Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2020

Data collection

Data on active clinical trials of PD drug therapies were obtained from ClinicalTrials.gov for analysis in this review. ClinicalTrials.gov provides information on publicly and privately supported clinical studies conducted worldwide and is the world’s most comprehensive clinical trial registry. To date, it includes over 2500 PD trials that have been registered since its launch in 2000. Data on the registry is maintained directly by trial sponsors and includes information about a trial’s design, outcome measures, enrollment targets, recruiting status, locations, expected start and end dates, and more.

To generate our dataset for analysis of active PD drug trials, data was downloaded from ClinicalTrials.gov, as of January 21, 2020, based on the following search criteria:

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  Condition: Parkinson disease

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  Study type: Interventional

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

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  Status parameter: “Recruiting”, “Not yet recruiting”, “Active, not recruiting”, or “Enrolling by invitation”.

The downloaded dataset included 193 trials. The therapy for each interventional trial registered on ClinicalTrials.gov is classified by the trial sponsor as “Drug”, “Behavioral”, “Biological”, “Combination Product”, “Device”, “Diagnostic Test”, “Dietary Supplement”, “Genetic”, “Other”, “Procedure”, or “Radiation” study. Since our pipeline review is focused on PD drug trials, we filtered out trials that were evaluating devices, biomarkers, or behavioral interventions (for example, exercise), as well as drug trials i) for which no supporting information could be found online, ii) that were already completed, though still listed as active, or iii) applied to atypical Parkinson’s only. The filter excluded 48 trials. The remaining 145 trials were included in our dataset for analysis of active Phase 1, 2, and 3 PD drug trials. Trials whose phase was classified “as early Phase 1” on ClinicalTrials.gov were grouped with Phase 1 trials in this report. If a trial was classified as Phase 1/Phase 2 or Phase 2/3 on ClinicalTrials.gov, we included the study in the lower of the two phases in our analyses (for example, a Phase 1/2 was considered Phase 1).

Trial categorization

Each trial in our dataset was first determined to be ST or DMT, and then assigned to one of 14 categories according to the mechanism being tested.

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  Each trial was classified as ST or DMT based on a review of the trial investigator’s stated hypothesis on ClinicalTrials.gov, as well as an online literature search to help determine the MOA when it was not otherwise clear. Our working definition of a DMT required a MOA, whether proven or proposed, that would interfere with the pathology of PD and/or outcome measures investigating disease-modifying properties. Trial coordinators were contacted when further information was needed to make an assessment. For each trial classified as ST, the symptom(s) for which the trial was evaluating treatment were identified based on information on ClinicalTrials.gov, including “Study Title”, “Study Description”, and “Outcome Measures”, as well as information on the sponsor’s website.

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  The categories to which each trial was allocated were developed using an iterative process in which the MOA, target, and source of the drugs in our trial dataset were all considered, and we accepted an element of overlap where a trial could have been allocated to more than one category. For example, immunotherapy trials could have been allocated to “targeting alpha-synuclein”, but we felt that immunotherapy deserved its own category given the focus and investment it has received, not just in PD. This process yielded 14 categories, ten of which were primarily based on MOA, three on drug target, and one on drug source (botanicals). “Botanicals” were a separate category as they are mixtures with a number of potential active agents and have attracted a lot of attention in the Parkinson’s community as a source of current and future medicines. Each of the 145 trials was then assigned to one of the 14 categories based on the characteristics of the trial’s agent.

The categories, together with the type of category, were:

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  ‘Dopaminergic symptom relief therapies’ (MOA) applied to ST agents that either restore, replace or mimic the neurotransmitter dopamine.

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  ‘Non-dopaminergic symptom relief therapies’ (MOA) applied to ST agents that impacted any neurotransmitters, other than dopamine, which include noradrenergic, serotonergic, glutamatergic, and cholinergic systems.

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  ‘Antioxidants’ (MOA) were agents that are primarily focused on reducing oxidative stress.

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  ‘Botanicals’ (source) was applied to agents derived from herbal extracts where the mechanism of action was unknown or unclear.

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  ‘Cell therapy’ (MOA) were trials including either intracerebral cell transplantation or peripheral delivery of cells.

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  ‘Energy and mitochondria’ (target) was a category for agents seeking to stimulate improvements in mitochondrial function.

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  ‘GBA’ (MOA) agents were focused on enhancing the activity of glucocerebrosidase (GCase).

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  ‘GLP-1 agonists’ (MOA) are a specific class of drugs activating the glucagon-like peptide-1 receptor.

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  ‘Immunotherapy’ (MOA) was designed to cover antibody-based agents.

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  ‘Kinase inhibitors’ (MOA) represented a broad category encompassing agents blocking specific kinase activity.

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  ‘Microbiome/GIT’ (target) were agents specifically targeting the activity of the gastrointestinal system.

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  ‘Neurotrophic factors’ (MOA) was assigned to therapies involving the delivery of GDNF or CDNF.

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  ‘Targeting alpha synuclein’ (target) covered small molecules specifically focused on alpha synuclein inhibition or disaggregation.

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  ‘Other’ (MOA) was assigned to trials whose therapy had a MOA that did not match another therapy. In situations where the MOA was unclear, a designation of ‘Other’ was also given.

A flow chart depicting the data collection and trial categorization methodology is provided in Fig. 1.

Overview

Our dataset for analysis included 145 active Phase 1– 3 clinical trials of PD drug therapeutics. Of these trials, 37 (26% ) were Phase 1, 14 (10% ) were Phase 1/Phase 2, 61 (42% ) were Phase 2, 5 (3% ) were Phase 2/Phase 3, and 28 (19% ) were Phase 3 (Table 1; see Supplemental File 1 for the complete list of trials and extracted data and Supplemental File 2 for a summary view). As mentioned previously, for our analyses, the Phase 1/Phase 2 and Phase 2/Phase 3 studies were incorporated into the Phase 1 and Phase 2 grouping, respectively.

Of the 145 trials, 57 (39% ) were considered to be DMT trials and 88 (61% ) were considered to be ST trials, as shown in Fig. 2. Of the DMT trials, 30 (53% ) were in Phase 2, while only 3 (5% ) of the DMT trials were in Phase 3. 36 (41% ) of the ST trials were in Phase 2, with the remainder split closely between Phase 1 and Phase 3.

About 2/3 of the ST studies (58/88) were focused on motor symptoms, including overall movement (45 trials), levodopa-induced dyskinesia (LID; 6 trials), gait and balance (4 trials) and tremor (3 trials). One of the ST studies was focused on both motor and non-motor symptoms. The remaining approximately 1/3 of the ST trials targeted a range of non-motor symptoms, including neurogenic orthostatic hypertension (nOH; 5 trials), general non-motor symptoms (4 trials), impulse control disorders (ICD; 3 trials), pain (3 trials), PD dementia (2 trials), PD psychosis (2 trials) and 1 trial each for anxiety, constipation, depression, fatigue, hallucinations, neuropsychiatric symptoms, PD MCI, sialorrhea, sleepiness, and urinary symptoms.

The therapeutic for each of the 145 trials in the dataset was mapped to one of 14 categories, resulting in the breakout shown in Table 2. Of the agents under evaluation in our dataset of 145 trials, we found that 49 agents (21 DMT/ 28 ST) were being evaluated in Phase 1, 60 agents (28 DMT/32 ST) in Phase 2, and 22 agents (3 DMT/19 ST) in Phase 3 (Fig. 3).

Therapy category analysis

Sponsor/collaborator information

ClinicalTrials.gov defines a trial sponsor as “the single person or entity who initiates the study, by preparing and/or planning the study, and who has authority and control over the study” and defines collaborators as “Other organizations (if any) providing support. Support may include funding, design, implementation, data analysis or reporting.” The sponsor is responsible for registering a trial on ClinicalTrials.gov and for maintaining the accuracy and timeliness of the data provided. The sponsor is not necessarily the funder of the trial. Table 3 shows the breakdown of sponsors/collaborators across the 145 active trials in our analysis (Supplemental File 1 provides the full list of these). In the analysis, a sponsor/collaborator that was a pharmaceutical or biotechnology company was classified as “Industry”, a university or hospital as “Academic Medical Center”, a U.S. or non-U.S. Government entity as “Government, and a non-profit such as a charity, foundation or consortium as “Foundation/Consortium”. Of note, industry are the primary sponsors/collaborators in PD clinical development, with involvement in over 60% of the trials in our dataset.

Enrollment analysis

The total target enrollment for the Phase 1– 3 trials was 16,023 (excluding the 100,000 target enrollment for a Phase 2 cannabis trial) (Fig. 7). There were 51 trials in Phase 1, which had a total target enrollment of 1,613 (10% of the total for all phases). The average number of participants being recruited in Phase 1 was 32 per trial. At the Phase 2 level, there were 65 trials that had total enrollment targets of 7,447 (46.5% of the total for all phases). In Phase 2, an average of 113 participants were being recruited per trial. Finally, there were 28 Phase 3 trials that had enrollment targets of 6,963, which averaged 249 participants per trial. Of interest, only 14 out of 145 trials involved in our analysis were recruiting healthy volunteers, of which 11 were Phase 1.

Trial site analysis

The trials included in this review were being conducted at research institutes around the world, as shown on the map in Fig. 8. The majority of these studies were in the USA and Europe, and many were conducted at sites across different geographic regions. The total number of trial sites for each region is presented on the map. Fourteen of the 145 trials in our dataset did not have trial sites listed, so our analysis and the map in Fig. 8 reflects data available for the remaining 131 studies.

60% of Phase 1 and Phase 1/2 trials (28/47) had one trial site and 30% (14/47) had 2– 5 sites (Fig. 9). No trials in Phase 1 had more than 10 sites. In contrast, 53% of the Phase 2 and Phase 2/3 trials (31/59) had one trial site, and 37% had >10 sites. 48% of Phase 3 trials had between 1– 5 sites (12/25), while 52% (13/25) had >10 sites. Interestingly, none of the trials in Phase 2, Phase 2/3 or Phase 3 trials had 6– 10 sites, but 35 trials had >10 sites.

Novel and existing compounds

In our review, we explored whether trials were evaluating novel or existing compounds. Existing compounds were classified as either “repurposed”, “reformulation” or “new claim”. Repurposing was defined as the testing of a therapy already approved by regulatory authorities for a different indication (i.e., disease or condition) besides PD. “New claim” was applied to therapies already approved for treatment of a PD symptom(s) now being explored for a different PD symptom. A reformulation was defined as an agent already in use in one delivery mode, such as an immediate release tablet, that was being delivered in a different way, for example by sub-cutaneous infusion.

Of the 145 Phase 1– 3 trials in our analysis, 66 (46% ) were evaluating novel agents, 50 (34% ) were testing repurposed agents, 20 (14% ) were evaluating reformulations, and 6% (9/145) were testing “New Claims” (Table 4; see Supplemental Files 1 and 2).

Notably, about one third of the trials were evaluating repurposed agents. An example of repurposing is the use of GLP-1 agonists, originally developed for use in type 2 diabetes, of which there were four molecules in five trials classified as repurposed in our analysis. Other indications from which therapies were being repurposed for PD were Alzheimer’s disease (five trials), antibiotics (four trials), hypertension (four trials), pain relief (four trials), and two trials each for nausea and vomiting (antiemetics), anxiety disorders, diuretics, gallstones/primary biliary cirrhosis, and respiratory diseases. PD trials were also evaluating compounds approved for the following 18 conditions: ADHD, adjunct to cancer treatment, anesthesia, bone transplantation stimulation, constipation, depression, epilepsy, hypercholesterolemia, excess iron reduction, MS spasticity, hepatic oxidation enhancement, neurogenic orthostatic hypotension, paracetamol/acetaminophen overdose, peptic ulcers, PET imaging, gut health, sleep and sleepiness.

New claims for existing PD drugs included three trials evaluating droxidopa (for fatigue, gait and balance, and nOH), two trials testing pimavanserin (ICD and neuropsychiatric symptoms), a Duodopa (ABT-SLV187) trial for non-motor symptoms, two trials evaluating safinamide (one for movement and one for LID), and a trial evaluating rasagiline as a DMT. Reformulated compounds in trial included apomorphine, Accordion Pill, CTC-413, Infudopa, IPX203, LD-CD intestinal gel, LY03003, ND0612, opicapone, P2B001, ropinirole, SER-214 (rotigotine polymer conjugate), and solifenacin.

Recently completed studies

This report of PD trials active as of January 21, 2020 has provided an overview of a broad spectrum of therapeutics being evaluated across all phases of clinical development. The breadth of this pipeline is both encouraging and inspiring. In addition to these ongoing efforts, other trials investigating therapies for PD have recently completed. These include high profile Phase 3 DMT trials, such as the STEADY-PD (evaluating isradipine) and SURE-PD (testing inosine) studies, which both announced that they had not reached their primary endpoints [28, 29], as well as Phase 1 and 2 studies that provided more encouraging results. The latter include the Herantis CDNF trial and the Denali-sponsored evaluation of their LRRK2 inhibitor, DNL-201, both of which focused on novel targets and achieved their primary endpoints. [30, 31]. We are also still awaiting the results of some studies that recently completed, such as the Phase 2 trial assessing the DMT potential of the iron chelator, deferiprone.

Recently approved therapeutics

Four therapeutics to treat PD “off” periods, when used as an adjunct to levodopa/carbidopa, recently received regulatory approval by the U.S. FDA. In December 2018, a new inhaled version of levodopa from Acorda Therapeutics, Inbrija, was approved for use in alleviating “off” “episodes [32]. In October 2019, Kyowa Kirin’s novel therapeutic, adenosine A2A receptor antagonist Nourianz/istradefylline, was approved in the U.S. for treating “off” episodes, as well. It was originally launched in Japan in 2013 [33]. In April 2020, the FDA approved the COMT inhibitor opicapone (Ogentys) from Neurocrine Biosciences, also for treatment for PD “off” episodes [34]. In May 2020, Kynmobi (APL-130277) was also approved for the treatment of PD “off” episodes[35].

Symptomatic therapies

Our analysis has highlighted some trends that will be interesting to revisit in future annual reviews. For example, the majority of ST trials aiming to deliver symptomatic relief via the dopaminergic pathway use well-established molecules (for example, levodopa/carbidopa or dopamine agonists), but there were some trials exploring novel approaches, including gene therapies aiming to deliver genes for biosynthetic enzymes to enable the striatum to synthesise dopamine, (such as Voyager Therapeutics’s VY-AADC01 and Axovant’s OXB-102 (AXO-Lenti-PD)). Cell therapy trials, which are also dopamine replacement ST efforts, were all at the early stages of the clinical development process, with eight studies in Phase 1 and one study in Phase 2. These are long term projects primarily assessing the safety of the transplanted tissue over time, but we did note additional developments suggesting interest from major pharmaceutical companies in this area (for example, the acquisition of stem cell-based biotech firm Bluerock Therapeutics by Bayer).

Our analysis also showed that only about a third of the ST trials were aimed at specific non-motor symptoms, prompting us to stress the importance of increasing research and development for the treatment of non-motor symptoms. Research has shown that non-motor symptoms are at least as prevalent and severe as motor symptoms, and also suggest that, in the opinion of PwP, these symptoms are being poorly treated and have a significant impact on their quality of life [36, 37]. This, of course, does not include the treatment of non-motor symptoms using medicines that address the symptom regardless of the presence of PD.

Disease-modifying therapies

As indicated in the introduction of this report, there have been significant developments in terms of our understanding of the biology potentially underlying PD, and this is now reflected in the range of DMT clinical trials. For example, recent research on the mechanisms of PD have identified mitochondria and lysosomes as organelles prone to malfunction [38, 39]. In our dataset, there were four studies focused on mitochondrial deficiencies, two of which involve ursodeoxycholic acid (UDCA). The others were BioElectron’s EPI-589 (also known as BioE-589) and CNM_Au8 (gold nanocrystals) from Clene Nanomedicine. Four studies were targeting the activity of the product of the GBA gene, glucocerebrosidase, closely linked to lysosomal function. Two studies were on repurposing the respiratory medication ambroxol; Sanofi has venglustat in Phase 2 which aims to reduce sphingolipid production; and finally, Prevail Therapeutics were investigating a gene therapy approach for PD patients who have mutations in their GBA gene.

Following the encouraging results of a Phase 2 clinical trial of exenatide in PD [40], GLP-1 agonists were well represented in our analysis. These molecules have been shown to have neuroprotective effects in models of PD, via multiple pathways [41]. The five GLP-1 agonist trials in our analysis consist of one in Phase 1, three in Phase 2 and one in Phase 3. In addition, as mentioned above, there is another Phase 2 study on exenatide in Sweden that was not registered on ClinicalTrials.gov but is listed on EudraCT (ID no 2019-000732-26). Peptron of South Korea registered a Phase 2 study on ClinicalTrials.gov for their version of sustained release exenatide after the cut-off date of our analysis. In all, we have identified eight trials of GLP-1 agonists – exenatide (n = 5), liraglutide, lixisenatide, semaglutide – currently in clinical evaluation for PD.

There is significant genetic, histological and pathological evidence pointing towards a role for α-synuclein in the biology of PD [42, 43], thus it is no surprise that there is intense clinical activity aimed at unravelling (or preventing) the formation of α-synuclein oligomers/fibrils and their intercellular spread. Five studies were using small molecules to target α-synuclein: anle138b, ENT-01 (2 trials), mannitol, and memantine. There were also seven trials of immunotherapy drugs against α-synuclein in our dataset, two of which were in Phase 2 (Biogen (BIIB054) and Roche (RO7046015/prasinezumab). This area is being watched closely by scientists and patients alike, as the potential for modifying the progression of PD through interrupting the spread of α-synuclein is strong. This is tempered somewhat by the recent experience of immunotherapy in Alzheimer’s disease, where this approach has had limited successto date.

Of the four kinase inhibitors in our analysis, three were targeting the c-Abl protein kinase [44]. This enzyme remains a target despite the recent disappointing outcome of two Phase 2 trials of nilotinib, although this may have been an issue of access through the blood-brain barrier rather than a failure of target engagement and MOA. FB-101, K0706 and saracatinib (dual Src & c-Abl inhibitor) were all targeting c-Abl in clinical trials of PD. The remaining kinase inhibitor study was a LRRK2 inhibitor (DNL151), the first in what is likely to be an active field in the future.

The influence of the gut microbiota in the context of PD has recently become an intense area of preclinical research [45] and this has given rise to a number of clinical trials targeting dysbiosis in the gastrointestinal system. There were five studies seeking to positively influence the content and activity of gut microbiota, all of which were under way in academic institutions. They included active intervention with two trials on rifaximin, one prebiotic (resistant maltodextrin), a lyophilised fecal extract (PRIM-DJ2727), and fecal microbialtransplantation.

In 2019, the results of the Bristol glial cell-derived neurotrophic factor (GDNF) clinical trial were published [46, 47] and while that study did not meet its primary endpoints, there is still significant interest in the potential use of neurotrophic factors for the treatment of PD. In our dataset, there were three studies evaluating neurotrophic factors. Two were gene therapies to introduce the gene for GDNF, and the other was assessing infusion of CDNF. The results of one of the GDNF gene therapy trials has been published [48], and the topline results of the CDNF study have been made available [49], both providing support for further evaluation of this experimental treatment class.

Biomarkers

In addition to a broad range of pharmacological agents being tested, it is also encouraging to see numerous biomarkers being used in the assessment aspects of many of these trials, although a detailed analysis of biomarker research was beyond the scope of this PD drug pipeline review. However, we believe that the importance of this research warrants a brief discussion. The lack of accurate and reliable biomarkers for PD causes great difficulty in early diagnosis, as well as in measuring disease progression. Better biomarkers may also allow for shorter and more efficient clinical trials.

In addition to the 145 trials in our analysis, there were more than 40 trials currently listed on ClinicalTrials.gov that involve research into specific biomarkers for PD. They were listed as either interventional studies or observational studies. Many of the 145 DMT and ST studies that we reviewed were measuring biomarkers for some of the outcome results, which were typically secondary. Most often, these involve testing for dopamine metabolites, amino acids and various forms of α-synuclein in blood and cerebrospinal fluid. There is also hope that microRNA analysis may bring progress to this area of research.

Definitions

An important consideration in our analysis was the absence of a universally accepted definition of whether a particular therapy for PD is “disease-modifying” or “symptomatic” [50, 51], which made it challenging to determine whether the therapies in some trials were DMT or ST. As discussed in the methods section, our working definition of a DMT required a mode of action, whether proven or proposed, that would interfere with the pathology of PD and/or outcome measures investigating disease-modifying properties. An example of the latter would be the post-treatment washout period prior to outcome measurement to assess residual disease-modifying effects in the Phase 2 lixisenatide study or the delayed start design of the prasinezumab Phase 2 trial. Despite this working definition, the allocation to DMT or ST was not always obvious. In those cases, we used a combination of judgment and consultation with experts in the relevant scientific field. There have been efforts to provide research ontology for neurodegenerative conditions (such as ‘Common Alzheimer’s Disease Research Ontology’ (or CADRO) [52] and ‘Parkinson’s disease ontology’ (PDON) [53]. The potential of similar standards may be relevant to future reviews of the PD drug development field.

Additional trials

Based on information in the literature and press releases, we identified additional active PD drug trials not listed on ClinicalTrials.gov that we would like to note, as they are part of the trial pipeline. The information provided on other registries was not a complete match to that on ClinicalTrials.gov, complicating like-for-like analyses. Thus, these trials were left out of our analyses. These trials include resTORbio’s Phase 1b study of their mTORC1 inhibitor RTB101, registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) [54], Yumanity Therapeutics’ Phase 1 trial of Stearoyl-CoA-Desaturase inhibitor YTX-7739 [55], the Lysosomal Therapies trials of their GCase activator LTI-29, listed on the Netherlands Trial Registry [56, 57], the Neuropore and UCB Phase 1b trial of UCB0599, an alpha-synuclein misfolding inhibitor [58], and a Phase 2 trial of Exenatide in Sweden listed on the EU Clinical Trials Register [59].

Conclusions

Our analysis has provided a broad overview of the pharmacological therapies currently being clinically tested for PD. While it is encouraging to see such a wide range of therapeutic approaches being applied to PD across multiple phases of clinical development, the process of bringing DMTs into clinical use in PD remains challenging. Improvements in the clinical trial process may accelerate the assessment of ST and DMTs, and we look forward with hope to further therapies becoming available for people with PD.