Abstract
Introduction
Non-motor symptoms (NMS) constitute a considerable portion of the Parkinson’s Disease (PD) syndrome. The spectrum of NMS is widespread and can range anywhere from olfactory to bladder dysfunction with a significant impact on the quality of life of a person with PD (PwP) [1]. Cognitive impairment (CI) is one of the most common and challenging NMS in PD. The spectrum of PD-CI ranges from subjective symptoms to dementia. Not only are the cognitive symptoms disabling by themselves, but their presence also may limit the management of motor disability as dopaminergic medication can worsen CI. As such, this also affects the motor profile furthering the debility. The reported prevalence rate of mild cognitive impairment (MCI) and PD dementia (PDD) varies depending on multiple factors, including the diagnostic criteria used in the first place. But largely, the prevalence increases with the disease progression. In general, PD-MCI is prevalent among 25-30% PwP, and approximately 10-20% may have it at the time of diagnosis [2]. Within three years of follow up, 25% of PwP with normal cognition may develop PD-MCI. Likewise, PD-MCI to PDD progression is around 20% within three years of follow up and 34% beyond that [3]. PDD is present in 83% of PwP at advanced stages, at 20+ years disease duration [4].
Currently, there are limited therapeutic options for PD-CI. Understanding the flow of progression of PD-CI with underlying mechanisms is essential to developing therapies aimed at reducing the evolution or providing symptomatic benefit. Similar to the underlying mechanism for motor impairment in PD, studies suggest that CI is a consequence of a complex multifactorial process. The various factors playing a role in PD-CI have been reviewed in detail elsewhere [2].
α-synuclein pathology is central to PD and is hypothesized to spread cortically from the brainstem [5]. PD-CI positively correlates with the presence of α-synuclein containing Lewy bodies in the limbic and neocortex. But the underlying mechanisms are considered more intricate and extend beyond α-synuclein to other proteinopathies. There is evidence to suggest an additive role of amyloid and tau pathology in PDD [6]. Synaptic dysfunction and subsequent retrograde somatic degeneration also play a role [7].
The fundamental role of neurotransmitters in PD-CI is more complex and goes beyond the archetypal dopaminergic system. Dopamine posits a more complex and non-linear relationship to PD-CI pathology. While there is some evidence of improvement of early executive dysfunction with dopamine replacement therapy, there is also evidence linking a relative cortical to striatum hyperdopaminergic state to CI [8].
There is convincing evidence highlighting the role of other non-dopaminergic systems in PD-CI, such as cholinergic, noradrenergic, GABAergic, and serotonergic systems. There is evidence indicating a widespread reduction of the subcortical and cortical cholinergic activity in PDD [9]. The acetylcholinesterase inhibitor (ACE-I), rivastigmine, is the only medication approved for the management of the cognitive functioning in PDD [10]. Serotonin and noradrenergic systems have also garnered increasing interest in PD therapeutics with evidence suggesting a positive impact on the frontal network dysfunction [11]. Though evaluated mainly for motor effects, there is a suggestion that modulation of adenosine A2A receptors on GABAergic neurons may also improve cognition [12].
One of the challenges in drug development for PD-CI is that animal models may not reflect the actual nature of PD-CI development. As such, molecules with promising preclinical data often fail in human clinical trials. There is a significant unmet need for developing therapies to improve the CI without impairing motor profile, and to reduce conversion rates to PD-MCI and PDD.
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Overview of clinical trials for PD cognition
There are nine programs at the clinical stage of development for the treatment of cognitive symptoms in PD. Eight are in phase 2, and one is in phase 1. A summary of the clinical trials targeting cognition in PD is shown in the table below.
*PDD - Parkinson’s Disease Dementia
PD-MCI - Parkinson’s Disease with Mild Cognitive Impairment
DLB – Dementia with Lewy Bodies
aSN – α-synuclein
It is immediately apparent that the nine trials listed are using eight different mechanisms of action. This diversity is unusual when compared to other areas of PD drug development. The targets include multiple neurotransmitter pathways, sigma-1, cholinergic and NMDA, as well as dopamine D1.
IRLAB has been developing a novel “cortical enhancer”- IRL752. It has “a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features” [1]. The recently published Phase 2a trial of IRL752 in PDD demonstrated a good safety profile. Interestingly, in the analysis, the drug improved the axial symptoms, including postural instability. IRL752 did not have a significant impact on the spatial working memory, and only had mild improvement in the executive function [2]. IRLAB has announced its plans for a phase 2b study but with a focus on postural instability and falls, possibly influenced by the phase 2a results. No announcements have been made regarding future trials to assess the impact on cognition. It is unknown whether the announced phase 2b trial for falls and postural instability will include any cognitive outcome measures [3].
The Yonsei University study was due to finish in August 2019, and the latest update to the clinicaltrials.gov entry was in January 2019. The results of the study are yet to be published. Previous studies of donepezil in MCI in other indications have failed to slow progression to dementia. This open-label study is assessing the potential of a different outcome in PD.
Two projects are targeting a reduction of levels of aggregated α-synuclein, directly in the case of Enterin’s ENT-01; and indirectly with Lawson Health’s ambroxol project, given that levels of glucocerebrosidase (GCase) have an inverse relationship with levels of α-synuclein. Michigan University’s trial is using the SSRI, citalopram, to target the loss of serotoninergic terminals to address visuospatial loss in PDD.
There is also a wide range in the types of participants being recruited. Two trials are recruiting participants in the earlier stages of cognitive decline (PD-MCI), and five of the nine studies are recruiting participants with confirmed PDD. The Michigan study is recruiting PD participants without any confirmed cognitive deficits, and Lilly’s study is recruiting both PDD and DLB participants.
Recruitment criteria also vary in the age range and the stage of PD, as defined by the Hoehn & Yahr (H&Y) scale. Four of the studies have a lower age limit of 50, two start at 40, and while Michigan’s lower limit is 65, Enterin’s trial inclusion is for PwP age range 30-90. Only three trials include H&Y status in the inclusion criteria with the University of Michigan having a tight range of 2.0 to 2.5, and the Lilly trial a lot wider at 0 to 4.
The duration of the trial treatment period ranges from IRL752 at 28 days, up to the University of Michigan at 26 months. The latter study is investigating the impact of citalopram treatment on the conversion rate of PD with normal cognition to PD-CI. Due to the nature of the question, the study is expected to require more time. The treatment duration for the remaining studies vary from only 10 weeks for ENT-01 to 52 weeks for Lawson Health’s ambroxol trial.
There is little commonality in the outcome measures of the trials. Only one primary measure is used in more than one trial, the Continuity of Attention composite score of the Cognitive Drug Research Computerised Cognition Battery (CDR-CCB; Lilly and Anavex). There is a wide range of cognitive assessment tools used, some of which were developed for Alzheimer’s disease (AD), including the AD assessment scale - cognitive subset (ASAS-cog), Dementia Severity Rating Scale (DSRS), Delis-Kaplan Executive Function Scale (D-KEFS), Clinical Dementia Rating Scale (CDR), and the Trail Making Test.
Five studies use a Neuropsychiatric Inventory (NPI) as a secondary outcome measure. Only four out of the nine studies use the Montreal Cognitive Assessment (MoCA), with a further two using the Mini-Mental State Examination (MMSE), one of which is a Korean adaptation.
Five of the nine trials are using objective instrumental outcome measures. Indeed, the only primary outcome for the University of Michigan study is the change in visuospatial cortex Pittsburgh compound B (PiB) distribution volume. This method can assess the density of β-amyloid plaques. The China Medical University study uses three different MRI techniques whilst Lawson Health are using MRI to assess brain ventricle volume and hippocampal atrophy. Yonsei University plans to use MRI to measure cortical thickness, and subcortical volume and shape. Both Yonsei and IRL use electroencephalography to assess functional connectivity.
The majority of the studies use the Movement Disorders Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) examination (seven of the nine trials) though none of the trials specify whether the test is performed on or off medication.
In summary, there is a significant variation in the design of the studies targeting CI, likely reflecting a lack of consensus on the best target population and outcomes. This will make it more difficult to compare potential treatments. A consensus on these parameters will accelerate the availability of effective symptomatic therapies and disease modifying therapies (DMTs) for PD-CI. On the positive side, there is a good range of mechanisms of action under investigation.
There are very few projects in the preclinical stage to target the mechanisms and symptoms of PD-MCI and PDD. In addition, it is not yet clear whether DMTs for PD will slow or stop the progression of all domains of PD, including cognitive symptoms. In that context, it is essential to continue the research and development of new medicines to deal with the severe impact that PD-MCI and particularly PDD has on the quality of life of PwP and their families.
[1] Hjorth S, Waters S, Waters N, et al. (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent. J Pharmacol Exp Ther. 2020;374(3):404-419. doi:10.1124/jpet.120.000037
[2] P. Svenningsson, P. Odin, N. Dizdar, A. Johansson, S. Grigoriou, P. Tsitsi, K. Wictorin, F. Bergquist, D. Nyholm, J. Rinne, F. Hansson, C. Sonesson, J. Tedroff, K. Andersson, M. Sundgren, W. Duzynski, C. Carlström, A Phase 2a Trial Investigating the Safety and Tolerability of the Novel Cortical Enhancer IRL752 in Parkinson’s Disease Dementia, Movement Disorders. 35 (2020) 1046–1054. https://doi.org/10.1002/mds.28020.
[3] IRL752 - Irlab, (n.d.). https://www.irlab.se/project-portfolio/irl-752.
Anavex®2-73
Change from baseline to end of treatment in cognitive drug research (CDR) computerized assessment system for Continuity of Attention. Number of participants with treatment-related adverse events as assessed by CTCAE (com-mon terminology criteria for adverse events) v4.0.
Secondary outcomes are: Change from baseline to end of treatment as measured by the MDS-UPDRS part III score (motor scores). Incidence of sleep disorders symptom checklist (SDS-CL-25).
The primary cognitive outcome measure is tightly focused on the attention domain. The MoCA score inclusion criterion is a relatively wide range, including both MCI and PDD.
Anavex 2-73 did not impair sleep and had a positive effect on REM sleep behavior disorder. It was generally safe and well tolerated, in common with experience in previous trials.
[1] https://www.anavex.com/wp-content/uploads/2020/02/Anavex-Presentation-February-2020.pdf
Aptinyx – NYX-458
NYX-458 is a novel molecule synthesized by Sai Life Sciences (Hyderabad, India) that is being developed by Aptinyx Inc. The molecule modulates the NR2 activity resulting in long-lasting changes in metaplasticity and dendritic spine morphology in the cortical regions. The preclinical studies report a rapid and long-lasting improvement across a number of cognitive domains – attention, working memory, and executive function. There was no effect on the PD motor profile [3]. According to the Aptinyx website, phase 1 human studies have demonstrated a favorable safety and pharmacokinetic profile [4]. The molecule has entered phase 2 clinical trial.
Worldwide Clinical Trials
Participants between 50-80 years of age with a primary diagnosis of MCI associated with PD will be eligible for inclusion. They should be on a stable antiparkinsonian medication regimen. Participants with MoCA <17 and those meeting criteria for dementia will be excluded. The exclusion criteria also include an ambiguous point of excluding those on medication with primarily central nervous system activities.
The study will be conducted over 16-18 weeks which will include the following, in sequential order: Screening: 2 to 4-weeks Intervention: 12-weeks Follow up: 2-weeks
The trial is studying the safety profile of 3 dosing regimens of the investigation drug. The participants will be randomized to one of the following four arms: Experimental: where participants will receive a 10mg daily dose for 12 weeks Experimental: where participants will receive a 30mg daily dose for 12 weeks Experimental: where participants will receive 100mg daily dose for 12 weeks Placebo
The study is being conducted at multiple sites across the USA.
NMDAR is an interesting potential target, and NYX-458 is a promising molecule based on preclinical studies. The current clinical trial, as expected and rightly so, is focusing on the safety and tolerability of 3 doses of NYX-458. Whether preclinical benefits will translate into clinically meaningful effect is yet to be determined with further studies, contingent upon Phase 2 safety results.
[1] P. Meoni, B.H. Bunnemann, A.E. Kingsbury, D.G. Trist, N.G. Bowery, NMDA NR1 subunit mRNA and glutamate NMDA-sensitive binding are differentially affected in the striatum and pre-frontal cortex of Parkinson’s disease patients, Neuropharmacology. 38 (1999) 625–633. https://doi.org/10.1016/S0028-3908(98)00219-6.
[2] B. Vanle, W. Olcott, J. Jimenez, L. Bashmi, I. Danovitch, W.W. Ishak, NMDA antagonists for treating the non-motor symptoms in Parkinson’s disease, Translational Psychiatry. 8 (2018). https://doi.org/10.1038/s41398-018-0162-2.
[3] A.L. Barth, J.S. Schneider, T.H. Johnston, M.P. Hill, J.M. Brotchie, J.R. Moskal, C.N. Cearley, NYX-458 Improves Cognitive Performance in a Primate Parkinson’s Disease Model, Movement Disorders. 35 (2020) 640–649. https://doi.org/10.1002/mds.27962.
[4] Pipeline - Aptinyx, (n.d.). https://www.aptinyx.com/pipeline
China Medical University- DAAOI-P
The study includes two arms, a placebo arm and an experimental arm where participants will receive the investigational drug DAAOI-P [250-1500mg].
Adult participants with PD between the ages of 50 and 90 years with clinically diagnosed PDD according to the criteria of the Movement Disorders Society will be included. Both probable and possible PDD will be included in this study. Co-existing medical conditions or medications that can independently cause cognitive impairment preventing a reliable diagnosis of PDD, will be excluded. Participants who have been on anticholinergics within 30 days of recruitment will also be excluded.
Secondary outcome measures except the neuroimaging will be assessed at baseline, 8, 16, and 24 weeks and include Change in gait function as measured by the cyclogram of gait. Fall assessment test of China Medical University hospital. Change in cognitive function as measured by Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), Behavioral pathology in Alzheimer’s Disease rating scale (Behave-AD), and clinical dementia rating (CDR) scale. Change in Neuropsychiatric inventory scale. Change in the PDQ-39 scale. Change in perceptual discriminability, emotion recognition accuracy, and imitation probability. Neuroimaging, including structural MRI, resting-state functional MRI, and working memory fMRI, assessed at baseline and 24 weeks. Changes in mismatch negativity in an electroencephalogram. Changes in transcranial magnetic stimulation assessments.
NMDA modulation has been the target of several medications for CI. No prior studies of DAAOI for PD-CI were found. The outcome of this Phase 2 study centers on efficacy assessments with a focus on the gait and cognition. The efficacy of DAAOI in PDD is yet to be established.
[1] L. Pollegioni, S. Sacchi, G. Murtas, Human D-amino acid oxidase: Structure, function, and regulation, Frontiers in Molecular Biosciences. 5 (2018) 107. https://doi.org/10.3389/fmolb.2018.00107.
[2] C.H. Lin, C.H. Lin, Y.C. Chang, Y.J. Huang, P.W. Chen, H.T. Yang, H.Y. Lane, Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added to Clozapine for the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial, Biological Psychiatry. 84 (2018) 422–432. https://doi.org/10.1016/j.biopsych.2017.12.006.
[3] S. Khasnavis, K. Pahan, Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons, Journal of Neuroimmune Pharmacology. 7 (2012) 424–435. https://doi.org/10.1007/s11481-011-9286-3.
Lawson Health Research Institute - Ambroxol
Ambroxol was licensed in 1978 as an expectorant for patients with acute or chronic respiratory disease. Ambroxol has been shown to be centrally penetrant and to increase the levels of glucocerebrosidase (GCase) in both Gaucher disease and PD models [1]. It is an inhibitory chaperone that mobilizes GCase from the endoplasmic reticulum by binding to and inhibiting the enzyme active site, thereby facilitating transportation to the lysosome [2].
Mutations in the GBA gene that codes for GCase are prevalent at around 5% to 15% of Caucasian PD patients, 25% of Ashkenazi Jewish PD patients, and 1% of individuals without PD [3]. There is an inverse relationship between levels of α-synuclein and GCase activity, opening the possibility of positive benefits on disease progression of PD [1]. As such, ambroxol is being studied by a number of groups as a potential disease-modifying therapy in both GBA+ PD and sporadic PD. The rationale for this study is two-fold. First, the inverse relationship between α-synuclein and GCase activity predicts that an increase in GCase activity will reduce levels of α-synuclein. Second, that reducing α-synuclein will lead to improvements in cognition, thereby assuming that α-synuclein levels are responsible for PDD.
A recent open-label 6 months study in 17 PD participants showed that ambroxol crosses the blood-brain barrier and increases the levels of GCase in the cerebrospinal fluid (CSF) in participants both with and without GBA mutations. The drug administered at high doses compared to the usual doses used for pulmonary indication was shown to be safe and tolerable. Further improvements in MDS-UPDRS Part 3 scores were noted, again in both those with and without GBA mutations [4].
The Lawson Health Research Institute now plans to evaluate the safety and efficacy of ambroxol in participants with PDD.
Ambroxol high dose (1050mg per day) Ambroxol low dose (525mg per day) Placebo.
Participants with a MoCA score between 16 and 24 and age >50 are being recruited. The GBA1 gene in each participant will be sequenced, but the mutation status is not an inclusion or exclusion criterion.
Changes in the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog). Changes in the ADCS-Clinician’s Global Impression of Change (CGIC).
Secondary outcome measures include a spectrum of scales measuring motor and non-motor disability, specific domains of cognition, CSF and peripheral ambroxol PK profile, and GCAse levels. The study also includes MRI imaging outcomes measuring brain ventricle volume and hippocampal atrophy (baseline and week 52). Changes in the MoCA (baseline, week 26 and week 52). Changes in the Clinical Dementia Rating Scale (CDR) (baseline, week 26 and week 52). Changes in the Trail Making Test (baseline, week 26 and week 52). Change in the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS) (baseline, week 26 and week 52). Changes in the Stroop Test (baseline, week 26 and week 52). Changes in the Unified Parkinson’s disease Rating Scale motor subsection (UP-DRS-III) (baseline, week 26 and week 52). Changes in the Purdue Pegboard (baseline, week 26 and week 52). Changes in the Timed Up and Go (baseline, week 26 and week 52). Change in Quantitative Movement Testing - gait assessment on electronic mat (Zeno Walkway System) (baseline, week 26 and week 52). Changes in Cerebrospinal Fluid (CSF) biomarkers - levels of ±-synuclein (pg/ml), Tau (pg/ml), phospho-Tau (pg/ml) and beta amyloid-42 (pg/ml) (baseline, week12 and week 52). Changes in Magnetic Resonance Imaging (MRI) - brain ventricle volume (cm3) and hippocampal atrophy (cm3) (baseline and week 52). Changes in the Mini-Mental State Examination (screening, baseline, week 4, week 6, week 12, week 18, week 26, week 34, week 42, week 52). Changes in GCase in lymphocytes (baseline, week 2, week 4, week 6, week 8, week 12, week 18, week 26, week 34, week 42, week 52). Changes in Plasma Ambroxol levels (baseline, week 2, week 4, week 6, week 8, week 12, week 18, week 26, week 34, week 42, week 52). Mayo Fluctuation Questionnaire (baseline, 26 weeks and 52 weeks).
A more detailed description of the trial has been published [5].
Targeting the GBA pathway is of great interest, and a number of programs are in development. This study focuses specifically on the impact on cognition. The secondary outcome measures are comprehensive and require a high number of participant visits (11) and procedures, including three lumbar punctures.
The dose of ambroxol under evaluation is 1,050mg per day, approximately 15mg/kg/day. This is much higher than the OTC dose. An even higher dose, 1,260mg, was used in the phase 2 efficacy trial described by Mullins et al. [4]. In the Lawson Health study, the number of 75mg tablets per day is up to 14 per day for the higher dose. The number of tablets to be taken each day by participants with PDD or MCI may thus be a challenge for compliance. However, one inclusion criterion requires the presence of a responsible caregiver for at least 4 days per week.
[1] Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV. Oral ambroxol increases brain glu-cocerebrosidase activity in a nonhuman primate. Synapse. 2017;71(7):e21967. doi:10.1002/syn.21967
[2] Bendikov-Bar I, Maor G, Filocamo M, Horowitz M. Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase. Blood Cells Mol Dis. 2013;50(2):141-145. doi:10.1016/j.bcmd.2012.10.007
[3] Zhang Y, Shu L, Sun Q, et al. Integrated Genetic Analysis of Racial Differences of Com-mon GBA Variants in Parkinson’s Disease: A Meta-Analysis. Front Mol Neurosci. 2018;11:43. Published 2018 Feb 15. doi:10.3389/fnmol.2018.00043
[4] Mullin S, Smith L, Lee K, et al. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020;77(4):427-434. doi:10.1001/jamaneurol.2019.4611
[5] Silveira CRA, MacKinley J, Coleman K, et al. Ambroxol as a novel disease-modifying treatment for Parkinson’s disease dementia: protocol for a single-centre, randomized, double-blind, place-bo-controlled trial. BMC Neurol. 2019;19(1):20. Published 2019 Feb 9. doi:10.1186/s12883-019-1252-3
Lilly – LR3154207
LY3154207 is a novel human D1R subtype-selective PAM that has been developed by Eli Lilly and Company [2]. Backed by preclinical evidence of positive motor and cognitive benefits, the safety profile of the molecule was studied in the phase 1 trial [NCT02562768]. The trial had 2 parts assessing the safety profile and pharmacokinetics in healthy and PD participants, respectively. The study is completed; however, the results are unavailable. The company has moved the molecule forward into the phase 2 trial, the PRESENCE study, which is discussed here. Separately, LY3154207 has been shown to improve wakefulness in sleep-deprived healthy males, highlighting its potential role in excessive daytime sleepiness [3].
Participants between the ages of 40 and 85 years with a clinical diagnosis of PD or dementia with Lewy bodies deemed to have increased functional impairment due to a decline in cognitive functions are eligible for inclusion. The MoCA score must be between 10-23. Certain medication classes are allowed if the participants have been on a stable dose for 3 weeks before the screening and expected to remain on a stable dose throughout the study. The medications allowed include antihypertensives, antiparkinson, antidepressants, medications for cognition and psychosis [clozapine, quetiapine, and pimavanserin]. Participants on antipsychotics other than listed above and anticholinergics will be excluded. Participants are required to have reliable caregivers. Standard exclusionary criteria apply.
Participants will be randomly assigned to one of the four arms: Experimental arm 1: high dose of the investigational drug orally Experimental arm 2: mid dose of the investigational drug orally Experimental arm 3: low dose of the investigational drug orally Placebo arm
The secondary outcome measures assess the change in various scales at 12 weeks from baseline. The scales included mostly assess the cognitive and psychiatric domains. Additional measures assess the change in the MDS-UPDRS total score, vital signs, and even the pharmacokinetics.
D1R is a potentially interesting target for the management of both PD motor and non-motor disability. While there are other D1R agonists being explored for motor benefits, LY3154207 focuses on cognition. The phase 2 has completed enrolment and is awaiting results.
[1] K.A. Svensson, J. Hao, R.F. Bruns, Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders, in: Advances in Pharmacology, Academic Press Inc., 2019: pp. 273–305. https://doi.org/10.1016/bs.apha.2019.06.001.
[2] J. Hao, J.P. Beck, J.M. Schaus, J.H. Krushinski, Q. Chen, C.D. Beadle, P. Vidal, M.R. Reinhard, B.A. Dressman, S.M. Massey, S.L. Boulet, M.P. Cohen, B.M. Watson, D. Tupper, K.M. Gardinier, J. Myers, A.M. Johansson, J. Richardson, D.S. Richards, E.J. Hembre, D.M. Remick, D.A. Coates, R.M. Bhardwaj, B.A. Diseroad, D. Bender, G. Stephenson, C.D. Wolfangel, N. Diaz, B.G. Getman, X.S. Wang, B.A. Heinz, J.W. Cramer, X. Zhou, D.L. Maren, J.F. Falcone, R.A. Wright, S.N. Mitchell, G. Carter, C.R. Yang, R.F. Bruns, K.A. Svensson, Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1 S,3 R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor, Journal of Medicinal Chemistry. 62 (2019) 8711–8732. https://doi.org/10.1021/acs.jmedchem.9b01234.
[3] K. Biglan, P. Ardayfio, W. Kielbasa, K. Svensson, A D1 receptor positive allosteric modulator (LY3154207) enhances wakefulness in sleep deprived healthy volunteers (P3.6-041), Neurology. 92 (2019).
University of Michigan - Citalopram
Citalopram is an SSRI that was first marketed in 1989 and is now widely prescribed, with 24 million prescriptions in the US alone in 2017 [4]. The current study explores the effect of citalopram on the visuospatial domain of cognitive decline, which is an important component of PD-CI.
Change in Benton Judgment of Line Orientation (JOLO) test for visuospatial cognition. Change in MoCA.
All the measures are taken at baseline and 26 months.
This study has a clear biomarker driven target and a low number of outcome measures focused clearly on plaque measurement and an improvement in the rate of visuospatial cognitive decline. From a participant perspective, the low number of study visits (2) is also an advantage, particularly for recruitment.
It is interesting that participants should be aged at least 65, a relatively high age for PD trials. The H&Y score is also within a narrow range, 2.0-2.5, unlike that seen in other PD trials. This may lead to reduced variability in results.
[1] B. Mdawar, E. Ghossoub, R. Khoury, Selective serotonin reuptake inhibitors and Alzheimer’s disease, Neural Regeneration Research. 15 (2020) 41–46. https://doi.org/10.4103/1673-5374.264445.
[2] V. Kotagal, C. Spino, N.I. Bohnen, R. Koeppe, R.L. Albin, Serotonin, β-amyloid, and cognition in Parkinson disease, Annals of Neurol-ogy. 83 (2018) 994–1002. https://doi.org/10.1002/ana.25236.
[3] A. Gatt, A. Ekonomou, A. Somani, S. Thuret, D. Howlett, A. Corbett, M. Johnson, E. Perry, J. Attems, P. Francis, D. Aarsland, C. Ballard, Importance of Proactive Treatment of Depression in Lewy Body Dementias: The Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study, De-mentia and Geriatric Cognitive Disorders. 44 (2017) 283–293. https://doi.org/10.1159/000484437
[4] “Citalopram Drug Usage Statistics”. ClinCalc. 23 December 2019.
Yonsei University - Donepezil
A large (n=550) double-blind, placebo-controlled trial of donepezil in PDD was published in 2012, showing significant improvements in symptoms and suggested that donepezil could improve cognition, executive function, and global status in PDD [3]. Donepezil is licensed for the treatment of PDD in Japan but not the USA. While studied in PDD, there is limited data exploring its effect in PD-MCI [4]. The current study aims to explore the effect of donepezil on the progression of PD-MCI.
The five secondary outcome measures are: Change in cognitive decline (24, 48, and 72 weeks). Change in UPDRS parts I-IV (24, 48, and 72 weeks). Brain structure (cortical thickness, and subcortical volume and shape) and default mode and network with conventional and functional MRI (48 weeks). Brain functional connectivity using digital electroencephalography (48 weeks). Comprehensive neuropsychological test using the Seoul Neuropsychological Screening Battery (SNSB) (48 weeks).
The rationale for the Yonsei University trial is that the cholinergic deficits seen in PDD are also present in PD-MCI. The hope is that earlier intervention with donepezil may delay the onset of PDD. The outcome measures are aiming to correlate the results of clinical measurement with structural change via fMRI and EEG. In parallel, the progression of other PD symptoms will be measured using UPDRS.
The treatment duration is 48 weeks, although changes in cognitive decline and UPDRS will be measured again at 72 weeks. The trial is recruiting participants with a confirmed diagnosis of PD-MCI aged over 40. It was due to finish in 2019, although no results appear to have been published yet.
[1] R.C. Petersen, O. Lopez, M.J. Armstrong, T.S.D. Getchius, M. Ganguli, D. Gloss, G.S. Gronseth, D. Marson, T. Pringsheim, G.S. Day, M. Sager, J. Stevens, A. Rae-Grant, Practice guideline update sum-mary: Mild cognitive impairment report of the guideline development, dissemination, and implemen-tation, Neurology. 90 (2018) 126–135. https://doi.org/10.1212/WNL.0000000000004826.
[2] W. Poewe, S. Gauthier, D. Aarsland, J.B. Leverenz, P. Barone, D. Weintraub, E. Tolosa, B. Dubois, Diagnosis and management of Parkinson’s disease dementia, International Journal of Clinical Practice. 62 (2008) 1581–1587. https://doi.org/10.1111/j.1742-1241.2008.01869.x.
[3] Dubois B, Tolosa E, Katzenschlager R, et al. Donepezil in Parkinson’s disease dementia: a randomized, double-blind efficacy and safety study. Mov Disord. 2012;27(10):1230-1238. doi:10.1002/mds.25098.
[4] J.G. Goldman, D. Weintraub, Advances in the treatment of cognitive impairment in Parkin-son’s disease, Movement Disorders. 30 (2015) 1471–1489. https://doi.org/10.1002/mds.26352.
Enterin – ENT-01
ENT-01 is not systemically absorbed and exerts its gastrointestinal effects topically via the enteric nervous system (ENS). The trial for PDD will examine the effect of its action on the ENS to influence the gut-brain axis, in theory via inhibition of α-synuclein aggregation.
All participants will receive the study drug as daily oral dosing for 10 weeks. The study will require 5 visits. Participants will be allowed to adjust the medication dose as specified in the protocol.
The secondary outcomes, also assessed at baseline and after 10 weeks of treatment are: Change in the MoCA. Change in symptoms adapted for Parkinson’s disease (SAPS-PD). This measures the frequency and/or severity of hallucinations and delusions. Change in Neuropsychiatric Inventory (NPI) and Caregiver Distress (NPI-D). Change in Parkinson’s Disease Questionnaire-39 (PDQ-39).
The study will also assess other outcome measures: Change in MDS-UPDRS. Change in skin temperature-determined circadian rhythm. Change in body weight.
This study intends to explore the ability of ENT-01 to influence α-synuclein aggregation and the subsequent impact on cognitive symptoms. The timeframe to assess this effect is 10 weeks. Open label design of the study will preclude any meaningful conclusions regarding potential efficacy.
Together with the RASMET (NCT03047629) and KARMET (NCT02781791 and NCT04483479) studies, Enterin are building a solid base of patient experience with ENT-01.
[1] Perni M, Galvagnion C, Maltsev A, Meisl G, Muller MB, Challa PK, Kirkegaard JB, Flagmeier P, Co-hen SI, Cascella R, Chen SW, Limbocker R, Sormanni P, Heller GT, Aprile FA, Cremades N, Cecchi C, Chiti F, Nollen EA, Knowles TP, Vendruscolo M, Bax A, Zasloff M, Dobson CM. A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity. Proc Natl Acad Sci U S A 114(2017), E1009–E1017.
[2] Hauser RA SD, Madrid JA, Rol MA, Frucht S, Isacson S, Pagan F, Maddux BN, Li G, Tse W, Walter BL, Kumar R, Kremens D, Lew MF, Ellenbogen A, Oguh O, Vasquez A, Kinney W, Lowery M, Res-nick M, Huff N, Posner J, Ballman KV, Camilleri M, Zasloff M, Barbut D. Targeting neurons in the gastrointestinal tract to treat Parkinson’s disease. Clin Parkinsonism Relat Disord 1(2019), 2–7.
Phase 3 Study in Focus – Tavapadon
While this issue focuses on clinical trials targeting the cognitive domain of PD disability, there are no active or recently completed Phase III studies for this indication. For that reason, we have decided to highlight tavapadon that is being developed for motor indication, but based on the mechanism of action targeting the D1 dopaminergic pathway, it may also be of future interest for cognitive indications.
Tavapadon has an interesting history of development. Formerly known as PF-06649751, it was initially being developed by Pfizer, who sponsored the initial clinical phase 1 and phase 2 studies. Cerevel Therapeutics, an offshoot of Bain Capital and Pfizer, which was created to continue working on their neuroscience portfolio, eventually took over the drug development.
Even though prior clinical evidence did not support the motor efficacy of partial D1 agonists, based on their unpublished data, the group proceeded with phase 1 studies initially. The phase 1 studies [NCT02373072, NCT02224664] provided a safe passage to phase 2 studies [1].
However, several phase 2 studies [NCT02847650, NCT02687542, NCT03185481] designed to study the safety and efficacy of flexible and fixed dosing were terminated early due to lack of efficacy [2–4]. NCT02687542 was designed to study the efficacy and safety of the multiple fixed dosing up to 15mg in participants with advanced PD. Due to a lack of efficacy in the interim analysis, the study was terminated early. This also lead to the termination of the planned continuation study, NCT03185481.
As a result of the lack of efficacy noted in the interim analysis of NCT02687542, NCT02847650 was also terminated early by the sponsor. Despite early termination with only 57 participants enrolled instead of 88, NCT02847650 did meet its primary goal. The results of NCT02847650 were published recently [5]. In this double-blind, placebo-controlled, flexible-dose, 15-week study in early PD participants, a statistically significant improvement in the MDS-UPDRS part III score [4.8 (2.26)] was noted with tavapadon compared to the placebo arm. The drug was well-tolerated, and common side effects included nausea, headache, dry mouth, somnolence, and tremor [6].
Based on this, the molecule has been moved to Phase 3 trials. TEMPO-1 and TEMPO-2 will study the efficacy and safety profile of the drug in a fixed and flexible dosing schedule in participants with early PD. Another Phase 3 study has been announced, TEMPO-3, which will study the flexible dosing of tavapadon but in late-stage PD. The primary outcome measure for TEMPO-3 will be the change in daily “on” time without troublesome dyskinesia. The study has recently been posted on clinicaltrials.gov and plans to start enrolment in late 2020 [7]. It has been registered on the EudraCT as 2019-002951-40 [8].
TEMPO-1
Clinically diagnosed PD participants between age 40-80 years with H&Y stage less than 2 and within 3 years of disease duration from the time of diagnosis are eligible to participate. The MDS-UPDRS part II and III scores should be ≥2 and 10, respectively, at the time of screening. Participants should be dopaminergic drug naïve and be willing to refrain from non-permitted PD medications. Participants who have been taking dopaminergic agents but for less than three months and at least two months before signing consent will be eligible for inclusion. The use of MAO-Inhibitors is allowed. Apart from standard exclusionary criteria, participants with impulse control disorders, certain neuropsychiatric symptoms, and MoCA <26 will be excluded.
The participants will be randomized to one of the three arms, which are: Experimental arms: there will be two experimental arms where participants will be randomized to receive tavapadon titrated to either 5mg or 15mg orally daily for 27 weeks. Comparator arm where participants will receive a matching placebo orally once a day for 27 weeks.
The study is being conducted at 11 sites across the USA.
The secondary measures include the following: Percentage of responders with ‘Much improved’ or ‘Very much im-proved’ rating on the Participant global impression of change (PGIC) up to 27 weeks. The PGIC score up to 27 weeks. Change in MDS-UPDRS I, II, and III combined and individual scores up to 27 weeks from base-line. Change in Clinical global impression (CGI) - severity of illness score and CGI- Improvement score up to 27 weeks from baseline. Change in Epworth sleepiness scale, Impulsive-compulsive disorders in Parkinson’s dis-ease rating scale up to 27 weeks. Change in Columbia-suicide severity rating scale up to 27 weeks. Number of participants with treatment-emergent adverse events will be monitored up to 31 weeks.
TEMPO-2
The inclusion and exclusion criteria for TEMPO-2 are the same as TEMPO-1
This study has two arms: Experimental arm where participants will be randomized to receive tavapadon anywhere from 5 to 15mg daily for 27 weeks. Placebo comparator arm where participants will receive a placebo for 27 weeks.
The study is being conducted at seven sites across the USA, different to the TEMPO-1 study sites.
The primary outcome remains the same as TEMPO-1 and will assess the change in MDS-UPDRS part II and III combined score up to 27 weeks from baseline.
The secondary measures are the same as TEMPO-1 except for the change in MDS-UPDRS I, II, and III individual scores will be assessed up to 29 weeks.
TEMPO-3
The inclusion criteria for TEMPO-3 is different to TEMPO-1 and 2 for obvious reasons. It will include clinically diagnosed PD participants between age 40-80 years with “on” state H&Y stage between 2–3. Participants should be levodopa responsive, taking at least 400mg/day and be on a stable dose for at least four weeks before screening. Other adjunctive therapies are allowed if started >90 days before signing the consent and is expected to be stable throughout the study. Standard exclusionary criteria apply. Participants from prior tavapadon trial will be excluded.
This study has two arms: Experimental arm where participants will be randomized to receive tavapadon anywhere from 5 to 15mg daily for 27 weeks. Placebo comparator arm where participants will receive a placebo for 27 weeks.
The study is being conducted at 21 sites across the USA.
Change in the total ‘Off’ times at 27 weeks Change in total “on” and “off” times without troublesome dyskine-sia at weeks 2, 5, 8, 11, 14, 18, 22, 26, and 27 Change in MDS-UPDRS part I, II, and III individual scores at 27 weeks.
Tavapadon is an exciting molecule with the potential for therapeutic benefit by modulating the direct pathways in the basal ganglia circuitry. However, the drug has had a few setbacks in phase 2 studies. The advanced stage of the disease and fixed medication dose may account for the lack of efficacy in the interim analysis of NCT02687542. TEMPO-3, likely learning from phase 2 results, will study the molecule as adjunctive therapy with flexible dosing. Notably, the NCT02847650 trial showed a safe profile with a positive change in motor scoring in early PD, but the results were not clinically meaningful. Given the results were from a Phase 2 study with partial data analysis, we will be on the lookout for TEMPO-1 and 2 study results. While D1R is a potential target for PD-CI, TEMPO studies do not include any secondary cognitive measures and exclude participants with MoCA less <26 for early PD and those with troublesome CI in advanced PD. Their focus remains on the motor profile of PD.
[1] U.S. Sohur, D.L. Gray, S. Duvvuri, Y. Zhang, K. Thayer, G. Feng, Phase 1 Parkinson’s Disease Studies Show the Dopamine D1/D5 Agonist PF-06649751 is Safe and Well Tolerated, Neurology and Therapy. 7 (2018) 307–319. https://doi.org/10.1007/s40120-018-0114-z.
[2] Efficacy, Safety and Tolerability of PF-06649751 in Parkinson’s Disease Patients With Motor Fluctuations - ClinicalTrials.gov, (n.d.). https://clinicaltrials.gov/ct2/show/NCT02687542.
[3] Efficacy, Safety and Tolerability of PF-06649751 in Parkinson’s Disease Patients at Early Stage of the Disease - ClinicalTrials.gov, (n.d.). https://clinicaltrials.gov/ct2/show/NCT02847650.
[4] Efficacy, Safety and Tolerability of PF-06649751 in Parkinson’s Disease Patients With Motor Fluctuations - ClinicalTrials.gov, (n.d.). https://clinicaltrials.gov/ct2/show/NCT02687542?term=PF-06649751&rank=5.
[5] Efficacy, Safety and Tolerability of Tavapadon in Subjects With Early Stage Parkinson’s Disease - MDS Abstracts, (n.d.). https://www.mdsabstracts.org/abstract/efficacy-safety-and-tolerability-of-tavapadon-in-subjects-with-early-stage-parkinsons-disease.
[6] R. Riesenberg, J. Werth, Y. Zhang, S. Duvvuri, D. Gray, PF-06649751 efficacy and safety in early Parkinson’s disease: a randomized, placebo-controlled trial, Therapeutic Advances in Neurological Disorders. 13 (2020). https://doi.org/10.1177/1756286420911296.
[7] Cerevel Therapeutics Initiates Phase 3 Program Testing Tavapadon in PD for Improved Motor Function, (n.d.). https://parkinsonsnewstoday.com/2020/01/16/cerevel-therapeutics-initiates-phase-3-program-testing-tavapadon-parkinsons-improved-motor-function.
[8] Clinical Trials register - https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-002951-40.