CLINICAL TRIAL HIGHLIGHTS – JULY 2019 DYSKINESIA
INTRODUCTION
To paraphrase the old saying, every silver lining has a cloud. Levodopa remains the
gold standard of symptomatic relief because it works, but as Parkinson’s Disease (PD)
progresses and the therapeutic window of levodopa narrows, many people with Parkinson’s
(PwP) develop involuntary movements. This phenomenon is termed levodopa-induced dyskinesia
(LID), despite the fact that the mechanism of LID is much more complex.
At this point we would like to comment on the nomenclature from the perspective of
PwPs. The term “levodopa-induced dyskinesia” suggests that dyskinesia appears purely
as a result of taking levodopa. In reality, it is now widely accepted that the emergence
of dyskinesia in the course of the disease reflects progressive neurodegeneration,
not the duration of levodopa therapy. Unfortunately, the mistaken view that levodopa
can only be taken for a certain length of time persists, leading to widespread “levodopa-phobia”.
Perhaps a small step towards dispelling this myth is to simply describe the symptoms
as “dyskinesia”.
The review below provides a summary of the prevalence and current understanding of
the pathogenesis of dyskinesia followed by a Phase 3 study in spotlight of amantadine
ER, the only molecule currently approved for management of dyskinesia in PD and then
a review of the novel therapeutic options in development.
PATHOGENESIS OF DYSKINESIA
Dyskinesia are involuntary hyperkinetic movements presenting mostly as chorea or choreoathetoid
form, but rare ballistic, dystonic or stereotypical variants have been described as
well. Various subtypes of dyskinesia and body distribution have been recently summarized
in a review by Espay et al. [1]. Briefly, dyskinesia can be classified as peak dose
and diphasic. The body distribution, timing and even treatment strategies for the
two subtypes differ [1].
The risk of developing dyskinesia is approximately 25- 40% after 4-6 years of levodopa
therapy and increases thereafter. Dyskinesia impacts both the social and functional
aspects of one’s life. Even though surveys validate a significant negative impact
of dyskinesia on social life, patients continue to prefer to be ON with dyskinesia
instead of being OFF [2]. Understanding the pathophysiology of dyskinesia aids in
developing newer and redirecting established drugs for adequate management.
For a long time, it was believed that levodopa therapy was a major cause of dyskinesia.
However, preclinical data have demonstrated that levodopa therapy may sensitize the
nigrostriatal system but does not induce dyskinesia in the setting of preserved dopaminergic
circuit [3]. Data from numerous clinical studies have established that delaying levodopa
initiation does not prolong the latency to dyskinesia onset. Accordingly, dyskinesia
is not a result of duration of levodopa therapy but rather a combination of various
intrinsic and extrinsic factors.
For a long time, it was believed that levodopa therapy was a major cause of dyskinesia.
However, preclinical data have demonstrated that levodopa therapy may sensitize the
nigrostriatal system but does not induce dyskinesia in the setting of preserved dopaminergic
circuit [3]. Data from numerous clinical studies have established that delaying levodopa
initiation does not prolong the latency to dyskinesia onset. Accordingly, dyskinesia
is not a result of duration of levodopa therapy but rather a combination of various
intrinsic and extrinsic factors.
Advanced stage of disease responds differently to levodopa owing to various molecular
and network alterations [4]. Primary molecular factors linked to dyskinesia include
a lack of presynaptic dopamine storage capacity, increased extracellular levodopa
and pulsatile stimulation of dopamine receptors [4,5,6]. Other factors associated
with higher risk of developing dyskinesia include young age of onset, female gender,
low body weight, certain subtype of PD, certain genetic mutations and polymorphisms
within various receptor genes [1].
Though the dopaminergic system plays a key role in the pathogenesis, various non-dopaminergic
neuromodulation has been linked to dyskinesia. Detailed coverage of all the systems
is beyond the scope of this paper but these non-dopaminergic pathways are currently
targeted by a number of drugs in development discussed later. Altered glutaminergic
signalling, by either disease-led redistribution of NMDA subunits or NMDA receptor
gene polymorphism, has been linked to dyskinesia [7, 8]. Amantadine is an effective
and the only anti-dyskinetic medication available in the market acting largely by
inhibition of glutaminergic hyperactivity, though it also affects other systems.
With the loss of striatal dopaminergic innervation, the aromatic amino acid decarboxylase
within serotonin neurons is used to convert exogenous levodopa to dopamine. Consequently,
the dysregulated dopamine delivery and maladaptive serotonergic transmission is linked
to expression of dyskinesia [9]. Preclinical data on modulating 5-HT receptors to
control dyskinesia has been promising and serve as the rationale for targeting the
serotoninergic system.
Other major systems within the basal ganglia linked to dyskinesia include cholinergic,
opioid, adrenergic and the cannabinoid system [1]. The current clinical trials and
available therapies focus on symptomatic management but there is a need to ultimately
direct our attention towards preventing the development of dyskinesia in the first
place.
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PHASE 3 IN FOCUS – ADAMAS PHARMA’S GOCOVRI
Background: The Phase 3 in focus for this edition of Clinical Trial Highlights continues
the theme of symptomatic relief of dyskinesia in PD. We will review two Phase 3 trials
already completed on amantadine ER (Gocovri), previously known as ADS-5102 during
development, EASE LID [1] and EASE LID 3 [2].
Gocovri is a capsule containing 137mg extended-release amantadine, an uncompetitive
antagonist at the N-methyl-D-aspartate receptor known to have benefit to relieve the
symptoms of dyskinesia and currently the only available molecule for management of
dyskinesia. The rationale of extended release is to provide a therapeutic level of
amantadine in the blood for a longer period of time, in this case enabling once a
day dosing. Two capsules are administered at bedtime to give a slow increase during
sleep, peak levels in the morning and a sustained concentration during the day.
Comments: The primary outcome measure was the change in the Unified Dyskinesia Rating
Scale (UDysRS) which has a range from 0 to 104. This is in common with most of the
clinical trials for dyskinesia in PD.
The two trial plans are summarised in Table 1 below. The designs were very similar,
with differences only in the additional extended timepoint of 24 weeks and some secondary
outcomes, for example, the use of Clinician’s Global Impression of Change (CGIC) in
EASE LID.
Among the inclusion criteria for EASE LID were a score of at least 2 on question 4.2
of the Unified Parkinson’s Disease Rating Scale (UPDRS); at least two episodes of
half an hour of troublesome dyskinesia when ON; and at least 3 administrations of
levodopa per day. Exclusion criteria included a history of dyskinesia that was exclusively
diphasic, OFF state, myoclonic, dystonic, or akathetic without peak-dose dyskinesia.
The inclusion and exclusion criteria for EASE LID 3 did not specify these restrictions,
although the baseline data would indicate that these criteria would be met comfortably.
TABLE 1
Summary of EASE LID and EASE LID 3 trial plans
EASE LID
EASE LID 3
Title
ADS-5102 for the Treatment of Levodopa-Induced Dyskinesia (EASE LID Study)
Efficacy and Safety Study of ADS-5102 in PD Participants with Levodopa-Induced Dyskinesia
(EASE LID 3)
Status
Complete
Complete
clinicaltrials.gov ID
NCT02136914
NCT02274766
Enrolment
121
75
Study design
Randomized, double blind, placebo-controlled, multi-centre (44 sites).
Randomized, double blind, placebo-controlled, multi-centre (32 sites).
Primary outcome measures
Change in UDysRS to week 12, measured at weeks 0, 2, 4, 8 and 12.
Change in UDysRS to week 12, measured at weeks 0, 2, 4, 8 and 12.
Key Secondary outcome measures
Change from baseline in the UDysRS total score at 24 Weeks.
Change in the standardized PD home diary (ON time without dyskinesia, ON time with
troublesome dyskinesia, OFF time) at 12 weeks.
ON time without troublesome dyskinesia (ON time without dyskinesia plus ON time with
non-troublesome dyskinesia) at 12 and 24 weeks.
OFF time (amount of time the PD medication is not controlling motor symptoms) at 12
and 24 weeks.
Change from baseline at 12 and 24 weeks in the UPDRS score.
ON time with troublesome dyskinesia.
The results from both trials are summarized in Table 2 below:
TABLE 2
Summary of EASE-LID and EASE-LID 3 results
EASE LID; Gocovri vs placebo*
EASE LID 3; Gocovri vs placebo*
Change in UDysRS at week 12
-7.90 (2.30)
-14.40 (3.0)
Change in UDysRS at week 24
-9.30 (2.70)
ND
Change in ON time without troublesome dyskinesia at week 12 (hours)
2.74 (0.61)
1.90 (0.78)
Change in ON time without troublesome dyskinesia at week 24 (hours)
2.22 (0.63)
ND
Change in ON time with troublesome dyskinesia at week 12 (hours)
-1.54 (0.51)
-1.13 (0.65)
Change in ON time with troublesome dyskinesia at week 24 (hours)
-1.45 (0.53)
ND
Change in OFF time at week 12 (hours)
-0.9 (0.37)
-1.10 (0.46)
Change in OFF time at week 24 (hours)
-0.81 (0.39)
ND
CGIC score (reported improvement) at week 12
51/63 vs 21/58
ND
CGIC score (reported improvement) at week 24
43/63 vs 27/58
ND
ND = not determined
* Standard error values in parentheses
There were no significant differences in the UPDRS score (total or parts I, II or
III) between Gocovri and placebo at either 12 or 24 weeks, suggesting Gocovri does
not make other PD symptoms worse.
In the EASE LID study, adverse events (AEs) were recorded for 88.9% of Gocovri participants,
compared to 60.0% in the placebo group. Most were mild to moderate, at 68.3% (Gocovri)
and 53.8% (placebo). The most common AEs, at >5% in the active arm, included visual
hallucinations, peripheral edema, dizziness, dry mouth, and constipation. Other AEs
occurring in less than 5% of participants in the Gocovri group included nausea (4.8%),
confusion (3.2%), and orthostatic hypotension (1.6%) [1].
Visual hallucinations were reported by 15 participants (23.8%) in the Gocovri group
and 1 participant in the placebo group. One report in the active group was classed
as severe but did not meet the criteria for a serious AE. Thirteen participants (20.6%)
in the Gocovri group discontinued the study drug because of AEs as did 4 participants
(6.7%) in the placebo group [1].
In the EASE LID 3 trial, AEs were reported for 84% of Gocovri participants and 50%
on placebo. Most reported AEs were classed as mild to moderate (70% with Gocovri and
45% with placebo). The most common AEs with an incidence of >5% in the Gocovri group
were dry mouth, nausea, decreased appetite, insomnia, orthostatic hypotension, constipation,
falls, and visual hallucinations. One participant reported 2 Gocovri–related serious
AEs (constipation and urinary retention) [2].
A further participant on Gocovri experienced suicidal ideation (assessed by the investigator
as related to the study drug), and a second participant attempted suicide (assessed
by the investigator as not related to the study drug). Nineteen percent of the Gocovri
group and 8% of placebo participants discontinued the study because of AEs [2].
Although Gocovri has not been compared to immediate release (IR) amantadine in a directly
comparative efficacy study, there is a pharmacokinetic comparison showing Gocovri,
administered once a day at bedtime, has a delayed time to maximum plasma concentration
(12-16 hours), with a sustained level of amantadine throughout the day [3]. The steady
state profile of Gocovri was significantly different to that of IR amantadine administered
twice daily, such that the two formulations are not bioequivalent.
The results clearly show a statistically and clinically significant improvement in
ON time without troublesome dyskinesia and a concomitant reduction in time with troublesome
dyskinesia. Further analyses of the participant diaries have been published using
pooled data from both trials [4].
Osmotica Pharmaceuticals has recently launched an extended release amantadine preparation
(Osmolex ER) in the US. The new drug is approved for the treatment of PD and for drug
induced extrapyramidal reactions in adults. Two Phase 3 trials were conducted for
dyskinesia, ALLAY-LID-I (NCT02153645) and ALLAY-LID-II (NCT02153632). Despite this,
the New Drug Application (NDA) was based on bioequivalence to amantadine and Osmolex
ER does not have the LID indication. It is not interchangeable with either amantadine
or Gocovri.
Many PwP find dyskinesia one of the most distressing and embarrassing symptoms of
PD, restricting social interaction and causing other knock-on effects such as weight
loss. Therapies that prevent dyskinesia or replace the troublesome kind will be valuable
tools to use in PD. While Gocovri is a valuable addition to the treatment armamentarium,
it does have a fairly high incidence of drug induced adverse effects and as such the
development of novel therapeutics remains of value. These are reviewed further in
this issue.
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EXPERIMENTAL THERAPIES FOR DYSKINESIA IN THE CLINIC
There are eight therapies in clinical phase, summarised in Table 1 below. Seven of
the programs are listed on www.clinicaltrials.gov, these will be described in more
detail later in this article. There are around a million people in the US with PD
of whom an estimated 150,000 to 200,000 suffer from associated dyskinesia [2]. This
is one reason why LID has been classified by the US FDA as an orphan disease.
When compared to clinical trials measuring the influence of a therapy on the progression
of PD, studies measuring symptom relief require a much shorter assessment time. The
duration of intervention for the dyskinesia therapies under review varies from seven
days to twelve weeks, although the former (Oregon University) includes a two-week
titration period and an assessment at six weeks post-treatment initiation.
All the projects have the Unified Dyskinesia Rating Scale (UDysRS) as the primary
outcome, with only one study having additional primary outcomes. This focus on efficacy
is complemented by secondary outcome measures that include the Unified Parkinson’s
Disease Rating Scale (UPDRS). Some studies have started to include digital technology
as exploratory outcomes hoping to collect more real life data.
Table 1
Dyskinesia therapies in the clinic
ORGANISATION
THERAPY
MODE OF ACTION
CLINICAL STAGE
Addex Therapeutics
Dipraglurant
mGluR5 negative allosteric modulator
Phase 2 (complete)
Coeptis/Elto Pharma
Eltoprazine
5HT 1A/1B partial agonist
Phase 2
Hôpitaux de Paris
Buspirone
5-HT1A agonist
Phase 3
Contera/Bukwang
JM-010 (buspirone and zolmitriptan)
5-HT1A agonist and 5-HT1B/5-HT1D agonist combination
Phase 2
Oregon University
Buspirone and amantadine
5-HT1A agonist and NMDA inhibitor combination
Phase 2
Integrative Research Laboratories
IRL-790
Dopamine D3 receptor antagonist
Phase 2
Prilenia
Pridopidine
Sigma-1 receptor inhibitor
Phase 2
Trevi Therapeutics
Nalbuphine
Opioid μ antagonist/ κ agonist
Phase 1
All of the targets are alternative, non-dopaminergic neurotransmitter systems, aiming
to reduce dyskinesia while ideally retaining the positive benefits of levodopa. One
program is focused on the glutamate pathway, using negative allosteric modulation
of metabotropic glutamate receptors.
Clevexel Pharma were developing CVXL-0107 (naftazone), a glutamate release inhibitor.
This mode of action is thought to help relieve the symptoms of dyskinesia by reducing
cortical input to the striatum; decreasing globus pallidus-mediated movement inhibition;
and slowing down neurodegeneration through inhibition of excitotoxicity. Pre-clinical
data then a multiple n=1 study [5] suggested that naftazone may have antiparkinsonian
and antidyskinetic properties. A Phase 2a study (NCT02641054) was initiated to test
the hypothesis but showed no difference between naftazone and placebo [6].
In addition, there are a number of molecules in earlier stages of development. Trevi
Therapeutics are developing nalbuphine for dyskinesia. The program is in Phase 1 but
has not yet been registered on www.clinicaltrials.gov. Four other projects are in
preclinical stage. Vistagen Therapeutics are developing AV-101, a NMDA receptor antagonist
which has preclinical data for dyskinesia in PD. While Vistagen’s priority appears
to be the current Phase 2 study for Major Depressive Disorder, they plan to move AV-101
into Phase 2 in 2020 [4]. Air Liquide Santé are developing inhaled xenon gas and Curemark
have CM-PK, although very few details are available. Neurolixis are planning to move
NLX-112, a 5HT1A inhibitor, into Phase 1 in 2019. IRL have IRL-488 and IRL-555 in
discovery phase.
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30297210
ADDEX THERAPEUTICS AND DIPRAGLURANT
Background: Addex Therapeutics have a technology platform aimed at discovering allosteric
modulators of key drug targets. ADX48621, or dipraglurant, is a product of this platform
and negatively modulates the metabotropic glutamate 5 receptor (mGluR5). It normalizes
abnormal glutamate stimulation and mirrors the pharmacokinetic profile of levodopa,
an advantage in the treatment of dyskinesia [1]. A Phase 2a study was carried out
in 2012, with results published in 2016 [2].
Title: ADX48621 for the Treatment of Levodopa Induced Dyskinesia in Patients With
Parkinson’s Disease.
Status: Complete.
Clinicaltrials.gov ID: NCT01336088
Sponsor: Addex Pharma.
Enrolment: 83
Completion: February 2012
Study Design: Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel Group,
Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of ADX48621 (dipraglurant).
The trial design contained a dose escalation from 50mg once daily up to 100mg three
times a day.
Outcome Measures: The primary outcome measure was the number of participants with
abnormal safety and tolerability assessment parameters after 4 weeks.
Secondary outcome measures were the severity of dyskinesia as measured by the modified
Abnormal Involuntary Movement Scale (mAIMS) after 4 weeks; change in PD severity as
measured by participant diary at weeks 1, 2, 3 and 4, UPDRS part III at weeks 2 and
4, UPDRS total score at week 4; and participant and clinician-rated global impression
of change in dyskinesia and PD at 4 weeks.
Comments: The dipraglurant treatment group of 52 participants had a higher incidence
of adverse events (AEs) – 88.5% - than the placebo group of 24 (75%). While most participants
completed the dose escalation, 2 participants in the active group discontinued due
to AEs. No treatment effects were seen in safety monitoring variables.
Dipraglurant had a statistically significant effect against placebo as measured by
mAIMS on day 1 (19.9% vs 4.1%). By day 28 a strong placebo response (21.5%) compared
to the dipraglurant measure (31.4%) meant that statistical significance was not achieved
at the end of the study.
The clinician-rated global impression of change showed a statistically significant
improvement with dipraglurant (71.2%) versus placebo (49.9%). According to participant
diaries, daily on time with dyskinesia reduced and on time without dyskinesia increased.
Two pivotal Phase 3 studies are scheduled to start by the end of 2019. Both studies
plan the same enrolment (200 participants) split equally between dipraglurant and
placebo, with the same primary and secondary outcomes. The first study (#301) will
start an open label extension (OLE) after 3 months; the second study (#302) starts
the OLE after 6 months. The Phase 3 studies are expected to report results in the
third quarter of 2021.
As with other experimental therapies for dyskinesia, dipraglurant has been granted
orphan drug status by the US FDA, allowing seven years of market exclusivity.
References
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27214664
ELTOPRAZINE
Background: Eltoprazine is a small oral molecule demonstrated to affect the serotonergic
pathway. Though it also interacts with other receptors in the 5-HT system, it has
strong affinity towards 5-HT1A/B receptors thought to be primarily responsible for
its action. Initially introduced in studies for pathological aggression in intellectually
disabled patients, it has since been repurposed to study its effect in ADHD, dementia,
and PD patients. Though clinical benefit for aggression is still inconclusive, its
safety and tolerability have been demonstrated in human trials in both oral and intravenous
forms [1].
In preclinical animal models, eltoprazine was shown to significantly reduce dyskinesia
in levodopa primed models in a dose dependent fashion. When used in combination with
levodopa in drug naïve models, it demonstrated protective effect. At lower dose, it
was also shown to potentiate the anti-dyskinetic effect of amantadine. However, the
benefit in dyskinesia came with mild loss of anti-parkinsonian benefit of levodopa
[2].
Based on positive results from the preclinical data, PsychoGenics along with the Michael
J Fox Foundation funded a double blind, placebo-controlled Phase 1/2a study exploring
the safety profile and efficacy of eltoprazine for dyskinesia in PD participants.
A total of 24 participants were recruited across two sites in Sweden. As a dose finding
study, this trial looked at the ability of eltoprazine to suppress dyskinesia in PD
participants after single dosing administered along with levodopa, while maintaining
the benefits of levodopa. The three tested doses of Eltroprazine, i.e. 2.5mg, 5mg
or 7.5mg, were pre-selected on the basis of safety profile from previous trials in
non-PD participants. Compared to randomized placebo dosing, 5mg single dose was shown
to have statistically significant reduction in dyskinesia up to 3 hr post dosing.
The 2.5mg and 7.5mg doses showed clinical improvement but failed to reach statistical
significance. The dosing was safely tolerated without altering levodopa benefits [3].
Though the benefits were modest, the trial successfully paved the way for the Phase
2 studies.
The molecule has survived multiple mergers and acquisitions. eltoprazine was initially
developed in the 1980’s as DU-28853 by Duphar and subsequently acquired by Solvay
pharmaceuticals. It was out-licensed to PsychoGenics Inc. once Solvay merged with
Abbott Pharmaceuticals [4]. Post the Phase 1/2a trial, PsychoGenics licensed eltoprazine
to Amarantus Bioscience Holdings Inc. in 2014 which has since launched the Phase 2
study in 2015 detailed below.
Title: Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, 4-way Crossover,
Dose-finding Study of Eltoprazine Safety, Tolerability, and Efficacy in the Treatment
of Levodopa-induced Dyskinesia in Patients With Parkinson’s Disease
Objective: The objective of the study is to assess the safety, tolerability, and efficacy
of eltoprazine in treating LID in PD participants.
Status: Active, not recruiting
Clinicaltrials.gov Identifier: NCT02439125
Sponsor: Amarantus BioScience Holdings, Inc.
Estimated Enrolment: 60 participants
Estimated Primary Completion Date: June 2017
Study Design: This is a double blind, placebo-controlled, crossover, dose range finding
interventional study designed to assess the safety, tolerability, and efficacy of
Eltoprazine on dyskinesia in PD participants. They are exploring 3 treatment doses
and will assess their efficacy as compared to the placebo on the severity of dyskinesia,
parkinsonian symptoms and participant function along with safety and tolerability.
The study uses standard scales as noted below along with motion sensors and electronic
diaries.
The inclusion criteria require individuals between 30 to 85 years of age with a diagnosis
of PD of at least 3 years duration and should be on stable dose of levodopa for 4
weeks prior to screening visit. The dyskinesia is required to be
1. moderate to severely disabling
2. present during 25% of the waking day on an average, and
3. present for at least 3 months prior to study entry.
Standard exclusionary criteria are applied. Participants with surgical treatment for
PD namely DBS are not blindly excluded but will be, if the procedure was done within
the last 6 months of study inclusion or is planned during the study.
There are 4 study arms as noted here, all with dosing for 3 weeks:
1. Eltoprazine HCl 2.5mg BID (5mg/day)
2. Eltoprazine HCl 5mg BID (10mg/day)
3. Eltoprazine 7.5mg BID (15mg/day)
4. Placebo capsules BID
Participants will be randomly assigned to each of the 4 arms. They will complete the
3-week treatment cycle before crossing over to the next study arm.
The study is being conducted in USA at the Parkinson’s Disease and Movement Disorders
Center at Boca Raton, FL.
Outcome:
The primary outcome measure is the change in the total UDysRS score. This will be
assessed at the end of each treatment period on days 21, 42, 63 and 84.
Secondary outcome measures will include
1. Effect on PD motor symptoms as assessed by MDS-UPDRS, participant diaries and physiological
meas-urement using the motion sensor system after 84 days.
2. Change in dyskinesia severity using the physiological motion sensor system after
84 days.
3. Participant function using the questionnaires in MDS-UPDRS and UDyRS to quantify
dyskinesia and par-kinsonian motor symptoms. This will also be assessed after 84 days.
4. Lastly, safety and tolerability as assessed by adverse events, physical and neurological
exams, safe labor-atory values, vital signs and ECG. This will be assessed after 94
days.
Current status
Though listed as active and not recruiting, it is unknown if they have met the target
already. The Clinicaltrials.gov website has not been updated and no results have been
posted yet.
Comments: The molecule carries potential for meaningful benefit in dyskinesia. The
design of the Phase 1/2a study limits any effective assessment of efficacy. In 2016,
the US FDA granted the molecule orphan drug designation status for PD. Since 2017,
Eltoprazine’s development has been handled by Elto Pharma, Inc., a joint venture between
Amanrantus and PsychoGenics. Elto Pharma recently entered into agreement with Coeptis
Pharmaceuticals, Inc. regarding further development.
Though the results from the phase 2b study were expected by now, given the delay,
we will have to wait to find out whether the molecule is truly efficacious for dyskinesia
without compromising the levodopa benefits.
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https://www.amarantus.com/therapeutics-pipeline/therapeutics/eltoprazine.
BUSPIRONE PROGRAMS
Background: Buspirone is an established anxiolytic that acts primarily on the serotonergic
system. Though it also affects the 5-HT2 receptors and is an antagonist for the D2
receptor, its efficacy is thought to be primarily mediated through the 5-HT1A receptors.
Given the evidence of serotonergic involvement in Parkinson’s-associated dyskinesia,
a number of studies are testing buspirone in PD. Previous human trials have established
a safe profile of the drug and it has a comparatively lower risk of serotonin syndrome
[1].
Preclinical data suggests that buspirone is effective in reducing dyskinesia and physiologically
reduces the firing rate of subthalamic neurons but requires an intact nigrostriatal
pathway to do so [2]. Buspirone has been studied in open label trials previously exploring
its effect on parkinsonism and dyskinesia. Studies that looked specifically into buspirone’s
role for parkinsonism demonstrated no benefit at lower doses (30mg/kg) but had worsening
of parkinsonism with anti-dyskinetic benefit at higher doses (~100mg/day) [3,4]. However,
when explored specifically for dyskinesia in open label studies, benefit was noted
in low to moderate dose (15-60mg/day) with variable worsening of parkinsonism [5,6].
The anti-dyskinetic benefit was noted only in moderate to severe cases [6].
Recent clinical data from three PD patients with off state dyskinesia post fetal neural
graft are of interest. Imaging studies showed increased serotonergic innervation of
the striatum and all three had significant suppression of dyskinesia after using buspirone
[7,8]. This supports the serotonergic hypothesis and lays the groundwork for further
studies to determine efficacy in dyskinesia.
ASSISTANCE PUBLIQUE – HOPITAUX DE PARIS
Title: Buspirone Treatment of Iatrogenic Dyskinesias in Advanced Parkinson’s Disease.
Multicenter, International, Placebo-controlled, Randomised, Double-Blind Trial.
Objective:
1. To validate the serotonergic hypothesis of hyperkinetic dyskinesia.
2. To evaluate the efficacy of buspirone to improve dyskinesia compared to placebo.
3. To evaluate for a dose-dependent response.
4. To determine if the combination of buspirone and amantadine is superior to single
drug administration for dyskinesia.
Status: Recruiting, although the clinical trials website has not been updated since
February 2018
Clinicaltrials.gov Identifier: NCT02617017
Sponsor: Assistance Publique – Hopitaux de Paris
Estimated Enrolment: 100 participants
Estimated Primary Completion Date: June 2018
Study Design: The study is a phase 3 multicenter, randomized, placebo-controlled,
double-blind trial looking at the efficacy of buspirone in reducing dyskinesia in
PD participants. They aim to enrol 100 clinically diagnosed PD participants between
35 to 80 years of age. The dyskinesia is required to be moderately disabling and to
be present more than 25% of the waking time. The participant should be able to identify
dyskinesia, ON and OFF periods. They should be on stable antiparkinsonian medications
and be considered optimally treated at the time of inclusion. Standard exclusionary
criteria are applied. Participants with DBS can be included if the procedure was done
12 months before inclusion and they are on stable stimulation parameters for at least
4 weeks prior to the first visit.
The study will randomly assign participants to two study arms. Arm 1 will receive
buspirone orally in escalating doses. For the first two weeks, they will be on 10mg
daily morning dose followed by 10mg twice a day for the next two weeks to finally
build up to 10mg three times a day from week 5 to 12. Arm 2 will receive capsules
of placebo and administered in escalating doses to match the arm 1. Assessments will
be done every 2 weeks and at the end of the study.
Outcome: The primary outcome evaluates change in the UdysRS between the placebo and
treatment arm from baseline to week 12.
Secondary outcomes include:
1. Comparison of efficacy between the two arms as measured by MDS-UPDRS parts 3 and
4 at different time points within the period of 13 weeks treatment duration.
2. Comparison of quality of life between the two arms as measured by MDS-UPDRS parts
1 and 2 at different time points within the 13 weeks treatment duration.
3. Comparison between the two arms as measured by side effects profile at different
time points within the 13 weeks treatment duration.
4. The maximum dose tolerated by the participants at different time points within
the 13 weeks treatment duration.
OREGON HEALTH AND SCIENCE UNIVERSITY
Title: Buspirone, in Combination With Amantadine, for the Treatment of Levodopa-induced
Dyskinesia
Objective: The study aims to evaluate the efficacy of combination therapy, buspirone
and amantadine, in reducing LID in PD participants.
Status: Recruiting
Clinicaltrials.gov Identifier: NCT02589340
Sponsor: Oregon Health and Science University
Collaborator: Portland VA Medical Center
Estimated Enrolment: 15 participants
Estimated Primary Completion Date: December 2019
Study Design: This is a phase 1, single-center, double-blinded, randomized, placebo-controlled,
two-period cross-over study designed to assess the safety, tolerability, and efficacy
of combination therapy of buspirone and amantadine on dyskinesia.
They are enrolling PD participants between 18 to 99 years of age on a stable medication
regimen. Participants should have mild to severe dyskinesia and should be on amantadine
(200-500mg/day) with insufficient control. Standard exclusionary criteria are applied.
This study will not include participants with DBS.
Included participants will be randomized to one of the two study arms.
Arm 1: Buspirone titrated up over the course of 2 weeks to reach 30mg/day for a week.
Arm 2: Placebo titrated up to match arm 1.
Participants will be crossed over the treatment sequence. Monitoring is done every
2 weeks for safety, tolerance, compliance and dyskinesia assessment.
Outcome:
The primary outcome measure will assess the
1. Area under the curve – measurements for dyskinesia for a 6-hr levodopa dose cycle.
2. Change in UdysRS up to 6 weeks
3. Safety and tolerability assessment by monitoring adverse events for up to 6 weeks.
No secondary outcomes have been specified.
JM-010 – CONTERA PHARMA AND BUKWANG
JM-010 is a combination of buspirone, a 5-HT1A agonist, and zolmitriptan, a 5-HT1B/5-HT1D
agonist. A US patent for this potential treatment was granted in 2015. A previous
Phase 2a/proof of concept study (NCT02439203) used a crossover study design in 30
participants and met the criteria for efficacy and safety. The current study is a
dose-ranging Phase 2 study focused primarily on efficacy.
Title: A Study in Parkinson’s Disease in paTients with mOderate to seveRe dyskInesiA
(ASTORIA)
Status: Not yet recruiting.
Clinicaltrials.gov ID: NCT03956979
Sponsor: Contera Pharma
Enrolment: 81 participants
Completion: June 2021
Study Design: Randomized, double-blind, double dummy, placebo-controlled, parallel
group study.
This Phase 2 study is comparing two dose levels of JM-010 with placebo - 4mg buspirone/0.8mg
zolmitriptan and 8mg buspirone/0.8mg zolmitriptan. The time period will be 12 weeks
with a further 2 weeks follow up for safety purposes. There will also be a pharmacokinetic
(PK) sub-study.
There are three sub-groups in the study with participants randomised in a 1:1:1 ratio.
Group 1 will receive the first active dose plus a placebo; group 2 the second active
dose plus a placebo; and group 3 two placebos.
The study is seeking PwP between the ages of 18 and 80 on a stable regimen of levodopa.
Inclusion criteria also include stable peak effect dyskinesia and at least one hour
of ON state dyskinesia during waking hours, with no more than six administrations
of levodopa per day. Exclusively diphasic, OFF state, myoclonic, dystonic, or akathetic
dyskinesia without peak-dose dyskinesia are all excluded.
Outcome Measures:
Primary - the efficacy of JM-010 compared to placebo using the UDysRS over 12 weeks.
Secondary outcomes are also focused on efficacy:
1. UDysRS total score changes from baseline to weeks 2, 4 and 8.
2. MDS-UPDRS Parts I to IV from baseline to week 2, 4, 8, 12.
3. Clinician’s Global Impression of Change (CGIC) score at week 12.
4. Change in ON time with troublesome dyskinesia, ON time with non-troublesome dyskinesia,
ON time without dyskinesia, and OFF time as measured by Hauser patient diaries at
weeks 2, 4, 8 and 12.
Comments:
The first trial specifically explores the anti-dyskinetic benefit of buspirone and
is monitoring its effect on parkinsonism as well. The 2nd study explores if buspirone
potentiates the anti-dyskinetic effect of amantadine and the last study tests the
synergistic effect of buspirone with zolmitriptan. All studies are studying a lower
dose of buspirone, unlikely to worsen parkinsonism. Whether buspirone will deliver
on the results as an anti-dyskinetic is yet to be seen.
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IRL-790 – INTEGRATIVE RESEARCH LABORATORIES
Background: IRL-790 is a dopamine D3 receptor antagonist with psychomotor stabilising
properties. A previous Phase 1b study with IRL-790 in 15 participants (NCT03531060)
using the UDysRS to assess symptoms showed a median reduction of 11.5 points vs placebo
and a mean reduction of 8.2 points vs placebo over four weeks. There was no effect
on standard anti-Parkinsonian medication.
Title: Efficacy and Tolerability of IRL790 in Parkinson’s Disease Dyskinesia.
Status: Recruiting.
Clinicaltrials.gov ID: NCT03368170
Sponsor: Integrative Research Laboratories
Enrolment: 74 participants
Completion: June 2019
Study Design: Randomized, double blind, placebo controlled, multi-centre (20 locations)
assessing a 2.5mg capsule of IRL-790.
Inclusion criteria require PwP between the ages of 18 and 79 on a stable regimen of
anti-parkinsonian medication. They must display waking day dyskinesia of >25% determined
as a score of >2 on question 4.1 of the UPDRS part IV. One intriguing inclusion criterion
is that participants must be willing and able to avoid direct exposure to sunlight
from day 1 to day 28.
Outcome Measure: Primary outcome: the UDysRS score at 4 weeks. Secondary outcomes
are also focused on efficacy, all measured at 4 weeks:
1. UDysRS parts III and IV.
2. Participant diaries assessing change in daily off time, measured every half hour
during 24 hours at visit 1.
3. UPDRS part III.
4. UPDRS part IV questions 4.1 and 4.2 related to dyskinesia.
Comments: This study is a Phase 2a study to further assess efficacy of IRL-790 in
the reduction of dyskinesia. The trial is still in the early stages but it will be
interesting to see if D3 antagonism can deliver anti dyskinetic benefits without compromising
motor control.
PRIDOPIDINE
Background: Pridopidine, developed by Arvid Carlsson Research Laboratories, is a potential
neuroprotective and neurorestorative molecule shown to exert its effect via the sigma-1
receptors. It has mostly been explored for Huntington’s Disease (HD) and was given
orphan drug status by FDA for HD. Teva pharmaceuticals took over the development of
the drug from NeuroSearch in 2012, but given the lack of positive data from the HD
trials Teva is letting go of the molecule and Prilenia Therapeutics Development Ltd.
has taken over its development.
In experimental PD animal studies, pridopidine has been shown to protect the nigral
dopaminergic cell bodies and upregulate growth factors leading to axonal sprouting
and restoration of striatal dopaminergic fibre density. The nigral neuroprotective
effect has been associated with reduced microglial activation [1]. Preclinical data
in PD models demonstrate dose dependent reduction in dyskinesia up to 71% without
jeopardizing the antiparkinsonian benefits of levodopa. There was also a notable reduction
in ON time with disabling dyskinesia [2,3].
Most of the data for pridopidine comes from HD trials. Though the trials fail to demonstrate
consistent significant benefit in motor impairment in HD participants, all the studies
established a safe and tolerable profile for the drug [4–6]. Since the safety profile
is established, the molecule is being explored for dyskinesia in a Phase 2 trial as
detailed below.
Title: A 14-week, Double-blind, Randomized, Three-arm, Parallel-Group Study to Assess
the Efficacy and Safety of Two Doses of Pridopidine Versus Placebo for the Treatment
of Levodopa-induced Dyskinesia in Patients With Parkinson’s Disease (gLIDe)
Objective: A multicentre, randomized, double-blind, placebo-controlled, Phase 2 study
evaluating the efficacy, safety, and pharmacokinetics of investigational drug pridopidine
as compared to placebo for the treatment of LID in PD participants.
Status: Recruiting
Clinicaltrials.gov Identifier: NCT03922711
Sponsor: Prilenia Therapeutics
Estimated Enrolment: 135 participants
Estimated Primary Completion Date: April 2020
Study Design: This is a multicentre, double-blind, randomized, three-arm, parallel-group
Phase 2 study evaluating the efficacy and safety of two doses of pridopidine vs placebo
for dyskinesia in PD participants. The study will include participants with a clinical
diagnosis of PD between the ages of 30 and 85 years. Mild to moderate dyskinesia is
a prerequisite. Participants are required to be on a stable medication regimen (PD
and non-PD) for at least 28 days prior to the study start date and be able to maintain
that through the study duration. Standard exclusionary criteria apply. Participants
with surgical intervention such as DBS are excluded.
The participants will be randomized to one of 3 parallel arms:
Arm 1- dose 1 in the form of oral capsules for 12 weeks following a 2 week titration
period.
Arm 2- dose 2 in the form of oral capsules for 12 weeks following a 2-week titration
period.
Arm 3- placebo in the form of oral capsules for 14 weeks.
The study is currently recruiting participants at two sites in the USA.
Outcome: The primary outcome measure explores the change in dyskinesia from baseline
to week 14. The score is calculated as a sum of parts 1, 3, and 4 of the UdysRS. No
secondary outcomes have been posted.
Comments: The pharmacology of the molecule and data from animal studies are promising.
Given an established safety profile, it is one step ahead in the development for dyskinesia.
Physiologically its effect is similar to GDNF growth factors in terms of neuronal
dopamine protection and sprouting in the nigrostriatal axons. Though it failed to
show efficacy for the HD population, its effect on dyskinesia is yet to be determined.
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CLINICAL TRIALS HIGHLIGHTS - RESOURCES
PARKINSON’S THERAPIES IN DEVELOPMENT
The Hope List - http://bit.ly/ParkinsonsHopeList
FINDING A CLINICAL TRIAL
ClinicalTrials.gov from the US National Library of Medicine - https://clinicaltrials.gov
PD Trial Tracker; analysing ClinicalTrials.gov for Parkinson’s specific trials - http://www.pdtrialtracker.info
Fox Trial Finder - https://foxtrialfinder.michaeljfox.org
European Parkinson’s Disease Association - https://www.epda.eu.com/about-parkinsons/treatments/clinical-trials/
Parkinson’s UK - https://www.parkinsons.org.uk/research/take-part-research
UK NHS Clinical Trials Gateway - https://www.ukctg.nihr.ac.uk
Cure Parkinson’s Trust - https://www.parkinsonsmovement.com/clinical-trials/
Parkinson’s Study Group - http://www.parkinson-study-group.org/clinical-trials
American Parkinson Disease Association - https://www.apdaparkinson.org/resources-support/living-with-parkinsons-disease/clinical-trials/
CenterWatch - https://www.centerwatch.com/clinical-trials/listings/condition/117/parkinsons-disease/
WHAT DOES IT MEAN TO PARTICIPATE IN A PARKINSON’S CLINICAL TRIAL?
Michael J Fox Foundation, Clinical Trial Companion – https://www.michaeljfox.org/pdcompanion.html
Parkinson’s Foundation - https://www.parkinson.org/Understanding-Parkinsons/Treatment/Clinical-Trials