs

Brian Fiske

Simon RW Stott

Kevin McFarthing

Author contributions

Concept and design: SB; data collection: SB, AP, KP, BF; trial classification: All; Analysis: SB, AP, KP, BF; writing and editing: All.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interest

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Kevin McFarthing is an Editorial Board Member of this journal, but was not involved in any way in the peer-review process of this article and had no access to any information regarding its peer review.

Supplemental material

Supplemental material for this article is available online.

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