Recent Advances in Drug Therapy for Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease manifesting with motor and non-motor symptoms. Current treatment mainly relies on medication as a symptomatic therapy modulating neurotransmitters. Dopamine replacement therapy has been established, and levodopa is the gold standard for treatment of PD. However, the emergence of motor complications, such as a wearing-off phenomenon, is a clinical problem. Both primary symptoms and motor complications have been targets for the development of treatments for PD. Recent progression in the management of motor complications is supported by newly developed agents and advances in device and formulation technology to deliver drugs continuously. Elucidation of the pathophysiology of PD and the development of disease-modifying therapy that affects the underlying fundamental pathophysiology of the disease are also progressing. In this review, we introduce current knowledge on developments concerning medications for patients with PD.

Introduction

Parkinson's disease (PD) is a neurodegenerative disease manifesting with motor symptoms of akinesia/bradykinesia, tremor, and muscle rigidity as a triad, together with various non-motor symptoms. The number of patients with PD has increased rapidly with the aging of the population, and this is now referred to as a Parkinson pandemic.

Advances in treatment are anticipated, but current approaches mainly rely on drug therapy as symptomatic therapy modulating neurotransmitters in the brain. Degeneration of nigrostriatal dopaminergic neurons is the most common pathological finding in PD. Therefore, dopamine replacement therapy is the most fundamental treatment for PD patients. However, dopaminergic treatment for several years results in complications, such as the wearing-off phenomenon, which has prompted the development of symptomatic therapies. In the first section of this review, we introduce current drugs used for the symptomatic treatment of PD.

The pathophysiology of PD, such as the cause of neuronal damage, is becoming increasingly clear. Thus, the development of disease-modifying therapy that affects the underlying pathophysiology of the disease is ongoing. In the second section of the review, we introduce candidate disease-modifying drugs currently in phase 2 or more advanced clinical trials.

I. Symptomatic Therapy

Dopamine deficiency in the striatum of PD patients was first reported in the 1960s, and levodopa was developed as a drug that improves both the symptoms and life prognosis of patients (1). This drug is still the gold standard for treating PD. However, by the mid-1970s, it became apparent that motor complications, such as a wearing-off phenomenon, appear after using levodopa for several years (2). To date, reduction of these complications has been a focus of drug development for PD. To compensate for the shortcomings of levodopa, drugs with various mechanism of action have been developed. These include dopamine agonists that stimulate neuronal dopamine receptors, monoamine oxidase-B (MAO-B) inhibitors that inhibit metabolism of dopamine in the brain, and catechol-O-methyl transferase (COMT) inhibitors that inhibit degradation of levodopa in the periphery. In this section of this review, we introduce drugs currently being used for symptomatic treatment of PD.

1. Levodopa

1) Problems with current levodopa treatment

Levodopa is the most reliable anti-PD drug for improvement of motor symptoms. However, the half-life of levodopa in blood is short (about 90 minutes), which causes fluctuations in blood levels that result in changes in clinical symptoms in the advanced stage, manifesting as the wearing-off phenomenon. Thus, the development of levodopa therapy with a longer half-life using a different route of administration or formulation is being examined.

Neurotoxicity of levodopa was also suggested in the 1990s, which decreased the use of the drug for some time. However, it is now clear that neurotoxicity does not occur at the dose used in clinical practice, and the use of levodopa has since been reestablished. This return to use of levodopa is also partially due to the influence of advances in device and formulation technology that allow for continuous dopaminergic stimulation (CDS) with levodopa, as shown by the following representative formulations.

2) Levodopa/carbidopa intestinal gel

To overcome the short half-life of levodopa and improve motor symptoms during daytime activity, levodopa/carbidopa intestinal gel (LCIG) was developed. The drug is continuously infused into the upper jejunum through gastrostomy during daytime activities. LCIG was approved in Japan in 2016. In a study in East Asian patients with ≥3 hours off-time per day, use of LCIG shortened the off-time by 4-5 hours and extended the on-time without harmful dyskinesia by 5-6 hours (3).

3) Sustained release preparation of levodopa

A sustained release capsule preparation (IPX066) packed with levodopa/carbidopa beads with a variety of fast to slow rates of dissolution in the gastrointestinal tract was developed to maintain the blood levodopa level longer than that using immediate release tablets. In a phase III study, the off-time was significantly shortened by IPX066 compared to immediate release tablets (4). Use of IPX066 has already been approved in western countries, but not in Japan.

4) Levodopa inhalant

A levodopa inhalant (CVT-301) has been approved in the US, but not in Japan, as a rescue medication during off-time. Levodopa is inhaled and rapidly absorbed from the lung. In a phase III study of inhalation of an 84-mg capsule, containing 42 mg of levodopa, motor symptoms during off-time tended to be improved after 10 minutes and were significantly improved after 30 minutes, compared with those before inhalation (5).

5) Other levodopa formulations under development

Levodopa formulations currently under development include an Accordion Pill^Ⓡ capsule utilizing a drug delivery system with a biodegradable polymeric film. The capsule is loaded with a folded multilayer film including levodopa/carbidopa. The ingested capsule dissolves in the stomach, and the folded film opens into a sheet shape and stays in the stomach for a maximum of 12 hours. Gradual release of levodopa/carbidopa from the film maintains a stable blood level, and the film is dissolved in the intestine after completion of drug release (6). A continuous subcutaneous levodopa injection (ND0612), of which efficacy to reduce fluctuations in plasma concentrations was shown in a phase 2 study (7), for PD patients with off-time is also under development. Phase 3 studies of both formulations are underway as of July 2021.

2. Monoamine oxidase-B inhibitors

1) Novel MAO-B inhibitors

MAO-B inhibitors increase the amount and duration of action of dopamine through inhibition of dopamine metabolism by MAO-B in the brain. In Japan, selegiline was approved in 1998 and has now been used for more than 20 years, while rasagiline was approved in 2018 and safinamide in 2019 as new MAO-B inhibitors. Single-agent administration of rasagiline at a dose of 1 mg/day improves motor symptoms in early-stage PD patients (8), and addition of 0.5 or 1 mg/day rasagiline significantly shortens the off-time and improves motor symptoms in advanced stage PD patients with motor complications under oral levodopa treatment (9). Safinamide extends the on-time and decreases the off-time in PD patients with a wearing-off phenomenon not accompanied by problematic dyskinesia and also improves motor symptoms during on-time (10). Selegiline, rasagiline and safinamide have different characteristics (Table 1), so selecting the most appropriate MAO-B inhibitor is now feasible. For example, safinamide has non-dopaminergic activity, including inhibitory effects on sodium channels and glutamate release, indicating a probable inhibitory effect on dyskinesia (11). However, the accumulation of further knowledge concerning appropriate use of MAO-B inhibitors is required.

Table 1.

Characteristics of MAO-B inhibitors.

	Selegiline	Rasagiline	Safinamide
Indication	Patients at Yahr severity scale I-IV for concomitant use of a levodopa-containing preparation, patients at Yahr severity scale I-III without concomitant use	PD patients (no limitation for concomitant drugs or severity)	Patients with a wearing-off phenomenon under treatment with levodopa
Monotherapy	Possible	Possible	Not possible (concomitant use with levodopa)
Dose	2.5-10.0 mg/day, 4 steps	1.0 mg/day (0.5 mg/day if liver disorder is present)	50 or 100 mg/day
Number of oral doses per day	1-2	1	1
MAO-B inhibition	Irreversible	Irreversible	Reversible
Dopamine activity of metabolite	Present	Absent	Absent
Designation as a raw material for stimulant	Yes	No	No

2) Monotherapy with a MAO-B inhibitor for de novo PD

Selegiline was initially developed as an antidepressant in the 1960s. Its utility for motor symptoms of PD was first reported in the mid-1970s, and selegiline has become used mainly as an adjuvant of levodopa (12). In Japan, selegiline was approved in 1998 for concomitant use with levodopa. Administration of selegiline without levodopa activates the patient's endogenous dopamine, and overseas studies conducted before the approval of selegiline in Japan suggested that improvement of motor symptoms was acquired with monotherapy in patients with early PD (13). In Japan, administration of selegiline without concomitant levodopa was approved for health insurance coverage in 2011, enabling monotherapy.

MAO-B inhibitors were initially described as an option for first-line treatment in the 2018 edition of the Japanese guidelines for treatment of PD. MAO-B inhibitors have beneficial effects in addition to direct improvement of motor symptoms. Thus, initiation of early treatment with selegiline delays the time at which levodopa becomes necessary, compared with placebo (14), and concomitant use of selegiline within six months after treatment initiation with levodopa improves long-term motor symptoms and keeps the required dose of levodopa at a low level (15). Reduced aggravation of activities of daily living (ADL) and gait by using selegiline or rasagiline from the early stage has also been reported (16). These findings suggest a neuroprotective effect of MAO-B inhibitors, but this has not been shown clinically. In the PD-MED study (17), the clinical course was investigated based on the drug used for early treatment. Patients treated without levodopa had a lower rate of dyskinesia during a maximum seven-year course than those who received levodopa, and there were also fewer motor complications in non-levodopa cases treated with MAO-B inhibitors compared to dopamine agonists (17).

MAO-B inhibitor monotherapy is useful, but its effects vary widely among cases. For example, we administered selegiline alone to 28 unmedicated patients with PD and observed a range of improvement in motor symptoms that varied from high to low among cases (18). Improvement of motor symptoms by MAO-B inhibitor monotherapy as first-line treatment may be poor and lead to the requirement for concomitant levodopa or a dopamine agonist in some cases, but use of a MAO-B inhibitor from the early stage may be significant for the long-term course. A combined formulation of rasagiline and pramipexole, which has an effect complementary to the MAO-B inhibitor, is currently being developed for first-line treatment of PD (19). Further discussion of the positioning of MAO-B inhibitors as first-line treatment is needed.

3. COMT inhibitors

Entacapone is a COMT inhibitor that promotes levodopa entry into the brain by inhibiting metabolism of levodopa by COMT in the periphery. Entacapone has been used for several years in Japan, and opicapone was approved as a second COMT inhibitor in 2020. In patients with PD with motor complications under treatment with oral levodopa, opicapone significantly shortened the off-time and extended the on-time without accompanying harmful dyskinesia at both doses of 25 and 50 mg/day compared with placebo (20). The long duration of action of opicapone permits once-a-day administration that supports levodopa activity at all time points. In contrast, entacapone has a relatively short duration of action that requires the drug to be taken simultaneously with levodopa at each time point. Appropriate use based on the status of each patient and characteristics of the drugs is required.

4. Dopamine agonists

Many dopamine agonists came into practical use in the 1980s to 1990s. Since these drugs have longer half-lives than levodopa and a low incidence of motor complications after early treatment, dopamine agonists are recommended to deal with the wearing-off phenomenon in early treatment and the advanced stage. Ergot-derived dopamine agonists were first used, but the main dopamine agonists have changed to non-ergot-derived drugs, as a risk of fibrosis, such as valvular disease of the heart, was pointed out with the earlier drugs. Sustained release preparations of two non-ergot-derived drugs, pramipexole and ropinirole, were produced with the aim of achieving CDS, and a patch capable of maintaining a stable blood level by once-a-day replacement has also been developed. In Japan, a rotigotine patch was approved in 2013 and a ropinirole patch was approved in 2019, increasing the options for dopamine agonists. The affinity for receptor subtypes varies among these agonists, and different clinical effects may be expected. Furthermore, an overnight switch between dopamine agonists is possible, whereas 2-week withdrawal is necessary when switching MAO-B inhibitors. This is useful for selecting the most appropriate drug for each patient, and the safety of switching has also been shown for the recently approved ropinirole patch (21).

Other advances in dopamine agonists include approval by the Food and Drug Administration (FDA) in 2020 of a sublingual film formulation of apomorphine that can be easily handled. Continuous subcutaneous injection of apomorphine has already been approved in western countries. Whereas, only subcutaneous injection is approved in Japan as a rescue medication during off-time. In addition, most dopamine agonists developed for PD treatment mainly stimulate the dopamine D2 receptor, but an agonist with affinity for the D1/D5 receptor, tavapadon, is now under development (22), with a phase III study underway as of July 2021.

5. Adenosine A2A receptor inhibitors

Istradefylline received the first approval worldwide in Japan in 2013 as an inhibitor of the adenosine A2A receptor in the indirect pathway in the relatively hyperfunctional state among patients with PD. The indication is for improvement of the wearing-off phenomenon in PD under treatment with a regimen including levodopa, but an off-time shortening effect has also been observed, and this use was approved by the US FDA in 2019.

6. Amantadine sustained release

Amantadine, which was introduced as an agent for type A influenza in the 1970s, inhibits dyskinesia by inhibition of the N-methyl-D-aspartate (NMDA) receptor. This drug was also approved by the FDA in 2017 in a sustained release formulation (amantadine 274 mg capsule), after a demonstration of the efficacy of this formulation in the EASE LID study (23). Sustained release of amantadine also improves motor symptoms during off-time in patients with PD with motor complications under treatment with levodopa (24), and this indication was added by the FDA in 2021.

7. Therapeutic drugs for psychosis

PD may be accompanied by hallucinations and delusions, and aggravation of motor symptoms by drugs interfering with the dopaminergic system is a concern. Pimavanserin, an inverse agonist of the 5-HT2A receptor, was approved in the US in 2016 for the treatment of hallucinations and delusions related to neurologic manifestations in patients with PD.

II. Disease-modifying Therapy

PD is a heterogeneous disease for which the pathophysiology is increasingly becoming understood. This includes dysfunction in mitochondria or lysosomes, formation of toxic aggregates of α-synuclein, neuroinflammation, oxidative stress, and other issues. These events are all potential targets of disease-modifying therapy that affects the underlying fundamental pathophysiology of the disease. Numerous studies have attempted to identify medications to inhibit progression of PD, and new compounds are under development. Drugs already used to treat other conditions and related disorders in clinical practice are also being repurposed as agents to treat PD in a process referred to as ‘drug repositioning’. Such repositioning of already approved drugs can save costs and time compared to the development of new drugs. In the second section of the review, we introduce candidate disease-modifying drugs currently in phase 2 or more advanced clinical trials. A summary of these drugs is shown in Table 2.

Table 2.

Candidate Disease Modifying Therapy for PD Currently in Phase 2 or More Advanced Clinical Trials.

Drugs	Trial number (abbreviation of trial name)	Phase	Subjects	Primary outcome
α-synuclein targeting therapy
Monoclonal antibody
PRX002 (prasinezumab)	NCT03100149, BP39529, EudraCT-2017-000087-15 (PASADENA)	2	Early PD	MDS-UPDRS part I, II, III
	NCT04777331, BN42358, EudraCT-2020-004997-23 (PADOVA)	2	Early PD	MDS-UPDRS part III
Vaccines
PD01A	Not registered yet	2 (in preparation)	PD	Unknown
Inhibitor of misfolding of α-synuclein
NPT200-11 (UCB0599)	NCT04658186, PD0053, EudraCT- 2020-003265-19	2	Early PD	MDS-UPDRS parts I, II, III
Enhancer of β-glucocerebrosidase
Oral drug
Ambroxol	NCT02914366, HSREB-105234, health Canada-181033	2	PD with dementia	ADAS-Cog, CGIC
LTI-291	Not registered yet	2 (in preparation)	PD	Unknown
Gene therapy using adeno-associated virus 9
PR001	NCT04127578, PRV-PD101 (PROPEL)	1/2a	PD with GBA1mutation	Severe adverse event
				Immunogenicity of AAV9 in blood/CSF
				Immunogenicity of Ccase in blood/CSF
GLP-1 receptor agonists
Exenatide	NCT04232969, 18/0320 (exnatide-PD3)	3	Mild to moderate PD	MDS-UPDRS part III
Sustained release Exenatide (PT320)	NCT04269642. PT320-201	2	Early PD	MDS-UPDRS part III
Semaglutide	NCT03659682, 120262PARK (GIPD)	2	Newly diagnosed PD	MDS-UPDRS part III
Liraglutide	NCT02953665, U1111-1173-0106	2	PD diagnosed at least 2 years	MDS-UPDRS, NMSS, MADRS-2
Lixisenatide	NCT03439943, RC31/16/8912 (LixiPark)	2	Early PD	MDS-UPDRS part III
NLY01	NCT04154072, NLY01-PD-1	2	PD	MDS-UPDRS part II, III
Neuroprotective drugs
c-Abl kinase inhibitor
K0706	NCT03655236, CLR_18_6	2	Early PD	MDS-UPDRS parts II, III
Radotinib	NCT04691661, RT51EP1902	2	Early PD without symptomatic medication	Incidence and severity of treatment emergent AEs
Antibiotics
Ceftriaxone	NCT03413384, BRICEFA20170414	2	Mild to moderate PDD	ADAS-Cog
Sigma-1 receptor agonist
Blarcamesine (ANAVEX 2-73)	NCT04575259, ANAVEX2-73-PDD-EP-001	2	PD with dementia	Number of participants with adverse events
Iron chelators
Deferiprone	NCT02655315, EudraCT-2015-003679-31 (FAIRPARKII)	2	Treatment naïve PD	Total MDS-UPDRS score
Analog of CoQ10
Idebenone	NCT04152655 (SEASEiPPD)	2/3	REM sleep behavior disorder	Diagnosis of PD
	NCT03727295, SZDX-1 (ITEP)	4	Early PD	MDS-UPDRS part III, Hoehn and Yahr scale, olfactory function test, anxiety and depression scale
Immunosuppressant
Azathioprine	ISRCTN14616801, EudraCT-2018-003089-14 (AZA-PD)	2	Early PD	MDS-UPDRS part III
Statin
Simvastatin	NCT02787590, ISRCTN16108482, EudraCT-2015-000148-40, PDSTAT2015	2	PD with wearing-off phenomenon	MDS-UPDRS part III
Lovastatin	NCT03242499, NCTRC201702	2	Early PD	MDS-UPDRS part III
Mitochondrial enhancer
Ursodeoxycholic acid	NCT03840005, STH18493, EudraCT-2018-001887-46 (UP study)	2	Early PD	Number of adverse treatment reactions
				Number of serious adverse events
				Number of patients completing the study

1. α-synuclein targeting therapy

1) Immunization for α-synuclein

α-Synuclein is a 140-amino acid protein that is encoded by the synuclein alpha (SNCA) gene. The physiological role of α-synuclein is unclear, but its aggregation is toxic for neurons (25). The α-synuclein oligomer causes mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation (26). Cell-to-cell propagation of α-synuclein through prion-like spread is considered to be a pathophysiology of PD, and this propagation may occur during secretion of α-synuclein by exosome exocytosis and endocytosis. According to Braak's theory (27), the pathology of α-synuclein aggregation is proposed to begin in the medulla and spread gradually to the brain. Therefore, removal of extracellular α-synuclein may prevent progression of the pathology and/or clinical symptoms of PD.

Immunization with anti-α-synuclein oligomer monoclonal antibodies is currently being explored. For passive immunization, BIIB054 (cinpanemab), a monoclonal antibody that binds to the oligomeric and fibrillary forms of α-synuclein, showed good tolerability and safety in a phase 1 trial (28), but the development of BIIP054 was halted in 2021 because of a lack of efficacy in the primary outcome of improvement of motor symptoms in the phase 2 (SPARK) study. PRX002 (prasinezumab) is also a monoclonal antibody directed against aggregated α-synuclein. The safety and tolerability of PRX002 have been shown in a phase 1 study (29) and PRX002 is currently in phase 2 trials for PD (PASADENA study and PADOVA study). As an active vaccine for α-synuclein, PD01A, which mimics the C-terminal region of α-synuclein, has shown safety and tolerability in PD patients (30), and the AFFiRiS Corporation stated in 2020 that a phase 2 trial of PD01A for PD was in preparation.

2) Inhibitor of misfolding of α-synuclein

NPT200-11 inhibits misfolding of α-synuclein and subsequently inhibits its accumulation. NPT200-11 (UCB0599) and related compounds were developed through structure-based drug-discovery that utilized dynamic molecular modeling to identify and target specific regions of the alpha-synuclein protein critical for the formation of misfolded oligomers (31,32). Experiments using transgenic mice overexpressing human wild-type α-synuclein showed that NPT200-11 reduced α-synuclein pathology in the cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved the motor function (32). Currently, a phase 2 study of the effects of NPT-200 on the motor and cognitive function and DAT imaging findings in patients with early PD is ongoing.

2. Enhancers of β-glucocerebrosidase

1) β-glucocerebrosidase in PD

β-glucocerebrosidase (GBA) is a lysosomal enzyme that cleaves glucocerebroside into ceramide and glucose by hydrolysis. Genetic variants of GBA are associated with Gaucher disease and PD. Decreased GBA activity results in the accumulation of glucocerebroside in neurons, which mediates decreased lysosomal activity, formation of toxic α-synuclein oligomers and consequent higher risks of developing PD, more severe disease and faster progression of the disease. Drugs that affect the GBA function are under development.

2) Ambroxol

Ambroxol is an expectorant that has been shown to improve GBA activity in cells carrying GBA mutations and lysosomal activity in cells from patients with GBA mutation-linked PD (33). In the AiM-PD study, a non-randomized and non-controlled study, treatment with ambroxol improved the motor function of PD patients with and without GBI-1 mutations (34). A phase 2 study of the effects of ambroxol on the cognitive and motor function and cerebrospinal fluid and magnetic resonance imaging (MRI) findings in PD is currently underway.

3) PR001A

PR001A is injected intrathecally as a gene-replacement therapy using adeno-associated virus 9 (AAV9) to deliver a functional copy of the GBA1 gene to the brain (35). A phase 1-2a open label trial of PR001A for patients with GBA-associated PD is currently being performed.

4) LTI-291

LTI-291 is an allosteric modulator of GBA that enhances its activity. The results of a phase 1 trial have been published and showed that LTI-291 is well tolerated (36). According to an announcement on October 1, 2020, on the company's homepage (https://www.bial.com/com/, accessed on September 19, 2021), a phase 2 trial should be ready to start in 2021 (37).

5) Venglustat (GZ/SAR402671)

Venglustat is a glucocerebroside synthase inhibitor designed to reduce production of glucosylceramide. This “substrate reduction therapy” inhibits an upstream enzyme to reduce pathogenic substrate accumulation and is expected to have therapeutic efficacy for PD with GBA mutations. However, a phase 2 trial of the efficacy of venglustat in PD patients with GBA mutations (MOVES-PD study) did not meet the primary or secondary endpoints. Thus, further follow-up was terminated in 2021.

3. Medication with neuroprotective effects

1) Glucagon-like peptide 1 receptor agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat type II diabetes mellitus. GLP-1 receptor stimulation has also been shown to protect dopaminergic neurons from neurodegeneration in PD model mice (38). The proposed mechanism involves enhanced mitochondrial biogenesis, suppression of microglial activation and inflammation, enhancement of autophagy and clearance of aggregated proteins (39). A phase 2 study of exenatide, a GLP-1 receptor agonist, showed efficacy for motor symptoms and a reduced rate of decline in nigrostriatal dopaminergic neurons using DAT imaging (40). A phase 3 trial to examine the disease-modifying effect of exenatide in PD is ongoing (41). Phase 2 trials of other GLP-1 receptor agonists, including semaglutide, liraglutide, lixisenatide, LNY01 and a sustained release form of exenatide (PT320), are also ongoing in PD patients.

2) c-Abl inhibitor

The protein Abelson (c-Abl) is a non-receptor tyrosine kinase that is activated by oxidative and cellular stress. c-Abl plays a role in the pathogenesis of PD, including in the aggregation of α-synuclein and formation of Lewy bodies, autophagic impairment, mitochondrial dysfunction, and activation of microglia (42). Therefore, inhibition of c-Abl may influence the pathogenesis of PD. Some c-Abl inhibitors are already approved for treatment of chronic myelogenous leukemia, and recent studies in PD model mice suggest that c-Abl inhibitors may have neuroprotective effects (42). Clinical studies have shown that nilotinib increased the cerebrospinal fluid (CSF) level of homovanillic acid, a dopamine metabolite (43,44), reduced that of α-synuclein oligomers (43), and improved the motor and cognitive function, suggesting a disease-modifying effect (45). However, another trial of nilotinib showed no improvement in motor symptoms of PD patients (46). Two other c-Abl inhibitors - K-0706, which is also under the development for chronic myeloid leukemia, and radotinib - are also in phase 2 clinical trials.

3) Ceftriaxone

Ceftriaxone is a widely used antibiotic that has exhibited neuroprotective functions in an animal model of PD with dementia (PDD) (47,48). Based on these findings, a phase II study to investigate the efficacy and safety of ceftriaxone in patients with mild to moderate PDD is ongoing in Taiwan.

4) Sigma-1 receptor agonist

Sigma-1 receptor is a chaperone protein localized in the mitochondria-associated endoplasmic reticulum membrane. Activation of sigma-1 receptor has neuroprotective effects, such as modulation of toxic intracellular cascades involving calcium ions and anti-inflammatory effects as well as the elevation of neurotrophic growth factors (49). Agonists of sigma-1 receptor induce autophagy and increase proteostasis capacity (50) and are candidate therapeutic agents for neurodegenerative diseases (51), especially PDD (52). A phase 2 study of blarcamesine (ANAVEX 2-73), a sigma-1 receptor agonist, is ongoing in PDD patients.

4. Anti-oxidative stress drugs

1) Iron chelators

In PD patients, iron accumulates in neurons of the substantia nigra (53), and the accumulated intracellular iron has a neurotoxic effect due to increased reactive oxygen stress (54). Therefore, iron chelators may be effective for preventing neuronal damage in PD. A phase 2 trial in 22 patients with mild PD showed that deferiprone, an iron chelator, was able to improve motor symptoms and decrease iron concentrations in the dentate and caudate nuclei (55). In the FAIRPARK trial, patients who started deferiprone immediately showed a significantly better motor performance at 6 or 12 months than those who started 6 months later (56). A phase 2 study of the efficacy of deferiprone (FAIRPARK-II study) is currently underway in patients with PD.

2) Analogs of coenzyme Q10

Idebenone is an analog of the well-known antioxidant coenzyme Q10 (CoQ10) and has been shown to mitigate motor impairment and to increase the neuron survival in PD model animals (57). Clinical trials of idebenone for protection against the development of PD in patients with rapid eye movement (REM) sleep behavior disorder (SEASEiPPD study) and therapeutic effects on motor and non-motor symptoms in patients with early PD (ITEP study) are ongoing.

3) Myeloperoxidase inhibitors

Oxidative stress is one of the implicated pathogeneses of PD. Myeloperoxidase (MPO) is a reactive oxygen generating enzyme, and MPO-immunoreactive cells are increased in brain regions affected by neurodegeneration in PD (58). Oxidative stress is associated with neuroinflammation and neural damage in PD, and inhibition of MPO may reduce oxidative stress, neuroinflammation and neuronal damage in PD patients. A phase 2 study of AZD3241 (verdiperstat), a MPO inhibitor, in PD patients showed a reduction in distribution of activated microglia using ¹¹C-PBR28 positron emission tomography (59). Other clinical trials for PD were planned, but whether or not the further development of AZD3241 for PD is underway is unclear.

5. Anti-inflammatory agents and immunosuppressants

1) Non-steroidal anti-inflammatory drugs (NSAIDs) and immunosuppressants

Dysregulated inflammatory and immune systems, in which activated astrocytes, microglia and peripheral immune cells as well as inflammatory cytokines are present, are also implicated in the etiology of PD (60-62). Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) at baseline has been associated with a reduced risk of PD (63), and among NSAIDs, ibuprofen has been shown to have a particularly marked effect (64). A population-based case-control study of United States Medicare beneficiaries showed that the use of immunosuppressants, such as azathioprine, and corticosteroids was also associated with a reduced risk of emergence of PD (65). Therefore, anti-inflammatory drugs and immunosuppressants may have disease-modifying effects in PD. Among immunosuppressants, azathioprine, which reduces the proliferation of B and T cells via the inhibition of nucleic acid synthesis, is widely used in various immune-related disorders in clinical practice. A phase 2 randomized placebo-controlled, double-blind trial of the effects of azathioprine on progression of motor and non-motor symptoms in early PD patients (AZA-PD study) is in preparation (66).

2) Statins

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are commonly used in clinical practice to treat dyslipidemia. These drugs have also been suggested to have anti-oxidative and anti-inflammatory effects (67,68) and to reduce intraneuronal α-synuclein aggregation (69). A population study showed that the continuation of lipophilic statin therapy was associated with a decreased incidence of PD compared to patients with discontinuation of statins (70). A recent trial showed that lovastatin treatment in patients with early-stage PD was associated with a trend of reduced exacerbation of motor symptoms (71). These findings suggest that statins are candidates for neuroprotective treatment for PD. A phase 2 trial examining the effect of simvastatin on PD with a wearing-off phenomenon is currently ongoing (72), and the effects of lovastatin on motor symptoms in early PD patients are being examined in a phase 2 trial.

6. Recovery of the mitochondrial function

Mitochondrial dysfunction is a pathogenesis of PD and believed to be a promising target for disease-modifying therapy (73). Mortiboys et al. showed that ursodeoxycholic acid, which has been used for the treatment of liver disease for over 30 years, improved the mitochondrial production of adenosine triphosphate (ATP) in an in vitro study using parkin-mutant fibroblasts and LRRK2^G2049S mutant fibroblasts (74). Ursodeoxycholic acid has also been shown to rescue the function of mitochondria in LRRS2^G2019S carriers in vivo (75). Therefore, ursodeoxycholic acid may ameliorate the pathophysiology of PD by improving mitochondrial dysfunction. A phase 2 trial to ascertain the effect of ursodeoxycholic acid on mitochondrial activity, progression of motor symptoms and other effects in patients with PD is ongoing (76).

Conclusion

In this review, we focused on recent developments of symptomatic and disease-modifying therapy for patients with PD. The search for medications for PD has continued with treatment utilizing already existing drugs, as well as the development of new drugs. Levodopa is still the gold standard for PD, but the high prevalence of motor fluctuation with levodopa is a concern. Treatment options for motor fluctuation as symptomatic therapy are being developing with novel agents and advances in device and formulation technology. Disease-modifying therapy is not yet available in clinical practice, but progress in this area is likely as the pathophysiology of PD is further understood, and this approach may become practical in the near future.

The authors state that they have no Conflict of Interest (COI).