REVIEWS

Therapeutic strategies for Parkinson

disease: beyond dopaminergic drugs
Delphine Charvin1*, Rossella Medori1, Robert A. Hauser2 and Olivier Rascol3
Abstract | Existing therapeutic strategies for managing Parkinson disease (PD), which focus on
addressing the loss of dopamine and dopaminergic function linked with degeneration of
dopaminergic neurons, are limited by side effects and lack of long-term efficacy. In recent
decades, research into PD pathophysiology and pharmacology has focused on understanding
and tackling the neurodegenerative processes and symptomology of PD. In this Review, we
discuss the challenges associated with the development of novel therapies for PD, highlighting
emerging agents that aim to target cell death, as well as new targets offering a symptomatic
approach to managing features and progression of the disease.

Bradykinesia
Abnormal slowness of
movement.
Autonomic dysfunction
Abnormal functioning of the
autonomic nervous system,
affecting the functioning of the
heart, bladder, intestines, sweat
glands, pupils and blood vessels.
Examples include constipation,
orthostatic hypotension, urinary
incontinence and erectile
dysfunction.
Synucleinopathy
A neurodegenerative disease
characterized by an excessive
accumulation of α-synuclein.
Examples include PD,
dementia with Lewy bodies
and multiple system atrophy.
1
Prexton Therapeutics,
Geneva, Switzerland.
2
Department of Neurology,
University of South Florida,
Tampa, FL, USA.
3
Centre d’Investigation
Clinique CIC1436, Services
de Neurologie et de
Pharmacologie Clinique,
Réseau NS‑PARK/FCRIN et
Centre COEN NeuroToul,
CHU de Toulouse, INSERM,
University of Toulouse 3,
Toulouse, France.
*e-mail: delphine.charvin@
prextontherapeutics.com
doi:10.1038/nrd.2018.136
Published online 28 Sep 2018
The year 2017 marked the 200th anniversary of the first
published description by James Parkinson of the disease
that would later come to bear his name. In his seminal
work ‘An essay on the shaking palsy’, Parkinson detailed
the clinical features of what is now termed Parkinson
disease (PD)1, although many decades were to pass
during which physicians could recognize the condi‑
tion but considered it to be a disease that “the physi‑
cian can do little for by way of relief or cure”2. Indeed,
the most important advance in the treatment of PD did
not emerge until the early 1960s, when Birkmayer and
Hornykiewicz first documented the clinical benefit of
levodopa (3,4‑dihydroxy-l‑phenylalanine), the precursor
of dopamine, in patients with PD3,4 (FIG. 1).
PD is an age-related neurodegenerative disorder,
characterized by progressive and selective loss of dopa‑
minergic neurons in the substantia nigra that contributes
to the cardinal motor symptoms of the disease: brady-
kinesia, rigidity and resting tremor (BOX 1). In addition
to dopaminergic neuropathology, there is dysfunction
in cholinergic, serotonergic, glutamatergic and noradr‑
energic pathways — some of which may be secondary
to the deafferentation associated with dopamine system
dysfunction and/or dopaminergic neuronal death, with
others being due to the same PD pathological process
affecting dopaminergic and non-dopaminergic systems
(for a review of our current understanding of PD neuro‑
pathology, refer to5–8). People with PD also experience
‘non-motor’ symptoms such as sleep disturbance, fatigue,
altered mood, cognitive changes, autonomic dysfunction
and pain (BOX 2).
PD is classified as a synucleinopathy, as α-synuclein, a
presynaptic neuronal protein, is a major constituent of
Lewy bodies, which are a pathological hallmark of PD.
Interestingly, α-synuclein has a unique importance in the
aetiology of PD because it appears to link familial and
sporadic forms of the disease. The presence of aggre‑
gates in patient brains suggests that the proteostasis
of α-synuclein is disturbed in PD. Indeed, α-synuclein
exists in various conformations in a dynamic equilib‑
rium that is modulated by many factors, including
oxidative stress, post-translational modifications and
concentrations of fatty acids, phospholipids and metal
ions, and a tight balance of these factors controls the
levels and aggregation of α-synuclein9,10 (FIG. 2). A pro‑
gressive, age-related decline in proteolytic defence mech‑
anisms in the brain might play a role in the accumulation
of α-synuclein11,12 and contribute to the role of ageing in
PD pathophysiology (BOX 3).
PD remains an incurable neurological condition.
Levodopa is a mainstay therapy and, to date, drug
treatments used in the management of PD attempt to
compensate for the loss of dopamine and dopaminergic
function. The shortcomings of such pharmacotherapies
include their diminished effectiveness over time; the
development of medication-related complications such
as motor fluctuations and dyskinesia (levodopa-­induced
dyskinesia (LID)) and potential side effects such as
impulse control disorders, sleepiness or sudden-onset
sleep; and dopamine dysregulation syndrome13,14. Moreover,
the disease continues to progress, and non-dopamine-­
responsive symptoms such as cognitive dysfunction and
imbalance become more prominent and lead to long-
term disability 15.
In the past decade, researchers and clinicians have
pioneered a new area of discovery — looking beyond
the progressive dopamine neuron loss in PD — to try
to understand and tackle the neurodegenerative pro‑
cesses and the symptomology of PD (FIG. 1). Two non-­
dopaminergic medications have already been marketed

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First POC clinical trial of

an A2A antagonist
First description Intravenous Introduction of the
of Lewy bodies L-DOPA Dopamine direct and indirect First POC clinical trial of Demonstration that the
agonists pathway model of the a cell-based therapy direct and indirect pathways
(apomorphine) basal ganglia circuitry are not alternatively but
First Trihexyphenidyl concomitantly active to
neurosurgical modulate motor function
First attempt
An Essay on the intervention of a cell-based Mutations in SNCA identified
Shaking Palsy is of the basal therapy for as the first genetic cause of PD First POC
published by ganglia to humans with clinical trial of
James Parkinson treat PD Amantadine PD Deep brain stimulation an mGlu5 NAM

1817 1872 1899 1913 1940 1960 1961 1962 1969 1970 1985 1988 1989 1990 1993 1995 1996 1997 1998 2001 2003 2008 2012 2014 2017

The shaking Evidence of Carbidopa and MAOB First POC First POC First phase I
palsy is striatal dopamine L-DOPA inhibitors clinical trial of clinical trial clinical trial
renamed PD deficiency in PD combination (selegiline) neurotrophic of a gene for immuno-
therapy factors therapy therapy in PD
Oral L-DOPA approved
by FDA
First suggestion that the COMT inhibitors α-Synuclein found to be First POC
substantia nigra could be (tolcapone) the main component of clinical trial of
the site of PD pathology Lewy bodies an mGlu4 PAM

First suggestion of First POC

Breakthrough in PD research cell-to-cell transmission clinical trial of a
Non-dopaminergic agents Dopaminergic agents of α-synuclein LRRK2 inhibitor

Figure 1 | History of Parkinson disease research and therapeutic advances. A2A, adenosine receptor type 2A; COMT, catechol-O‑methyltransferase;
l‑DOPA, levodopa; LRRK2, leucine-rich repeat serine/threonine-protein kinase 2; MAOB, monoamine oxidase type B; mGlu,Reviews
Nature metabotropic
| Drug Discovery
glutamate receptor; NAM, negative allosteric modulator; PAM, positive allosteric modulator; PD, Parkinson disease; POC, proof of concept.
Adapted from REF. , Springer Nature Limited.
239

Dyskinesia
Abnormal involuntary
movements. Levodopa-induced
dyskinesia is associated with
chronic levodopa treatment
in patients with PD. It is
characterized by hyperkinetic
movements including chorea,
athetosis and dystonia.
Dopamine dysregulation
syndrome
Dysfunction of the reward
system associated with
long-term dopaminergic
treatments. It is characterized
by addictive behaviours and
excessive use of dopaminergic
medication, with patients
taking quantities of medication
well beyond the dose required
to treat their motor disabilities.
Disease modification
Efficacy of a therapy in
stopping, slowing or delaying
disease progression, and
therefore the clinical decline,
through an effect on the
underlying pathological
process (either cellular
protection or restoration
of cellular function).
for many years for the treatment of PD symptoms —
namely, the anti-muscarinic trihexyphenidyl16 and the
anti-­glutamatergic amantadine17. Recent research has
helped uncover some of the pathogenic mechanisms
underlying PD, which include α-synuclein aggrega‑
tion, mitochondrial dysfunction, endoplasmic reticu‑
lum stress, impaired autophagy and the loss of calcium
homeostasis (BOX 3). Furthermore, studies have identified
a number of potential biomarkers, highlighted ways in
which existing drugs may be repurposed for PD, revealed
alternative formulations of dopaminergic therapies to
improve their benefit/risk ratio and singled out novel tar‑
gets for pharmacological manipulation (BOX 3; TABLES 1,2).
A number of the resulting pharmaceutical candidates
have progressed and are now in clinical development.
New approaches to research are helping to change the
paradigm of PD treatment — allowing a ‘rethinking’ of
the overall objectives of treatment and helping expand
these to include innovative, dual symptomatic and
complication-­preventive (or complication-limiting) and
disease-modifying approaches. Today, the remaining
unmet medical needs include preventing or slowing dis‑
ease progression (disease modification), robust alleviation
of symptoms throughout the day while avoiding motor
complications and managing non-motor symptoms.
This Review provides an overview of the under‑
lying rationale for, progress with and associated chal‑
lenges in the development of novel treatments for PD
in recent years — looking beyond levodopa and other
dopaminergic therapies — to include both potentially
disease-modifying drugs and novel symptomatic thera­
pies. The mode of action, and the drug-specific preclin‑
ical performances, of candidate treatments for PD are
assessed, and some of the most promising biological tar‑
gets and therapeutic agents in contemporary research
are highlighted.
This Review does not purport to be systematic or
exhaustive, but is a narrative review aiming to provide
an overview of the symptomatic and disease-modifying
approaches for the treatment of PD that have advanced to
clinical studies and that are targeting non-­dopaminergic
pathways. An extensive review of the pathogenetic
mechanisms of PD is beyond the scope of this article,
and readers are referred to BOX 3 and referenced reviews
in each section for more information. One important
objective of this Review is to analyse and understand
apparent translational discrepancies between preclinical
studies and the clinic. Thus, the preclinical research and
approaches that are discussed here have been selected
on the basis of their clinical status and availability of
published preclinical studies in animal models.
Disease-modifying therapies
Recent advances in understanding the mechanisms
contributing to PD pathophysiology (BOX 3) have initi‑
ated the investigation of therapeutic approaches beyond
targeting dopaminergic pathways. However, the discov‑
ery of therapies to halt, slow or delay PD progression
(through either neuroprotection or restoration of neu‑
ronal function), and therefore the clinical decline, has

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Box 1 | Neuronal pathways and motor symptoms of Parkinson disease
Neural circuits of the basal ganglia are critical for motor planning and action selection,
and they are directly linked to Parkinson disease (PD) motor symptoms. A model of this
circuitry has been described in past decades202,203 and is evolving to reflect improved
understanding of its function204–207 (FIG. 3). Two major neuronal pathways exert
opposing influences on the output of this circuitry, and dopamine acts as a
neuromodulator, reinforcing the direct, stimulatory pathway and inhibiting the indirect
inhibitory pathway. It is the adequate balance and coordination between these two
pathways that is important for action selection and execution of appropriate
movements202,204,205,208. In PD, the loss of dopaminergic control leads to an imbalance in
favour of a hyperactive indirect pathway and a subsequent pathological global
inhibition of the motor cortex, leading to bradykinesia204,205,209,210. Thus, in order to
improve the management of PD motor symptoms, a novel promising therapeutic
strategy is to restore the relative balance between the direct and indirect pathways
instead of acting only on one of the pathways (FIG. 3).
proved difficult 18–21. Despite the various challenges and
recent clinical trial failures, promising novel therapeutic
strategies are beginning to emerge.
Challenges in drug development
Part of the challenge in developing drugs aiming to modify
disease is that the pathophysiology of PD is multifactorial
and still emerging (BOX 3). Compounding this are the dif‑
ficulties of developing reliable animal models of PD pro‑
gression and neurodegeneration as well as the challenges of
designing and performing appropriate clinical trials.
Disease models should reproduce the progressive nature
of PD. Appropriate experimental conditions mimicking
PD neurodegeneration need to be selected because many
animal models, including the classical toxic models, fail
to reproduce the progressive nature of PD22. Recently,
several α-synuclein transgenic mice have been devel‑
oped, expressing wild-type or mutated α-synuclein, but
they fail to reproduce the combination of progressive and
specific dopamine cell loss, protein aggregation and man‑
ifestations of PD23,24. The progress made towards a better
understanding of PD pathogenesis and recent advances
in research techniques have opened up new possibili‑
ties regarding disease modelling. Thus, very recently,
novel disease models have been described to replicate
the progressive degeneration of the nigrostriatal path‑
way, accompanied by a progressive motor dysfunction,
in rats and primates25–27. For example, adeno-­associated
virus (AAV) vector-mediated overexpression of mutated
α-synuclein (hybrid AAV2/9 A53T human α-synuclein)
in the substantia nigra induced a progressive degenera‑
tion of the nigrostriatal pathway in both rats and mar‑
mosets and a progressive motor dysfunction in rats28. The
development of similar models has recently been initiated
in macaques29. Although these disease models require fur‑
ther predictive validity for disease-modifying drug devel‑
opment, they may represent a considerable step towards
the translational validation of new therapies.
Biomarkers reflecting progression of the disease need
to be validated. For regulatory purposes, the European
Medicines Agency (EMA) guidelines on clinical inves‑
tigation of medicinal products in the treatment of
PD notes “for a disease modifying claim a two-step
procedure is foreseen, first a delay in disease progres‑
sion should be shown, second an effect on the under‑
lying pathological process should be established”30.
Unfortunately, validated biomarkers reflecting progres‑
sion of the disease are still lacking, therefore disease
modification can be assessed only by a delay in symp‑
tom progression in PD clinical trials20,31,32. No definitive
biomarker of PD has yet been identified, but research is
very active in this field, involving increased application
of proteomics, metabolomics and transcriptomics32–35.
Recently, free water volume in the posterior substantia
nigra was evaluated as an imaging marker of PD pro‑
gression in a 4‑year follow‑up multicentre longitudinal
study of de novo patients with PD from the Parkinson’s
Progression Markers Initiative (PPMI) cohort study 36.
This study showed a progressive increase of free water
over 4 years in patients with PD, and the 1‑year and
2‑year increases predicted subsequent long-term pro‑
gression of motor symptoms as assessed on the Hoehn
and Yahr staging system. These results suggest that free
water is a valid outcome measure in future clinical trials
of disease-modifying therapies.
Potential biomarkers for the diagnosis and progres‑
sion of PD neuropathology, including clinical (olfactory
impairment and rapid eye movement sleep behaviour
disorder), biochemical (α-synuclein, protein DJ1,
β‑glucocerebrosidase (GBA), amyloid-β (Aβ)/tau ratio
and homovanillic acid/xanthine ratios in cerebrospinal
fluid (CSF); α-synuclein, protein DJ1, reactive oxygen
species (ROS), uric acid/urate or glutathione/glutathione
S‑transferase ratios in blood; and α-synuclein in colonic
and/or skin biopsy samples), genetic (GBA, PINK1,
SNCA, PARK2 (also known as PRKN), PARK7 and
LRRK2) and imaging biomarkers (dopamine transporter
imaging with single photon emission computed tomog‑
raphy (DaT-SPECT), deformation-based morphometry
MRI (DBM-MRI), electroencephalography and tran‑
scranial sonography) have also been reported; some are
promising but not yet fully validated32,37. Combining
different classes of biomarkers could also increase the
predictability of disease progression in patients38.
Clinical trial design should allow the evaluation of clini-
cal progression. To detect slowing of clinical progression
in PD, patients will require follow-up in controlled clini‑
cal studies for a substantial period of time. One option is
to evaluate such patients in the practically defined OFF
state after withholding their symptomatic dopaminergic
medications overnight 39,40 in an effort to evaluate clini‑
cal progression of ‘untreated’ disease. However, it is not
clear that overnight withdrawal of dopaminergic medi‑
cations is sufficient to wash out symptomatic effects41,42.
Therefore, most disease-modifying clinical trials today
evaluate early untreated patients with PD and monitor
them off symptomatic therapy for up to 9–12 months.
The main difficulty with this design is that some patients
will require symptomatic therapy before the designated
end point. In addition, there is no guarantee that a med‑
ication that works in early disease will work in more
advanced disease. Finally, evaluation of patients with

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Box 2 | Targeting non-motor symptoms of Parkinson disease
Many of the motor symptoms of Parkinson disease (PD) are preceded, often by
several years, by non-motor symptoms (NMSs) that include hyposmia, sleep disorders,
depression and constipation. NMSs, including sleep impairment, pain syndromes and
neuropsychiatric symptoms (depression, impulse control disorders, hallucinations,
psychosis and cognitive impairment progressing to dementia), increase with advancing
age and duration of PD211,212. The neuroanatomical and neuropharmacological bases
of non-motor abnormalities in PD remain largely undefined, although some are induced
by current dopaminergic therapies.
Given the major impact of NMSs on the quality of life for patients with PD, this
represents an emerging unmet need in the management of patients with PD213,214
and another major development area for the future.
Current therapies for NMSs in PD are limited. However, the 5‑HT2A inverse agonist
pimavanserin has been approved in the United States for the treatment of dopami-
metic-induced psychosis in PD (TABLE 2). Evidence in support of pimavanserin for the
management of psychosis comes from a phase III placebo-controlled trial215. The
primary outcome was antipsychotic benefit as assessed by the PD-adapted Scale for
the Assessment of Positive Symptoms (SAPS‑PD), and active treatment was
associated with a significant reduction in psychosis. Pimavanserin was well tolerated
with no significant safety concerns or worsening of motor function.
early disease does not allow for an assessment of critical
symptoms that cause morbidity in late disease, including
balance and cognitive dysfunction.
Clinical trials aimed at demonstrating disease modi‑
fication may rely on simultaneous assessment of changes
in progression of clinical symptoms plus imaging mark‑
ers (for example, DaT-SPECT) over time43. Validated
biomarkers and additional imaging techniques (for
example, synuclein imaging) are being sought to enable
better demonstration of disease modification.
Clinical trial protocols should better stratify and select
patients. PD is a multifactorial neurodegenerative dis‑
order, the aetiology of which remains largely unknown,
and patients present and progress in different ways8,44.
Recently, the National Institutes of Health (NIH) estab‑
lished disease subtype identification as one of the top
three clinical research priorities in PD45. Understanding
the pathophysiological differences among individuals
and defining PD subtype populations may ultimately
allow for a better definition of the target population of
each treatment strategy. Improved and, where necessary,
targeted patient selection may be crucial for future trials
assessing disease-modifying therapies.
Well-defined criteria have not yet been widely
accepted to identify PD subtypes, but by using clinical,
biochemical or genetic markers (or a combination), it
may be possible to improve patient stratification for
inclusion of more homogeneous cohorts into future tri‑
als. Fereshtehnejad et al. recently used hierarchical clus‑
ter analysis of data collected from the PPMI to define
three clinical PD subtypes (‘mild motor-predominant’,
‘intermediate’ and ‘diffuse malignant’), demonstrating
Unified Parkinson their validity in terms of both imaging (MRI morpho‑
Disease Rating Scale metry data) and CSF (Aβ levels and Aβ/tau ratio) bio‑
(UPDRS). Used to assess markers37. Furthermore, they demonstrated that these
severity and impact of PD signs
and symptoms. It is made up of
subtypes have longitudinal validity with the diffuse
sections (parts I–IV) assessing malignant group, demonstrating a more profound dopa‑
different aspects of the disease. minergic deficit, increased atrophy in PD brain networks
and faster progression of motor and cognitive deficits
after an average of 2.7 years37. Long-term predictive
validity of those criteria remains to be established.
Ultimately, clinical subtyping of patients using base‑
line clinical information should improve the stratifica‑
tion of patients for a more efficient personalized clinical
trial. A precision or personalized medicine approach in
combination with genetic testing is commonplace in
patient selection for cancer clinical trials and has yielded
numerous successes. Similarly, this approach is begin‑
ning to be utilized in PD clinical trials and may improve
outcomes, considering that cohorts may be better focused
on participants most likely to show a measurable change
over the course of study 46,47.
Recent clinical trial failures
Several disease-modifying strategies have recently
been tested in clinical trials but have largely proved
to be unsuccessful. Such approaches include antioxi‑
dant agents, dopamine agonists, monoamine oxidase
type B (MAOB) inhibitors, trophic factors and anti-­
inflammatory and gene-therapy-based approaches47.
The examples we discuss below have been chosen as
they allow comparison of the outcomes that have been
described in animal models and the results observed in
human studies. The negative outcomes of these phase II
and III types of trials highlight the difficulties of dem­
onstrating an effect in PD cohorts, but they may help
progress our understanding of what should define dis‑
ease modification and how to move forward with thera­
peutically innovative concepts.
Antioxidant agents. At both a cellular and a physiolog‑
ical level, oxidative stress is considered to be a potential
driver of PD progression (BOX 3; FIG. 2). Post-mortem
brain tissues from patients with PD have shown accu‑
mulation of oxidative damage markers, especially in the
substantia nigra48. Mitochondrial dysfunction has also
been implicated in PD pathogenesis, partly through an
increase in generation of ROS49 (BOX 3). Oxidative stress
may increase mitochondrial DNA (mtDNA) mutations
and accelerate α-synuclein aggregation50, parkin inac‑
tivation51,52 and proteasome dissociation53. Oxidative
stress can also affect dopamine release and affect cellu‑
lar self-defence mechanisms54,55. These are areas ripe for
potential therapeutic manipulation.
-Recently, the Parkinson Study Group attempted to
evaluate the disease-modifying potential of coenzyme
Q10 (CoQ10)56 on the basis of the rationale that this
agent might reduce the oxidative stress reported in PD.
CoQ10 is a component of the electron transport chain
involved in ATP generation, and studies in a rodent
model of PD suggested a mild neuroprotective effect
of CoQ10 (REFS57–59). The phase III, placebo-controlled
clinical trial aimed to assess the impact of CoQ10 on
disease progression in early PD by means of a change
in total Unified Parkinson Disease Rating Scale (UPDRS)
score in 600 early untreated patients over 16 months
or until dopaminergic therapy was required, which‑
ever came first. However, after a prespecified futility
criterion was reached, the study was terminated early

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Presynaptic neuron
Gene mutations and/or SNCA post-translational
modifications, toxins, neuroinflammation, etc.
siRNA or miRNA

Anti-inflammatories
SNCA synthesis
Altered SNCA
proteostasis

SNCA clearance SNCA monomers

Immunotherapy Antioxidants

Activation of autophagy,
proteasome, proteases
and chaperones
Mitochondrial Oxidative
SNCA oligomers dysfunction stress

Endoplasmic reticulum Impairment of

stress response homeostasis
Amyloid fibrils

Impairment of Cell death

Lewy body axonal transport

Immunotherapy Trans-synaptic transmission

and prion-like propagation

Figure 2 | Pathogenic mechanisms involved in Parkinson disease and associated therapeutic strategies. Schematic
diagram depicting interactions between major molecular pathways that are implicated inNature Reviews | Drug
the pathogenesis Discovery
of Parkinson
disease (PD) and possible therapeutic strategies (grey boxes) to combat cell death. Although α-synuclein (SNCA) is
depicted as a principal player in PD pathophysiology, cell death can be induced in its absence by any of the pathogenic
mechanisms outlined (blue boxes). Intracellular levels of SNCA are tightly regulated by the balance between the rates of
synthesis, clearance and aggregation of the protein. Abnormalities altering SNCA proteostasis, including gene mutations,
post-translational modifications, external toxins, neuroinflammation or oxidative stress, may increase intracellular SNCA
levels and induce its accumulation (yellow boxes). Accumulating SNCA monomers interact to form oligomers that grow to
form amyloid fibrils and Lewy bodies (purple boxes). Cellular damage induced by the toxic forms of SNCA includes
impairment of axonal transport, mitochondrial dysfunction and endoplasmic reticulum stress response, which ultimately
induce cell death. Dysfunction in these processes can also induce cell death in the absence of SNCA and thus may
precede and cause or contribute to SNCA dysfunction or follow as a consequence of SNCA toxicity and in turn feed back
and enhance its toxicity. Toxic forms of SNCA can be transferred between cells and induce disease spreading to other
brain regions. Targeted mechanisms to confer neuroprotection include decreasing SNCA synthesis using small interfering
RNA (siRNA) or microRNA (miRNA); increasing the clearance of SNCA by activating autophagy, the proteasome, proteases
or chaperones; or blocking SNCA aggregation and spreading using immunotherapy. In addition, anti-inflammatories and
antioxidants can be used to decrease cellular stress.

Methyl-4 phenyl 1,2,3,6
tetrahydropyridine
(MPTP). A neurotoxin that
causes irreversible loss of
dopamine neurons and
parkinsonism in mice, monkeys
and humans. The neurotoxicity
of MPTP was first discovered
when a young man
self-injected an illicit narcotic
(desmethylprodine (MPPP))
containing MPTP as a major
impurity. He developed PD
motor symptoms and
responded to levodopa
therapy, and the autopsy
showed selective degeneration
of dopaminergic neurons of
the substantia nigra.
when no evidence of clinical benefit of the intervention
treatment was demonstrated56. Likewise, a long-term
placebo-controlled study of creatine monohydrate was
terminated after a median follow‑up of 4 years owing
to futility. In this study, futility was defined as a failure
to detect a difference in clinical decline, measured by
a global statistical test that included five clinical status
outcome measures. Here, creatine was assessed versus
placebo in 1,741 patients with early PD who had been
on dopaminergic treatment for 90 days to 2 years, and
patients were monitored for 5–8 years, during which
time treating physicians used all available medications
to provide the best response19.
Another antioxidant approach is to target peroxi‑
some proliferator-activated receptor-γ (PPARγ) with the
agonist pioglitazone, which belongs to a class of drugs
with reported potential to control mitochondrial bio‑
genesis and oxidative stress by inhibiting the activation
of microglia and astrocytes and the production of pro-­
inflammatory cytokines and nitric oxide60. Preclinical
studies performed with pioglitazone in Methyl-4 phenyl
1,2,3,6 tetrahydropyridine (MPTP) monkeys have shown
neuroprotection and improvements of motor symptoms
that were qualified as modest by the study authors61.
In phase II, pioglitazone failed to show any disease-­
modifying activity in the subsequent 44‑week placebo-­
controlled study in 210 patients with early PD on a
stable dosage of an MAOB inhibitor (rasagiline or sele‑
giline) assessing UPDRS scores62. Moreover, the selected
peripheral biomarkers for PD progression, including
leukocyte PPARγ coactivator 1α (PGC1α) and target
gene expression, plasma interleukin 6 (IL‑6) as a marker

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of inflammation and urine 8‑hydroxydeoxyguanosine neurons, which resulted in robust improvements of

(8OHdG) as a marker of oxidative DNA damage, did not
correlate with UPDRS changes62,63.
In the CoQ10 and pioglitazone examples, the neuro‑
protective effects described in preclinical animal models
were of mild amplitude. This finding may explain why
these two compounds failed to produce significant benefit
for patients in clinical trials.
Gene therapy-based strategies. Many gene therapy
approaches aim to rescue degenerating neurons by
delivering neurotrophic factors or to restore function
by delivering key enzymes involved in or required for
dopamine synthesis and metabolism64.
Early trials of disease-modifying gene therapy met
with a number of obstacles. In preclinical studies using
animal models of PD, injection of glial cell line-derived
neurotrophic factor (GDNF) and neurturin (NRTN) were
found to enhance function and protect dopaminergic
motor function65–67. However, several clinical trials failed
to reproduce these beneficial effects but allowed for the
progressive improvement of gene delivery protocols68,69.
In a recent double-blind, randomized controlled trial,
gene delivery of NRTN was improved by utilizing an
AAV2 vector that was genetically engineered to express
and secrete the human gene for NRTN (CERE‑120). This
agent was then injected directly into the putamen and
substantia nigra of patients with advanced PD. However,
this therapy was not shown to affect clinical outcomes in
the trial. The study end point was the change from base‑
line to final visit at 15 months in the motor subscore of
the UPDRS in OFF state, but no difference was observed
between AAV2–NRTN-treated and sham-operated
patients in this or any of the secondary end points of the
study 70. Human studies suggest that Ret, the receptor for
GDNF and NRTN, is downregulated in PD71, and this
has been shown to result from α-synuclein accumulation

Box 3 | Emerging pathogenic mechanisms of Parkinson disease

Parkinson disease (PD) is an age-related neurodegenerative disorder, characterized by progressive and selective loss
of dopaminergic neurons in the substantia nigra and by Lewy body deposition in the midbrain, with widespread
involvement of other central nervous system structures and peripheral tissues. PD pathology is composite and due to
the action of genetic and environmental factors. The precise molecular mechanisms causing neuronal loss are still not
fully understood, but intensive research has helped uncover several pathways and mechanisms involved in PD
pathophysiology, establishing a vicious cycle in which these mechanisms exacerbate each other. The usual suspects
are the following:
• α-Synuclein aggregation. α-Synuclein exists in various conformations in a dynamic equilibrium that is modulated by
many factors, including oxidative stress, post-translational modifications and concentrations of fatty acids,
phospholipids and metal ions, and a tight balance of these factors controls the levels and aggregation of α-synuclein
(for a review of our current knowledge on α-synuclein, refer to10,216). α-Synuclein may acquire neurotoxic properties
during a pathogenetic process in which soluble monomers initially form oligomers then progressively combine to form
small protofibrils and further aggregate into large, insoluble fibrils forming Lewy bodies (FIG. 2).
• Prion-like cell‑to‑cell transmission of α-synuclein (possibly invading via the gut–brain axis). Several lines of
experimental evidence suggest that pathogenic misfolded α-synuclein is released into the extracellular space,
internalized by neighbouring neurons and seeds aggregation of endogenous α-synuclein once inside its new cellular
host217,218. Thus, initial α-synuclein misfolding in a small number of cells could progressively lead to the spread of
α-synuclein aggregates to multiple brain regions over years219. However, definitive proof of this intercellular
propagation has proved difficult to secure220.
• Mitochondrial dysfunction. Dysfunction of complex I (due in part to mitochondrial accumulation of α-synuclein),
change in membrane potential, impairment of mitochondrial quality control, disruption of calcium homeostasis and
enhanced release of cytochrome c (reviewed in detail in49,221,222).
• Oxidative stress, which is intimately linked to mitochondrial dysfunction and to which nigral dopaminergic neurons are
particularly vulnerable223–225. Mitochondrial dysfunction and increased oxidative stress can lead to functional
impairment of the lysosomal autophagy system, further demonstrating that several putative pathogenetic pathways in
PD are intimately linked226.
• Severe endoplasmic reticulum stress, resulting from the accumulation of misfolded or unfolded proteins and
contributing to neuronal death or apoptosis5,227.
• Impairment of autophagy, which may boost α-synuclein release and transfer from cell to cell228 and lead to the
accumulation of dysfunctional mitochondria229.
• Dysfunction of axonal transport, potentially due to the energy deficiency (due to mitochondrial dysfunction) and/or the
presence of α-synuclein aggregates becoming obstacles to normal axonal transport230,231.
• Motor circuit pathophysiology, with abnormal neural synchronization in the basal ganglia, and synaptic alterations,
in particular in corticostriatal plasticity, with both presynaptic and postsynaptic modifications232–234. Changes in
cerebellar circuits and in interactions between the cerebellum and the basal ganglia are also considered important in
the pathophysiology of PD235. The motor circuit pathophysiology results from dopamine loss but also from disturbances
in other neurotransmitters, in particular cholinergic and glutamatergic transmitters236,237.
• Neuroinflammation, with intense astrogliosis and microgliosis that may be associated with abnormal corticostriatal
plasticity. Although perhaps not the initial trigger, neuroinflammation is suspected to be an essential contributor to
PD pathogenesis238.

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Table 1 | Non-dopaminergic therapies currently in development for PD modification

Compound and/or agent, Mechanism of action Phase of Clinical trial Refs
company development number
AXO-LENTI‑PD (OXB‑102; Triple gene therapy (Lenti‑TH– Phase I/IIa in ProSavin: 76,77,

ProSavin analogue with AADC–GTPCH) to restore striatal preparation • NCT01856439 79,80

increased level of transgene dopamine production • NCT00627588

expression), Oxford BioMedica
and Axovant Sciences
VY‑AADC, Voyager Gene therapy (AAV2–hAADC) Pivotal phase II/III • NCT01973543 81–85

Therapeutics to restore striatal dopamine ongoing • NCT03065192

production • NCT03562494
PRX002 (RO7046015), Passive immunotherapy targeting Phase II ongoing NCT03100149 88–91

ProThena and Roche α-synuclein

PD01A and PD03A, Affiris Active immunotherapy targeting Phase I • NCT01885494 88,92–94

α-synuclein completed • NCT01568099

• NCT02216188
• NCT02618941
• NCT02267434
BIIB054, Biogen and Passive immunotherapy targeting Phase II ongoing NCT03318523 95,96

Neurimmune aggregated α-synuclein

NPT200‑11, UCB and α-Synuclein aggregation Phase I NCT02606682 98

Neuropore Therapies modulator completed

Ambroxol, Lawson Health Increase glucocerebrosidase Phase II in • NCT02941822 120,122

Research Institute and Van activity preparation • NCT02941822

Andel Research Institute
LTI‑291, Allergan and Lysosomal Glucocerebrosidase activator Phase II ongoing NTR6960 123

Therapeutics (EudraCT
2017‑004086‑27)
Venglustat (GZ/SAR402671), Glucosylceramide synthase Phase IIa ongoing NCT02906020 124

Sanofi and Genzyme inhibitor in patients with PD

carrying a GBA mutation
Deferiprone, ApoPharma Iron chelator Phase II ongoing • NCT02655315 130

• NCT02728843
Exenatide, National Institute GLP1 agonist Phase I ongoing NCT03456687 39,133

of Neurological Disorders and

Stroke
Liraglutide, The Cure Parkinson’s GLP1 agonist Phase II ongoing NCT02953665 240

Trust and Novo Nordisk

DNL151 (backup of DNL201), LRRK2 inhibitor Phase I ongoing NA 141

Denali Therapeutics
KM‑819 (KR33493), Kainos FAF1 inhibitor to protect Phase I ongoing NCT03022799 144

Medicine dopaminergic neurons from

apoptosis
AAV2, adeno-associated virus type 2; FAF1, Fas-associated factor 1; GLP1, glucagon-like peptide 1; Lenti, lentiviral vector;
LRRK2, leucine-rich repeat serine/threonine-protein kinase 2; NA, not available; PD, Parkinson disease.

in rat models of α-synucleinopathy 71,72. Thus, it is pos‑ Emerging disease-modifying therapies

sible that, in the case of neurotrophic factors, benefits
observed in MPTP monkeys do not translate into ben‑
efits in patients because this model does not recapitu‑
late the accumulation of α-synuclein found in PD. It is
also possible that the patients enrolled in the clinical
trials had disease that was too advanced to benefit from
neurotrophic factor therapy. Indeed, to limit misdiagno‑
sis and to have clinical disease sufficiently advanced to
observe benefit, inclusion criteria often include a mini‑
mum 5‑year duration of PD from diagnosis (average of
7.8 years in the NRTN-treated patient cohort)70. Notably,
there might not be sufficient neuronal fibres remaining
for growth factors to be beneficial in these patients.
Despite the succession of past failures of disease-­
modifying approaches in clinical trials, research
efforts in the pursuit of neuroprotective strategies in
PD are still very intense. Increased understanding of
the pathogenetic mechanisms underlying PD (BOX 3)
have prompted the development of new therapies
and identified novel targets, including gene delivery
of enzymes involved in dopamine metabolism, glu‑
tathione replacement, iron chelators and glucagon-like
peptide 1 (GLP1) agonists.
In the past 10 years, 24 loci have been identified
as risk factors for sporadic forms of PD73, and sev‑
eral drugs that target the related proteins are now in

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Table 2 | Non-dopaminergic therapies currently in development for the symptomatic treatment of PD

Compound and/or agent, company Mechanism of action Phase of development Clinical trial Refs
number
Motor fluctuations
Istradefylline (KW‑6002), Kyowa Adenosine receptor • Approved in Japan • NCT01968031 155–159

Hakko Kirin Pharma type 2A antagonist • Not approved by the • NCT02610231

FDA in February 2018
Dyskinesia
Amantadine ER (ADS‑5102 (Gocovri)), NMDA receptor • Approved in United NCT02136914 183,184

Adamas Pharmaceuticals antagonist States

• Phase III ongoing
Dipraglurant (ADX48621), Addex mGlu5 NAM Phase III in preparation NCT01336088 189–191

Therapeutics
Buspirone, Assistance Publique, 5‑HT1A and Phase III ongoing • NCT02617017 196,241

Hôpitaux de Paris, Oregon Health and α1-adrenergic receptor • NCT02803749

Science University and University of agonist • NCT02589340
Rochester
Eltoprazine, Amarantus BioScience 5‑HT1A/1B receptor Phase IIb in preparation NCT02439125 197,198

Holdings agonist
Motor fluctuations and dyskinesia
Foliglurax (PXT002331), Prexton mGlu4 PAM Phase IIa ongoing NCT03162874 192–194,

Therapeutics and Lundbeck 242,243

Other symptoms
Varenicline (gait and balance, excessive Partial agonist of • Phase II ongoing for • NCT01341080 244,245

daytime sleepiness), Rush University the α4β2 nicotinic gait and balance • NCT02473562
Medical Center and VU University acetylcholine receptor • Phase IV ongoing for
Medical Center sleep
Pimavanserin (formerly ACP‑103) 5‑HT2A receptor inverse Approved in United • NCT00550238 215,

(psychosis), Acadia Pharmaceuticals agonist States • NCT01174004 246–249

• NCT00477672
SYN120 (PD dementia), Acorda 5‑HT6/2A receptor Phase II ongoing NCT02258152 250

Therapeutics antagonist
5‑HT, serotonin; D1, dopamine receptor D1; FDA, US Food and Drug Administration; mGlu, metabotropic glutamate receptor; NAM,
negative allosteric modulator; NMDA, N‑methyl-d‑aspartate; PAM, positive allosteric modulator; PD, Parkinson disease.

early development. Some promising approaches aim
to address mutations in genes encoding α-synuclein,
leucine-rich repeat serine/threonine-protein kinase 2
(LRRK2), GBA and parkin47,74,75.
Gene therapy. Among the emerging and promising gene
therapies for PD are novel agents that aim at delivering
key proteins involved in dopamine metabolism directly
into the basal ganglia (TABLE 1). ProSavin (also known
as OXB‑101) is a viral vector that offers a restorative
approach by delivering three key enzymes involved in
the synthesis of dopamine76. This triple gene therapy
has demonstrated strong improvement in parkinso‑
nian motor symptoms and restoration of approximately
50% of normal striatal dopamine concentrations in
MPTP macaques77. Therefore, ProSavin has been eval‑
uated in a small-scale phase I/II open-label study in 15
patients with PD. Treatment was injected directly into
the putamen and patients were monitored for a period
of 12 months. ProSavin was reported to be well toler‑
ated and offered patients significant dose-dependent
improvements at 6 and 12 months in UPDRS motor
scores when compared with baseline78, which was con‑
sistent with the results of preclinical efficacy studies in
MPTP macaques77. However, the study had no placebo
arm, and it is known that in PD, the placebo effect can
be significant, especially with a surgical intervention78.
Although the results were encouraging, some patients
displayed less than 50% improvement in the UPDRS
part III motor score and continued to require a sub‑
stantial daily dose of oral levodopa therapy to achieve
maximal benefit. It was then concluded that higher lev‑
els of dopamine replacement might be required79 and
a more potent vector construct (OXB‑102, now AXO-
Lenti‑PD) has been developed to increase the level of
transgene expression79. A phase I/II dose escalation
study is expected to be initiated by the end of 2018 in
patients with advanced PD80. In the meantime, longer-
term safety and efficacy evaluation of ProSavin has been
pursued (NCT01856439).
Another gene therapy approach currently being inves‑
tigated is the use of the recently developed VY‑AADC
vector, which provides AAV2–hAADC gene delivery
with the aim of restoring the loss of DOPA decarboxy‑
lase (DDC; also known as AADC) in nigrostriatal dopa‑
mine neurons that occurs in advanced PD81. VY‑AADC
is given as a single treatment that aims to enable neurons
of the putamen to express the AADC enzyme and thus

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ON/OFF
Alternating periods of good
(ON) and poor (OFF) control of
motor symptoms by levodopa
treatment. ON refers to time
when medication is providing
benefit with regard to mobility,
slowness and stiffness.
OFF refers to time when a
medication’s efficacy has worn
off and is no longer providing
benefit with regard to mobility,
slowness and stiffness.
NATURE REVIEWS | DRUG DISCOVERY ADVANCE ONLINE PUBLICATION | 9
REVIEWS
offer a durable therapy that enhances the conversion of mouse models of PD or dementia with Lewy bodies88,89.
levodopa to dopamine. A study in non-parkinsonian The tolerability and safety of a single intravenous infu‑
monkeys showed that MRI-guided infusion of sion of PRX002 was demonstrated in a phase I clinical
VY‑AADC into the midbrain was feasible and tolerable, trial in healthy volunteers90 and in a 12‑week phase Ib
without any assessment of efficacy at this stage82. After multiple-­ascending-dose study of PRX002 in patients
demonstration of the clinical safety of this approach83, a with early PD. This study demonstrated central nerv‑
phase Ib trial was initiated and is currently ongoing in ous system (CNS) penetration of PRX002 and dose-
15 patients with advanced PD (NCT01973543). Interim dependent and time-dependent reduction in levels of
results presented in 2017 at the annual meeting of the free serum α-synuclein, but effected no reduction in
American Academy of Neurology (AAN) and at the CSF α-­­synuclein91. However, no efficacy results have
American Association of Neurological Surgeons (AANS) been described as yet. A randomized, double-blind,
annual scientific meeting suggest that this treatment placebo-controlled phase II study was initiated by Roche
effects a durable, dose-dependent and time-dependent in July 2017 to evaluate the efficacy of monthly intra­
increase in AADC activity, as shown by positron emis‑ venous PRX002 over 52 weeks in patients with early PD.
sion tomography (PET) imaging using 18F-fluorodopa, The primary end point will be change from baseline in
which correlates with improvement of motor function MDS-UPDRS (a Movement Disorder Society (MDS)
(assessed by ON/OFF times and UPDRS part II and III revised version of the UPDRS) total score at week 52.
scores)84. Because of pulmonary embolism and related Neurodegeneration will be assessed by dopamine
heart arrhythmia reported in one treated subject, deep transporter imaging (DaT-SPECT) (NCT03100149).
vein thrombosis prophylaxis was added to this protocol, In parallel to the development of this passive
and a separate phase I study designed to further optimize immunotherapy, Affiris has developed two active
the intracranial delivery of VY‑AADC has been per‑ vaccines with short α-synuclein-mimicking pep‑
formed. The US Food and Drug Administration (FDA) tides — Affitopes PD01A and PD03A. This approach
has cleared investigational new drug (IND) application has shown efficacy in transgenic mouse models for
status and granted regenerative medicine advanced decreasing α-synuclein oligomers in axons and syn‑
therapy (RMAT) designation for a pivotal phase II/III apses and reducing loss of dopaminergic neurons88,92.
programme for VY‑AADC, which is currently ongo‑ In June 2017, top-line results of a 36‑week phase I clin‑
ing and is expected to conclude in late 2020/early 2021 ical study were announced at the 21st International
(NCT03562494)85. Congress of Parkinson’s Disease and Movement
The need for surgical injection of current gene thera­ Disorders93. It was reported that Affitope PD03A may
pies is likely to make these approaches unsuitable for be safe and well tolerated in patients with early PD and
patients with early stages of PD. Improving the modes indicates a dose-dependent immune response against
of delivery and rendering them less invasive will be key the peptide itself and cross-reactivity against the
to the advancement of gene therapy approaches in the α-synuclein targeted epitope. In March 2018, long-term
treatment of PD. Development of gene therapy that data were presented at the Advances in Alzheimer dis‑
directly affects progression of PD pathology and clinical ease and Parkinson disease Therapies (AAT-ADPD)
course might still be entertained as a possible treatment Focus Meeting, reporting that both tested doses of
for early PD in the future. PD03A induced peak titres 4 weeks after the third
injection, which were reactivated by the boost injection
α-Synuclein-targeted therapies. Common variants in at week 36 (REF.94). These results provide an encouraging
the gene encoding α-synuclein are believed to act as risk basis for further clinical development.
factors for sporadic forms of PD and, in all patients with Several unanswered questions remain regarding
PD, there is toxic aggregation of α-synuclein86 (FIG. 2). the application of immunotherapies for CNS disorders
Three approaches to therapeutically interfere with and chronic conditions such as PD, including whether
α-synuclein toxicity in PD pathology have been proposed: antibodies reach the brain compartment at sufficient
blocking α-synuclein spreading using immunotherapy; levels and are able to exert the desired effect on the tar‑
inhibiting α-synuclein aggregation; and increasing the get protein and for how long and with what amplitude.
clearance of α-synuclein by either decreasing its produc‑ Assessments of such antibodies in patients in the coming
tion or promoting its degradation6,10,87 (FIG. 2). years will bring a decisive part of the answer.
In the past decade, several research groups have Other agents targeting α-synuclein are also in clinical
worked extensively towards the development of anti-­ development. Among them, another passive immuno‑
α-synuclein antibodies or a α-synuclein vaccine as therapy agent, BIIB054, recognizes the aggregated form
potential disease-modifying treatments. Researchers of α-synuclein and a phase II study is underway 95,96. An
have developed a passive immunotherapy, PRX002 alternative strategy consists of preventing or decreasing
(also known as RG7935 or RO7046015), a humanized α-synuclein aggregation using oligomer modulators,
immuno­g lobulin G1 (IgG1) monoclonal antibody such as anle138b, which binds to a structure-dependent
directed against the carboxy terminus of α-synuclein epitope and inhibits formation of pathological α-­synuclein
with higher affinity and avidity for aggregated than oligomers in vitro and in vivo97. Although this compound
monomeric forms. Its murine homologue 9E4 has been is still in preclinical validation in animal models26, another
shown to reduce α-synuclein pathology and to improve oligomer modulator, NPT200‑11, which is designed to
memory and motor functions in several transgenic alter α-synuclein interactions with membranes, thereby
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reducing oligomer formation98,99, has been advancing
through phase I trials. A single-­ascending-dose study was
completed in early 2016 (REF.100). However, data from this
study are not available, and further plans for the devel‑
opment of this compound have not been announced.
Potential benefits of these agents are those of small mol‑
ecules, with them being more likely to reach the brain
than monoclonal antibodies, without the risk of being
neutralized by host antibodies. However, these candi‑
dates face the challenge of being able to achieve suffi‑
cient levels in the right location in the brain to prevent
α-synuclein misfolding.
Additional approaches aimed at targeting toxic
α-synuclein accumulation in PD are also being investi‑
gated. Feasibility to reduce α-synuclein levels by using
gene-­silencing mechanisms (small interfering RNA
(siRNA)) in the primate brain has been shown in squirrel
monkeys101. In this study, the siRNA molecule directed
against α-synuclein was directly infused into the left
substantia nigra of non-parkinsonian monkeys and it
resulted in a 40% suppression of α-synuclein expression
when compared with expression in the untreated intact
hemisphere. No assessment of antiparkinsonian efficacy
has been performed at this stage101. This approach may be
particularly attractive for patients who carry SNCA gene
duplication or triplication. Recent reports of gene silenc‑
ing tested in phase III for spinal muscular atrophy102–104, in
phase I for Huntington disease105,106 and the first approval
by the FDA of a siRNA therapy (patisiran, for the treat‑
ment of hereditary transthyretin-mediated amyloidosis)
are very encouraging for other disorders such as PD.
Approaches that are currently being investigated as
possible therapies for PD but are further from clinical
trials include strategies to modulate levels and activity
of chaperones such as heat shock proteins (for a review
see REF.107) and small molecules that enhance auto‑
phagy (see REF.108). Despite the strong interest in these
novel anti-α-synuclein approaches, it remains to be seen
whether enhancement of clearance mechanisms can
prove effective in patients with PD, in whom clearance
mechanisms may be so far deteriorated by the time clas‑
sical PD motor symptoms emerge that the potential to
provide meaningful clinical benefit is limited.
Although promising, there are a number of chal‑
lenges facing the development of therapies aimed at
preventing α-synuclein aggregation and propagation75.
First, there is no animal model that naturally replicates
α-synucleinopathy in humans, and α-synuclein has not
proved to correlate with neurodegeneration. Second,
there is currently no established method to assess target
engagement in the brain for anti-α-synuclein therapies.
As a consequence, it is difficult, for example, to define
optimal dosing for clinical trials. Finally, it is not known
when during the natural history of PD the synucleinop‑
athy appears and whether there is a ‘point of no return’
beyond which the damage to the neural system can no
longer be protected or revived.
Although several pressing knowledge gaps remain,
these are exciting times for α-synuclein-targeted thera‑
pies, with large clinical trials currently underway. These
studies will bring informative outcomes to the field.
Glutathione replacement. Reduced glutathione appears
to be involved in scavenging ROS and cellular detoxifi‑
cation, and this tripeptide appears to be depleted early
in the course of PD109. There has therefore been interest
in attempting glutathione replacement in patients with
PD, although delivering sufficient levels of therapy to
the brain has been difficult thus far because of its short
half-life of around 2.5 min in plasma and negligible oral
bioavailability in humans110. Early-phase clinical studies
have failed to show appreciable benefits for treatment
— in terms of changes in UPDRS scores — as compared
with placebo111,112. Although nasal delivery, as used in
these studies, has been proposed as a potentially useful
approach for delivering glutathione to the brain113, it is
still unknown whether glutathione administration in its
current form allows glutathione to remain in the brain
for sufficient time and at sufficient levels to produce a
therapeutic effect. This may represent the biggest current
challenge of this approach, and further dose–response
and steady-state administration studies will be required
to optimize glutathione delivery before evaluating thera­
peutic efficacy.
Lysosomal pathway and GBA activators. Current esti‑
mates indicate that 5–10% of patients with PD carry
mutations in GBA that result in deficiency of the lysoso‑
mal enzyme114,115 (a condition named Gaucher disease),
which makes GBA mutations the most common genetic
risk factor for PD and an area of very active research.
The clinical presentation of PD associated with GBA
mutations is almost identical to idiopathic PD, except
for a slightly younger age of onset and a tendency for
more cognitive impairment 116. Interestingly, there is
a reciprocal relationship between GBA activity and
α-synuclein function: enhancing GBA activity may lead
to regulation or even attenuation of the formation of mis‑
folded oligomeric α-synuclein through glycosphingo­
lipid clearance117–119, supporting the development of GBA
augmentation therapies for PD.
However, a key challenge facing GBA-related thera­
pies is the limited understanding of the precise mech‑
anism by which GBA mutations increase the risk of
synucleinopathy and accelerate disease progression.
Thus, there may be fundamental differences between
PD forms that are due to GBA mutations and those that
are due to other causes, and uncertainty remains regard‑
ing the extrapolation of results in a wider heterogeneous
population. Therefore, trials should first study patients
with GBA mutations, which is difficult owing to limited
numbers of patients with PD having been screened for
these mutations, followed by further studies to assess the
response in a more heterogeneous patient population.
Several phase II studies targeting GBA are cur‑
rently ongoing. Ambroxol is a small-molecule chap‑
erone that has been shown to increase GBA activity
in vitro and in vivo and to decrease α-synuclein pro‑
tein levels120. Ambroxol’s effects on neurodegener‑
ation were not assessed in animal models, but it is
expected that reducing α-synuclein levels might be
of therapeutic importance in PD. A phase II study is
planned with ambroxol as a potential therapy in patients

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Type 2 diabetes mellitus
(T2DM). Type of diabetes that
is characterized by insulin
resistance in appropriate
hepatic glucose production
and impaired insulin secretion.
Onset is usually after 40 years.
with PD (NCT02941822) 121,122. LTI‑291 is another
GBA activator that is moving to a phase II study in
patients with PD carrying GBA mutations (NTR6960,
EudraCT2017‑004086‑27) in the Netherlands123.
Other strategies target the same lysosomal pathway.
Venglustat (GZ/SAR402671) is a glucosylceramide syn‑
thase inhibitor, thus targeting the reduction of glyco­
sphingolipid levels in patients with PD with a mutation
of GBA124. Venglustat is currently being assessed in a
phase II study in patients with early-stage PD carrying
a GBA mutation (NCT02906020)125.
Results of these ongoing phase II studies, and fol‑
low-up studies, will be very informative to determine
whether the lysosomal pathway may lead to novel treat‑
ments for PD, with or without GBA mutations, despite
the previous failure of afegostat (AT2101; also known as
plicera) in a phase II trial in 2009 (REF.126).
Iron chelators. In PD, excess iron is detected in the brain
— primarily in the substantia nigra pars compacta, where
dopaminergic neurons are exposed to high levels of ROS
produced by the metabolism of dopamine — and corre‑
lates with disease severity 127. The underlying mechanism
of overdeposition of iron in PD brain remains unknown.
However, iron chelation has been proposed for confer‑
ring neuroprotection in PD128,129. Recently, deferiprone,
a membrane-permeant chelator of labile iron, was shown
to dose-dependently relieve the oxidative damage gen‑
erated by MPTP in mice and to improve their motor
functions130. A subsequent 12‑month, single-centre, pilot
double-blind placebo-controlled trial with deferiprone
was performed in 40 patients with early PD who were
already stabilized for dopamine regimens (the FAIR
PARK I study). On the basis of a 6‑month delayed-start
(DS) paradigm, early-start patients compared with DS
patients responded significantly earlier and sustainably
to treatment in both substantia nigra iron deposits, deter‑
mined by MRI, and UPDRS motor indicators of disease
progression130. Deferiprone is now being tested further in
a phase II clinical trial in 338 patients with early PD over
9 months (FAIR PARK II study, NCT02655315). Notably,
modifying iron metabolism in vivo in humans may
induce a number of undesirable adverse events, affecting
haematological or other systemic parameters. This pos‑
sibility is why the concept of a chelation strategy aimed
at reducing oxidative damage associated with regional
iron deposition without affecting circulating metals is
appealing with drugs such as deferiprone. However, as
for antioxidant strategies, iron chelation remains to be
validated in humans as a therapeutic strategy in PD.
GLP1 agonists. Epidemiological and clinical data suggest
that PD and type 2 diabetes mellitus (T2DM), both age-
related diseases, share similar dysregulated pathways,
suggesting common underlying pathological mechanisms
(reviewed in REF.131). In its earliest stage, T2DM develops
from insulin resistance, leading to a variety of detrimental
effects on metabolism and inflammation. Similar dysreg‑
ulation of glucose and energy metabolism also appears to
be an early event in PD132, and loss of insulin signalling in
the brain may contribute to PD pathogenesis131.
Exenatide is a licensed drug for the treatment of
T2DM. Exenatide is a GLP1 receptor agonist with
anti-inflammatory and antioxidant effects that improves
glucose control by stimulating insulin release from the
pancreas and inhibiting glucagon release133. Encouraging
pilot results have recently been reported with exenatide in
PD39. Indeed, exenatide had positive effects on the prac‑
tically defined off-medication state that were sustained
for 12 weeks after cessation of the exenatide treatment,
which suggests disease modification39. However, method‑
ological issues such as the small sample size (62 patients
with moderate PD), single-centre design, selection of
overnight washout UPDRS scores that may or may not
reflect ‘untreated’ disease and rapidity of the occurrence
of the between-group differences prevent robust conclu‑
sions39,134. An additional clinical trial with exenatide is
currently ongoing with a small number of patients with
PD to assess the effects of a 1‑year treatment on qual‑
ity of life and depression, strength and motor function,
cognition and functional and structural brain MRI135. A
phase II trial is also currently ongoing with liraglutide,
an analogue of human GLP1 with longer half-life that
is licensed for T2DM, as a single-centre, double-blind,
placebo-controlled study with 57 patients with PD136.
Further larger studies are required in order to assess
whether targeting GLP1 truly represents a durable and
meaningful neuroprotective effect of treatment in PD.
LRRK2 inhibitors. Among the genes involved in PD, the
LRRK2 gene is considered a key player 137. Mutations in
LRRK2 in PD are associated with pathological kinase
activity in cultured neurons — an observation that
prompted interest in the development of drugs that
could act as LRRK2 kinase inhibitors. However, the
development of agents targeting LRRK2 faces a number
of challenges.
A large number of LRRK2 kinase inhibitors have
been studied in vitro, but an appropriate transgenic
animal model in which to study these agents in vivo is
still lacking. Moreover, issues regarding the safety of
LRRK2 inhibition emerged from preclinical studies
reporting potential undesirable effects in the lung and
kidneys138,139. There are also concerns that measuring the
effects of LRRK2 inhibition by assessing changes in phos‑
phorylation of serine residues may not be an appropriate
end point, that there are no central measures of inhibi‑
tor target engagement that are suitable for human drug
trials and that there is no clear target patient population
in which to study the effects of drugs with this mode of
action137. In addition, it may be difficult at this time to
conduct large clinical trials that enrol only patients with
PD with LRRK2 mutations as they only represent a small
proportion of the PD population, and many patients with
PD have not undergone genetic testing. However, in a
recent study, Di Maio and colleagues140 developed a novel
assay and showed that wild-type LRKK2 kinase activity
was enhanced in dopaminergic neurons and in micro‑
glia in post-mortem substantia nigra tissue from patients
with idiopathic PD. This suggests that LRKK2 inhibitors
may be beneficial not only for mutation carriers but for
the broader sporadic PD population.

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The first small-molecule LRRK2 inhibitor, DNL201, side effects of dopaminergic agents (such as motor fluctu‑
reached clinical testing in 2017 and showed inhibition ations and dyskinesia, daytime sleepiness, nausea, ortho‑
of LRRK2 kinase activity in a healthy volunteer phase I static hypotension and impulse control disorders), thus
study 141. Another LRRK2 inhibitor, DNL151, is currently addressing the unmet needs of present PD therapies.
being assessed in healthy volunteers in the Netherlands in It should be noted that often many years before the
order to select the most promising molecule to be assessed onset of motor symptoms of PD, non-motor symptoms
in patients with PD carrying an LRRK2 mutation141. occur, which can ultimately have a major impact on
the quality of life of patients with PD, and represent an
FAF1 inhibitors. Mutations in the parkin gene (PARK2) emerging unmet need (BOX 2).
are associated with early-onset PD142. The discovery that
parkin normally acts as an inhibitor of the proapoptotic Adenosine receptor type 2A antagonists
Fas-associated factor 1 (FAF1) by promoting its degra‑ Adenosine receptor type 2A (A2A) is mainly expressed
dation recently led to the novel therapeutic approach of within the caudate and putamen nuclei of the basal gan‑
inhibiting FAF1 (REF.143). KM‑819 (also named KR33493), glia. Blockade of A2A in striato-pallidal neurons reduces
a small-molecule inhibitor for FAF1, is now entering a the postsynaptic effects of dopamine depletion and the
phase I clinical trial in Korea (NCT03022799) (TABLE 1). excessive firing of striato-pallidal neurons, thus sug‑
In MPTP mice, KM‑819 slightly increased striatal dopa‑ gesting a potential for A2A antagonists to improve motor
mine transporter activity as measured by PET studies, as deficits in PD153 (FIG. 3). Clinical trials to date have shown
described in a symposium abstract 144. variable efficacy to improve motor fluctuations154.
Istradefylline (KW‑6002) was the first A2A antago‑
Emerging symptomatic treatments nist evaluated as an adjunctive therapy with levodopa in
Despite the intense research focus on disease-modifying patients with PD with motor fluctuations. When char‑
therapies, traditional pharmacotherapeutic concepts are acterized in MPTP-lesioned macaques, istradefylline
still worthwhile because symptomatic therapy for con‑ increased ON time but did not improve PD scores and
trol of motor symptoms with dopaminergic and non-­ exacerbated dyskinesia155. This finding is in accordance
dopaminergic drugs is far from optimal. with phase II/III clinical findings in which istradefylline
The research of treatments to address motor symp‑ decreased OFF time but had no effect on UPDRS score
toms of PD is privileged by the growing knowledge on and increased dyskinesia156,157. Istradefylline was licensed
the functioning of the basal ganglia motor circuit and in Japan in 2013 for adjunctive treatment use in patients
the cause of PD motor symptoms (BOX 1) as well as the with PD experiencing wearing-off fluctuations, but the
availability of good animal models for this particular FDA has requested additional data for the United States.
indication. This understanding has led to the identifica‑ Expected timing of resubmission is in 2018, although the
tion of novel non-dopaminergic strategies that may be last global phase III study turned out to be negative158,159.
combined with dopaminergic treatments to improve the Preladenant was the second A2A antagonist evalu‑
motor functioning of patients with PD. ated in patients with PD. In MPTP-lesioned macaques,
The gold-standard model of PD motor symp‑ when added to a suboptimal dose of levodopa, prelade‑
toms is produced by administration of MPTP into old nant improved PD scores but could not reach the level
world non-human primate species (Macaca mulatta of efficacy of optimal levodopa. Preladenant produced
and Macaca fascicularis). With a close resemblance to a significant decrease in PD score in only half of the six
humans in physiology and brain anatomy, the PD motor MPTP macaques included in the study160. Again, this is in
features in macaques give an accurate model for PD accordance with the observations made in clinical trials:
clinical motor signs24,26,145,146. MPTP-lesioned primates after initial positive phase II results161, reduction of OFF
respond to dopaminergic drugs, including levodopa, time did not reach significance compared with placebo
and develop the same motor complications as patients in large phase III trials162. The phase III trial also failed to
with PD, including LID. This model has been widely and show the efficacy of the comparator therapy rasagiline,
successfully used to study the effects of drugs targeting thus rendering difficult the interpretation of the global
the symptoms of PD, including levodopa, dopamine ago‑ outcome. However, the development of preladenant for
nists147, MAOB inhibitors148 and many others149, as well PD has been abandoned.
as side effects including motor fluctuations and LID. A third A2A antagonist, tozadenant (SYN115), was
Consequently, the MPTP primate model and the use of recently evaluated in a phase III study (NCT02453386)
clinically relevant end points have been instrumental for after positive results in a phase IIb study 163. However,
evaluating the efficacy of symptomatic therapies. development of this agent has been terminated follow‑
Below, we review some of the emerging drugs being ing serious haematological adverse events resulting in
investigated for their efficacy in treating motor symptoms deaths164. Therefore, at the moment, there is no perspec‑
(TABLE 2). Some novel dopaminergic agents are currently tive for new A2A antagonists reaching the market in the
in development, but a full summary of such agents is near future.
outside the scope of this current Review, which focuses
on non-dopaminergic agents (for a review of current Agents targeting the glutamatergic system
dopaminergic agents developed for PD, see REFS6,150–152). Glutamate operates through two classes of receptors:
It is expected that non-dopaminergic agents may have ionotropic and metabotropic receptors. Ionotropic glu‑
improved tolerability profiles, being devoid of the classical tamate receptors (iGluRs) are directly coupled to the

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Movements opening of cation channels in the cellular membrane

of postsynaptic neurons. iGluRs are divided into three
subtypes, which are named according to their selective
agonists: N-methyl-d-aspartate (NMDA) receptors,
Cortex
α-amino‑3‑hydroxy‑5‑methyl‑4‑isoxazole propionic
Foliglurax acid (AMPA) receptors and kainate receptors. These
Dipraglurant
are non-­selective cation channels, and their activation
Amantadine ER always produces excitatory postsynaptic responses.
A2A Metabotropic glutamate (mGlu) receptors are G pro‑
mGlu4 Striatum mGlu4 tein-coupled receptors. They are localized both pre‑
synaptically and postsynaptically, and their role is to
mGlu5 A2A Istradefylline mGlu5
regulate the activity of the ionic channels or enzymes
producing second messengers via G proteins165. Unlike
NMDA D2 D1 NMDA
the excitatory iGluRs, mGlu receptors cause slower syn‑
aptic responses, modulating the efficacy of the synapses
A2A
by regulating either the postsynaptic channels and their
receptors or the presynaptic release or recapture of glu‑
D2 mGlu4
tamate166. Therefore, mGlu receptors play an important
GPe mGlu5 role in a variety of physiological processes such as long-
SNpc Thalamus term potentiation and long-term depression of synaptic
NMDA
transmission. To date, eight mGlu receptors have been
mGlu4 cloned and classified into three groups according to
their sequence homologies, pharmacological properties
and signal transduction mechanisms: group I (mGlu1
and mGlu5), II (mGlu2 and mGlu3) and III (mGlu4,
STN GPi mGlu6, mGlu7 and mGlu8)167,168.
mGlu5 mGlu4 mGlu5
SNr There is extensive evidence implicating gluta‑
NMDA NMDA mate in PD and in LID, and glutamate receptors may
represent therapeutic levers to restore basal ganglia
motor circuit functioning in these pathological condi‑
Inhibitory GABA transmission Hyperactive in PD tions169–173. Overactive glutamate transmission is a key
Excitatory glutamate transmission Hypoactive in PD feature underlying the pathophysiology of LID154,174,
Modulatory dopamine transmission Hypoactive in PD and/or leading to the concept that blocking glutamate trans‑
Therapeutic agents in development hyperactive in PD with LID
mission should be beneficial. This blockade could be
mGlu4 A2A obtained either by decreasing signalling downstream
Glutamate of excessive glutamate release, through inhibition
mGlu5 receptors Dopamine receptors
of postsynaptic NMDA or mGlu5 receptors, or by
NMDA
decreasing glutamate release itself through activa‑
tion of presynaptic mGlu4 or mGlu3 receptors and
Figure 3 | The basal ganglia motor circuit that controls movement, highlighting key restoring physiological neurotransmitter levels at the
targets and agents in the treatment of Parkinson disease.
NatureIn healthy| conditions,
Reviews Drug Discovery synapse.
the direct pathway, originating in dopamine D1 receptor (D1)-expressing striatal
medium-sized spiny projection neurons (MSNs), disinhibits the thalamo-cortical Amantadine ER. Amantadine, a non-selective NMDA
neurons through two successive inhibitory (GABAergic) transmissions: from the receptor antagonist, is commonly used to treat LID170,175.
putamen to the internal segment of the globus pallidus (GPi) and then to the thalamus.
This old drug has been used for nearly 50 years and is
The indirect pathway, originating in dopamine D2 receptor (D2)-expressing striatal
MSNs, maintains the thalamo-cortical inhibition through four successive transmissions: still the drug with the greatest antidyskinetic effect in
inhibitory (GABAergic) projections from the putamen to the external segment of the patients with PD176,177. However, its clinical utility may
globus pallidus (GPe) and then to the subthalamic nucleus (STN), an excitatory be limited by cardiovascular and psychiatric side effects
(glutamatergic) synapse between the STN and GPi/substantia nigra pars reticulata (SNr) such as insomnia, confusion and hallucinations178–180
and finally an inhibitory (GABAergic) synapse between the GPi/SNr and the thalamus. that may be directly due to inhibition of NMDA recep‑
Dopamine, which is released by nigro-striatal neurons, stimulates the direct pathway tors181,182. Amantadine ER (ADS‑5102 (Gocovri)), a
and inhibits the indirect pathway. In Parkinson disease (PD), progressive degeneration of novel extended-release formulation of amantadine,
the dopaminergic neurons in the substantia nigra pars compacta (SNpc) results in the was recently approved by the FDA for the treatment
loss of dopaminergic control in the striatum and leads to an imbalance in favour of a of LID in patients with PD receiving levodopa-based
hyperactive indirect pathway and a subsequent global inhibition of motor cortex areas.
therapy. Interestingly, in a phase III study, amantadine
This figure highlights some of the key receptors that are currently targeted for the
treatment of PD: metabotropic glutamate receptor 4 (mGlu4) and mGlu5 as well as ER reduced LID and slightly reduced OFF time whereas
NMDA (N-methyl-d-aspartate) glutamate receptors and adenosine receptor type 2A placebo increased it 183. However, the spectrum of
(A2A). Note that although the therapeutic agents in development are depicted only once adverse events was similar to immediate release forms
in the figure, they are expected to act everywhere their target is present in this circuit of amantadine, suggesting that some improvement can
(mGlu4 for foliglurax, mGlu5 for dipraglurant, NMDA for amantadine ER and A2A for still be pursued in the benefit/risk ratio of a treatment
istradefylline). LID, levodopa-induced dyskinesia. for LID183,184.

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Allosteric modulators
Molecules that bind a site that
is different from the binding
site of the endogenous agonist.
As modulators, they act only in
presence of the endogenous
agonist, either potentiating
(PAM) or reducing (NAM) the
receptor response.
Negative allosteric modulators of mGlu5. The three
groups of mGlu receptors are widely expressed in
the basal ganglia (except mGlu6 receptors, which are
exclusively localized in the retina), where they act as
key regulators of the motor circuit in both normal and
diseased conditions by modulating neuronal excitabil‑
ity, synaptic transmission and plasticity 166. Therefore,
targeting specific mGlu receptor subtypes by means of
selective drugs could be a possible strategy for restoring
normal activity in the basal ganglia in PD, thus improv‑
ing motor function. In this context, the development of
subtype-­selective mGlu receptor agonists, antagonists
and allosteric modulators has provided scientists with a
wide range of neuropharmacological tools that may lead
to effective treatments185.
Antagonism of postsynaptic mGlu5 could potentially
decrease glutamate signalling downstream of excessive
glutamate release, an approach that could reduce LID186
(FIG. 2). Mavoglurant (AFQ056) was the first mGlu5
negative allosteric modulator (NAM) evaluated in PD
patients with LID. In an MPTP-lesioned macaque model
of LID, mavoglurant decreased peak dyskinesia while
maintaining the antiparkinsonian effects of levodopa187.
Mavoglurant was tested in two placebo-controlled
phase II studies in 31 patients with PD with moderate
to severe LID (study 1) and 28 patients with PD with
severe LID (study 2)188. In both studies, significant anti‑
dyskinetic effects of treatment were observed. Treatment
effects on PD motor symptoms were inconsistent
between the studies and adverse events were reported.
The most common side effects were dizziness, worsen‑
ing of dyskinesia when stopping treatment (rebound
effect) and psychiatric disturbances (hallucinations, illu‑
sions and euphoric mood)188. Consequently, the clinical
development of mavoglurant for the treatment of LID
was discontinued.
Another agent of this class, dipraglurant (ADX48621),
has recently been assessed in PD patients with LID. In an
MPTP macaque model, dipraglurant dose-­dependently
decreased LID189. There was no comparator in this study,
such as amantadine for example. When assessed in a
phase II, placebo-controlled 4‑week study in 76 patients
with PD who exhibited moderate to severe LID, dipraglu‑
rant did not show a significant effect on LID at study end
point (day 28) despite encouraging results at days 1 and
14 (REF.190). Side effects were reported with dipraglurant,
including dizziness, dyskinesia and hallucinations191, the
same as the other mGlu5 NAM, mavoglurant181,182.
Overall, these studies support a potential antidys‑
kinetic effect of mGlu5 NAM, validating the approach
of blocking the excessive glutamate transmission in
the basal ganglia to reduce LID. Both amantadine and
mGlu5 NAMs have postsynaptic targets, involving
either direct or indirect NMDA blockade, which may
be the cause of psychiatric side effects. Further stud‑
ies are needed to explore strategies to decrease the side
effects of this mode of action. Targeting presynaptic
receptors such as mGlu4 (currently being tested in a
proof‑of‑concept clinical study) and mGlu3 (still in
preclinical investigations) may be one avenue worth
exploring.
Positive allosteric modulators of mGlu4. The presyn‑
aptic mGlu4 receptor is considered to be a promising
candidate for drug targeting in PD given its role in
modulating neurotransmitter release in the basal gan‑
glia motor circuit 173,185 (FIG. 2). Two candidate mGlu4
positive allosteric modulators (PAMs) from a novel
chemical series have recently been studied in rodent 192
and non-human primate models193,194, with foliglurax
(PXT002331) now advancing into phase II clinical
development. Foliglurax has the potential to reduce
both wearing-off and dyskinesia in patients with PD. In
models of MPTP-induced parkinsonism and LID, foli‑
glurax has shown robust and dose-dependent reversal
of parkinsonian motor symptoms, reduction of wear‑
ing-off and a decrease of peak dyskinesia with a higher
efficacy and better tolerability than amantadine193,194.
However, the efficacy of an mGlu4 PAM still remains to
be proved in patients. Results of the ongoing phase IIa
study (NCT03162874), expected in 2019, will be very
informative in this regard.
Other non-dopaminergic targets
Other non-dopaminergic targets are under investigation,
the most advanced involving serotoninergic agents.
In advanced stages of PD, serotonin (5‑HT) terminals
take up levodopa and convert it to dopamine. The result‑
ing non-physiological release of dopamine and abnormal
pulsatile stimulation of dopamine receptors within the
striatum may participate in the development of LID195.
Presynaptic 5‑HT1A receptor agonists can reduce dopa‑
mine release from these serotonergic striatal terminals
and thus potentially reduce dyskinesia. Several clinically
available drugs that partly act as 5‑HT1A agonists have
thus been assessed in patients with PD. Buspirone is a
combined 5‑HT1A and α1-adrenergic receptor agonist,
indicated for the management of anxiety disorders, with
antidyskinetic effects that were first reported in the early
1990s196. Buspirone is currently being assessed in three
clinical trials in PD patients with LID: as monotherapy
in a phase III study (NCT02617017), in combination
with a triptan in a phase II study (NCT02803749) and
in combination with amantadine in a phase I study
(NCT02589340).
Eltoprazine is a mixed 5‑HT1A and 5‑HT1B agonist
that exerts antidyskinetic effects in rats by reducing
striatal glutamate transmission197. A single oral treat‑
ment with eltoprazine was tested in combination with
a suprathreshold dose of levodopa in a phase I/IIa
study in 22 PD patients with LID198. Following levo‑
dopa challenge, eltoprazine significantly reduced LID
in this study. A phase IIb is currently in preparation
and is expected to be initiated in the first half of 2019.
Among the symptoms of PD, cognitive impairment,
dementia, gait (freezing) and balance (falls) problems
remain unmet needs. Currently there are no substantial
hopes, although positive results have been reported in
the past with cholinergic agents for falls199 and noradr‑
energic compounds for gait hypokinesia and freezing 200.
Droxidopa, a prodrug of noradrenaline indicated in
patients with orthostatic hypotension, was evaluated
in a 10‑week phase III placebo-controlled study in

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225 patients with PD with orthostatic hypotension201.
In this study, treatment with droxidopa reduced falls in
patients with PD. These findings should be confirmed
in more focused clinical evaluations in order to assess
their clinical relevance. Additional references on non-­
dopaminergic approaches for symptomatic control in
PD are reviewed in154,175.
Outlook
Substantial progress has been made in the search for
and development of new agents to manage the clinical
features of PD, and a number of drug candidates are
poised ready to enter clinical study as treatments with
disease-modifying potential. Although there is still much
to be learned about the pathophysiology of PD and the
processes and chronology of neurodegeneration in this
condition, with the identification of better disease bio‑
markers and treatment targets, there is much scope for
the development of improved therapies for PD.
Symptomatic treatments remain of interest to address
the still high unmet needs of patients linked with, for
example, the motor complications of levodopa treat‑
ments. Indeed, even when disease-modifying treatments
become available, there is likely to be a continuing need
for agents, with optimized tolerability, that alleviate
symptoms.
In the field of preclinical research, there is a need for
a better focus on the robustness of the effects of a new
compound, confirmation of findings across different stud‑
ies and models and comparison of the intensity of effects
with those of known benchmark molecules. As described
in this Review, therapies that have shown a mild, non-­
robust effect in preclinical animal models have then failed
to demonstrate efficacy in phase II or III trials. Although
a high attrition rate is a feature of all drug development,
contemporary and forward-thinking research is doing
much to advance endeavours to discover and develop
more effective drug entities for patients with PD.

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Acknowledgements
D.C. thanks P. Hongaard for inspiring this Review.
Competing interests
D.C. has received scientific grants from the Michael J. Fox
Foundation (MJFF). D.C. and R.M. are members of the
Management Team of Prexton Therapeutics. O.R. has
received scientific grants from Agence Nationale de
la Recherche, CHU de Toulouse, France-Parkinson,
INSERM-DHOS Recherche Clinique Translationnelle, MJFF,
Programme Hospitalier de Recherche Clinique and the
European Commission (FP7, H2020). O.R. is a scientific
adviser or consultant for AbbVie, Adamas Pharmaceuticals,
Acorda Therapeutics, Addex Therapeutics, AlzProtect,
ApoPharma, AstraZeneca, Bial, Biogen, Britannia, Clevexel,
Cynapsus, INC Research, Lundbeck, Merck, MundiPharma,
Neuroderm, Novartis, Oxford Biomedica, Parexel, Pfizer,
Prexton Therapeutics, Quintiles, Sanofi, Servier, Teva, UCB,
XenoPort and Zambon. R.A.H. reports consulting fees from
Guidepoint Global, Gerson Lehrman Group, LCN Consulting,
Putnam Associates, the National Parkinson Foundation,
eResearch Technology, Inc., Lundbeck, Cynapsus, Sarepta
Therapeutics, Adamas Pharmaceuticals, Neurocrine
Biosciences, Back Bay Life Science, US WorldMeds, Biotie
Therapies, MJFF, Neuropore Therapies, the US National
Institutes of Health, Projects in Knowledge, Prexton
Therapeutics, Acorda Therapeutics, Vista Research, LifeMax,
Peerview Press, ClinicalMind Medical and Therapeutic
Communications, Sunovion Pharmaceuticals, Inc., the
Academy for Continued Healthcare Learning, Outcomes
Insights, Expert Connect, HealthLogix, Teva, Cowen and
Company, Pharma Two B, Ltd., Pfizer, RMEI Medical
Education for Better Outcomes, ClearView Healthcare
Partners, Health Advances, Kyowa Kirin Pharmaceutical
Development, Ltd., Impax Laboratories, Quintiles, Pfizer,
AbbVie, AstraZeneca, Eli Lilly & Company, Decision Resources
Group, Seagrove Partners, LLC, Intec Pharma, Ltd.,
Schlesinger Associates, Huron Consulting Group, Pennside
Partners, Bracket, Phase Five Communications, LCN
Consulting and the Windrose Consulting Group.

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