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OBJECTIVE: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A(2A) receptor antagonist, istradefylline, shows promise for the treatment of PD. METHODS: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake 'off' time, recorded by subjects using a patient PD diary. Secondary end points evaluated 'on' time (including 'on time with dyskinesia'), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. RESULTS: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake 'off' time for istradefylline was a mean (+/- standard deviation) of -10.8 +/- 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 +/- 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake 'off' time of -1.8 +/- 2.8 hours for istradefylline and -0.6 +/- 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. INTERPRETATION: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in 'off' time without increased troublesome dyskinesia. [ABSTRACT FROM AUTHOR]

Anticholinergic (AC) drugs, a medication class that acts by blocking nicotinic and muscarinic acetylcholine receptors, were first utilized for therapeutic purposes in the mid-19th century. Initial applications were as symptomatic therapy for Parkinson disease (PD), a practice continuing to the present. Initially, the AC drugs used were naturally-occurring plant compounds. Synthetic AC drugs were developed in the late 1940s and predominated in neurological therapeutics. Until the advent of pharmaceuticals acting upon striatal dopaminergic motor pathways, AC drugs provided the only effective means for lessening tremors and other clinical problems of the PD patient. However, because dopaminergic compounds are so effective at meeting the needs of the typical PD patient, AC medications are far less utilized by clinicians today. In recent years, there has been only a few investigations of AC drugs as neurological treatments. This review will revisit the clinical landscape of AC pharmacology and application for movement disorders along with recent research in search of improving therapeutics with AC drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease., Methods: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete., Findings: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury)., Interpretation: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment., Funding: NeuroDerm., Competing Interests: Declaration of interests AJE, FS, RP, AA, AE, JJF, NG, TG, SH-B, JH-V, SHI, KK, PAL, LL-M, WP, HS, and OR were investigators in the study and they or their institution received fees for participation. CWO and KK have stock ownership in Clintrex, which was contracted by NeuroDerm to provide services for this study. TY, LA, LS, NL, and NS are employed by NeuroDerm. RC was employed by NeuroDerm at the time of the study and is now employed by Mitsubishi Tanabe Pharma America. AJE has received grant support from the National Institutes of Health and the Michael J Fox Foundation; personal compensation as a consultant or scientific advisory board member for NeuroDerm, Herantis Pharma, Amneal, Acadia, Acorda, Kyowa Kirin, Sunovion, and Supernus; personal compensation as honoraria for speakership for Avion; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. AJE cofounded REGAIN Therapeutics (a biotech startup developing non-aggregating peptide analogues as replacement therapies for neurodegenerative diseases) and is co-owner of a patent that covers synthetic soluble non-aggregating peptide analogues as replacement treatments in proteinopathies. FS reports honoraria and consulting fees from BIAL, Sunovion, AbbVie, Luosofarmaco, Kyowa, Synagile, Lundbeck, TEVA, UCB, Zambon, Blue Rock, NeuroDerm, Contera, Zambon, Biogen, Ever, and Britannia; speaker fees from BIAL, Sunovion, AbbVie, Luosofarmaco, Kjowa, Synagile, Lundbeck, TEVA, UCB, and Zambon; and travel support from Bial, Zambon, Synagile, and AbbVie. RP reports grants from Abbott, AbbVie, Alexza, Annovis, Biogen, Bluerock, Bukwang, Cerevel, Global Kinetics, Jazz, the Michael J Fox Foundation, NeuroDerm, Neuraly, the Parkinson's Foundation, Praxis, Roche, Sage, Scion, Sun Pharma, UCB, and Voyager; and consulting fees from Abbott, AbbVie, ACADIA, Acorda, Allevion, Amneal, Artemida, BioVie, CalaHealth, Convatec, Global Kinetics, Inbeeo, Insightec, Jazz, Kyowa, Lundbeck, Merz, Neurocrine, NeuroDerm, Ono, PhotoPharmics, Sage, Sunovion, Supernus, UCB, and Wren. AA has received speaker's honoraria from Ipsen and Merz; is President of the International Association on Parkinsonism and Related Disorders; and is Section Editor for Frontiers in Movement Disorders. AE reports honoraria and consulting fees from AbbVie, Acadia, Acorda, Adamas, Affiris, Allergan, Arbor, Biohaven, BioVie, Cerevel, Ipsen, Mitsubishi Tanabe Pharma America, NeuroDerm, Praxis, Revance, Supernus, Teva, US WorldMeds, and XW Labs. JJF has provided consultancy for AbbVie, BIAL, Biogen, Lundbeck, and Sunovion; received grants from Angelini, Novartis, Medtronic, AbbVie, Zambon, BIAL, Biogen, and Grunenthal; and received speaker fees for BIAL, Ono, SK Chemical, and Infucure. NG serves as consultant to NeuroDerm, Sanofi, and Biogen. NG also reports payment for lectures, travel support, or both from BIAL, NeuroDerm, and Biogen; stock options in Vibrant and Longevity AI; and a patent pending for GaitBetter. TG has served as consultant to NeuroDerm, AbbVie, Medisson, Truemed, and Tradis Gat; has received research support from the Movement Disorders Society; and has received the Center of Excellence grant from the Parkinson's Foundation. TG reports fees for lectures, travel support, or both from AbbVie, Medisson, Teva, Boston Scientific, and Alphamedix; stock options in Cytora and Neurosteer; and a patent for an automated analysis of speech and development of vocal biomarkers in Parkinson's disease. SH-B serves as consultant to NeuroDerm, AbbVie, Teva, Takeda, Medison, Trumed, and Abbott; has received payment for lectures from AbbVie, Medisson, and Teva; and has received research support from AbbVie and the Michael J Fox Foundation. JH-V reports grants from Fondo de Investigación Sanitaria; honoraria for lectures, travel support, or both from BIAL, Zambon, Italfarmaco, and AbbVie; and stock in Sense4care. SHI reports honoraria for CME, consultant fees, research grants, or promotional speaker fees on behalf of AbbVie, Acadia, Acorda, Adamas, Addex, Affiris, Alexva, Allergan, Amarantus, Amneal, Aptinyx, Axial, Axovant, Benevolent, Biogen, Britannia, Cadent, Cala, Cerecor, Cerevel, Cipla, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Impel, Intec Pharma, Ipsen, Jazz, Kyowa, Lundbeck, Merz, the Michael J Fox Foundation, Mitsubishi Tanabe, Neuralys, Neurocrine, NeuroDerm, Parkinson Study Group, Pharma2B, Prilenia, Promentis, Revance, Roche, Sanofi, Sunovion, Sun Pharma, Supernus, Teva, Theravance, UCB, and Zambon. KK reports equity interest in Clintrex and Hoover Brown; patents for information management; and participation in safety monitoring boards for Roche, Lilly, and Janssen. PAL reports advisory roles for Abide, Acorda Therapeutics, Adamas, Amneal, Aptinyx, Biogen, Britannia, Bukwang Pharma, Cavion, Cerevel, Denali, F Hoffmann–La Roche, Jazz Pharmaceuticals, Kyowa Kirin Hakko, Neurocrine, Mitsubishi NeuroDerm, Sage, Supernus, and US WorldMeds; and research grant support from the Michael J Fox Foundation, NeuroDerm, Parkinson Study Group, Pharma Two B, Hoffmann–La Roche, Sunovion, Sun Pharma, and US WorldMeds. CWO reports equity interest in Clintrex and expert witness testimony in the Paraquat litigation. WP has received lecture fees and honoraria for consultancy in relation to clinical drug development programs from AbbVie, AC Immune, Alterity, BIAL, Boehringer, Britannia, Lilly, Eisai, Lundbeck, Roche, Takeda, Britannia, Eisai, Roche, Stada, and Zambon; grant support from the Michael J Fox Foundation and the EU FP7 & Horizon 2020 programs; and safety monitoring board membership for UCB. WP also reports leadership roles in the Movement Disorder Society, Austrian Society of Neurology, and Austrian Parkinson's disease Society. HS reports consultancy fees from Novo Nordisk, Blue Rock Therapeutics, and Neurocrine; clinical trial support from Insightec, Sun Pharmaceuticals, Prevail Therapeutics, Blue Rock Therapeutics, Novo Nordisk, Biogen, Genentech–Roche, Bukwang, and the National Institutes of Health. OR has participated in advisory boards or provided consultancy for AbbVie, Adamas, Acorda, Addex, AlzProtect, ApoPharma, AstraZeneca, Axovant, Bial, Biogen, Britannia, Buckwang, CereSpir, Clevexel, Denali, INC Research, IPMDS, Lundbeck, Lupin, Merck, MundiPharma, NeurATRIS, NeuroDerm, Novartis, ONO Pharma, Osmotica, Parexel, Pfizer, Prexton Therapeutics, Quintiles, Roche, Sanofi, Servier, Sunovion, Theranexus, Takeda, Teva, UCB, Vectura, Watermark Research, XenoPort, XO, and Zambon; and has received grants from Agence Nationale de la Recherche, CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, the Michael J Fox Foundation, Programme Hospitalier de Recherche Clinique, European Commission (FP7 and H2020), and Cure Parkinson's., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Preclinical evidence suggests that co-administration of the 5-HT 1A agonist buspirone and the 5-HT 1B/1D agonist zolmitriptan act synergistically to reduce dyskinesia to a greater extent than that achieved by either drug alone., Objectives: Assess the therapeutic potential of a fixed-dose buspirone and zolmitriptan combination in Parkinson's disease (PD) patients with levodopa-induced dyskinesia., Methods: Single-center, randomized, placebo-controlled, two-way crossover study (NCT02439203) of a fixed-dose buspirone/zolmitriptan regimen (10/1.25 mg three times a day) in 30 patients with PD experiencing at least moderately disabling peak-effect dyskinesia., Results: Seven days of treatment with buspirone/zolmitriptan added to levodopa significantly reduced dyskinesia as assessed by Abnormal Involuntary Movement Scale scores versus placebo (mean treatment effect vs. placebo: -4.2 [-6.1, -2.3]) without significantly worsening Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON) scores (mean treatment effect vs. placebo: 0.6 [-0.1, 1.3]). No serious adverse events were reported., Conclusions: In this proof-of-concept study, addition of buspirone/zolmitriptan to the patients' PD medication regimen significantly reduced dyskinesia severity without worsening motor function. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

In the advanced Parkinson's disease, motor and non-motor symptoms become more severe and more difficult to treat. Oral therapy may become insufficient in controlling a patient´s motor complications, which results in a substantial deterioration of the patient's quality of life, ability to work and self-reliance. This is when device-aided treatments should be considered and offered, if suitable for a given patient. They include subcutaneous and intestinal infusion therapies, deep brain stimulation and, more recently, MRI-guided focussed ultrasound. Device-aided treatments should be offered in accordance with guidelines and treatment standardization. Also there is a need to ensure availability of treatment and education of patients and physicians., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Importance: Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations., Objective: To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations., Design, Setting, and Participants: RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial., Interventions: Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks., Main Outcome and Measures: The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period., Results: A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P < .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%)., Conclusions and Relevance: In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently., Trial Registration: ClinicalTrials.gov Identifier: NCT03670953.

Parkinson's disease (PD) is a neurodegenerative disorder that leads to the degeneration of dopaminergic neurons resulting in a widespread pathology of motor and non-motor symptoms. Oral levodopa remains the most effective symptomatic treatment of PD, but motor complications such as Off episodes occur over time. The spectrum of manifestation of OFF episodes varies, e.g., early morning akinesia, end-of-dose wearing OFF, delayed ON, suboptimal ON and dose failure. The functional disability substantially impacts the quality of life for PD patients. An innovative on-demand therapy to treat Off episodes was approved for patients receiving oral levodopa/dopa deacarboxylase inhibitor: inhaled levodopa powder (Inbrija®). The pulmonary delivery of inhaled levodopa powder provides a predictable and fast treatment effect, independent of gastrointestinal dysfunctions or food intake, which could affect levodopa absorption. Levodopa is administered with a breath-actuated inhaler device and the approved dose is 84 mg per Off episode. During the pivotal SPAN-PD phase III trial, significant improvement in Unified Parkinson Disease Rating Scale III score was measured 30 min post-dose at week 12. Improvement was already seen for the first measured time point 10 min post-dose. No differences in pulmonary function was observed when using inhaled levodopa powder regularly for up to 12 months. Inhaled levodopa powder was also approved for early morning Off episodes. The aim of this review article is to give an overview of the different clinical studies of the innovative inhaled levodopa powder, a new on-demand therapy to treat Off episodes in PD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Abstract: Oral levodopa is the most effective treatment for Parkinson disease, but OFF periods emerge over time. Gastrointestinal dysfunction and food effects impact levodopa absorption, contributing to unpredictable control of OFF periods. Inhaled levodopa powder (Inbrija) is approved for on-demand treatment of OFF periods in patients receiving oral levodopa-dopa decarboxylase inhibitors. The 84-mg dose is administered via a breath-actuated inhaler. It provides pulmonary delivery of levodopa to the systemic circulation and is taken when a patient has an OFF period in between doses of regular oral levodopa medication. The pivotal SPAN-PD trial in patients experiencing OFF periods on oral dopaminergic therapy showed that levodopa inhalation powder 84 mg produced significant improvement in Unified Parkinson Disease Rating Scale Part III score, as measured 30 minutes postdose at week 12, and improvement was seen as early as 10 minutes. More patients in the levodopa inhalation powder group turned ON within 60 minutes of treatment and remained ON at 60 minutes than in the placebo group. Levodopa inhalation powder can also be used to treat early-morning OFF periods and, when used for up to 12 months, produced no clinically significant differences in pulmonary function compared with an untreated cohort. Levodopa inhalation powder 84 mg increased plasma levodopa concentration rapidly and with less variability than oral levodopa/carbidopa (25/100 mg). Most common adverse event associated with levodopa inhalation powder is cough, found in ~15% of patients in the SPAN-PD trial; otherwise, reported adverse events were consistent with those known to be associated with oral levodopa., Competing Interests: Conflicts of Interest and Source of Funding: Funding for editorial assistance to the authors was provided by Acorda Therapeutics. The authors received no payment for their work on this article. The work described in this article was supported by Acorda Therapeutics. Editorial assistance was provided by Emily Kuhl, PhD, and Robin Smith, PhD, of The Curry Rockefeller Group, LLC (Tarrytown, NY). The funding for this assistance was provided by Acorda Therapeutics, Inc. R.A.H. received consulting fees from AbbVie, Acadia Pharmaceuticals, Acorda Therapeutics, Adamas Pharmaceuticals, Affiris, Alliance for Aging Research, AlphaSights, Amneal Pharmaceuticals, Apopharma, Aptis Partners LLC, Aranca, Axovant, Britannia, Cadent, CAVR, Cerespir, ClearView, Clinical SCORE LLC, CNS Ratings LLC, Compass Group, Decision Resource Group, Dedham Group, Defined Health, Denali, Enterin, Ernest and Young S.L., Extera, Gerson Lehman Group Inc, Global Kinetic Consulting, Guidepoint Global, Health Advances, Huron, Impax Laboratories, Impel Neuropharma, Inhibikase, InSearch Consulting, Insignia Strategies, International Stem Cell Corporation, Intrace, IQVIA, Jazz Pharmaceuticals, Kaiser, Kashiv Pharma, KeiferRX LLC, KeyQuest, KX Advisors, Kyowa Kirin Pharmaceuticals, L.E.K. Consulting, Lundbeck A/S, Medscape, MediTech, Michael J. Fox Foundation, Movement Disorder Society, MPTA, NeuroChallenge Foundation for PD, Neurocrine Biosciences Inc, Neuroderm, NOVUS, Orion, Parkinson's Foundation, Parkinson's Study group, Penn Technology Partnership, Pennside Partners, Perception OpCo (CEREVEL Therapeutics LLC), Prescott Medical Group, Regenera Pharma, ROCHE (F. Hoffmann Ltd), Schlesinger Associates, Scion Neurostim LLC, Seelos Therapeutics, Slingshot Insights, Sunovion Pharmaceuticals Inc, TEVA Pharmaceuticals, The Lockwood Group, Tolmar Inc, and US WorldMeds. Dr Hauser participated in company-sponsored speakers bureaus for Acorda Therapeutics, Adamas Pharmaceuticals, Amneal Pharmaceuticals Inc, Kyowa Kirin Pharmaceutical Development, Neurocrine Biosciences, and US WorldMeds. Dr Hauser has received research support from AbbVie Inc, Acorda Therapeutics, AstraZeneca, Axovant Sciences, Biogen Inc, Cavion, Centogene, Cerevance, Cerevel, Covance, Enterin Inc, Global Kinetics Corp, Impax Laboratories LLC, Intec Pharma Ltd, Jazz Pharmaceuticals, NeuroDerm Ltd, Lundbeck, Michael J Fox Foundation for Parkinson's Research, Neuraly, Pharma2B, F. Hoffman-La Roche, Revance Therapeutics Inc, Sanofi-Genzyme, and Sunovion Pharmaceuticals. Dr Hauser received grant support from the Parkinson's Foundation. Dr Hauser has stock option ownership in Axial Biotherapeutics and Inhibikase Therapeutics Inc. P.A.L. has served as a consultant or advisor for Acorda Therapeutics, Amneal, Appello, Axovant Biosciences, Biogen, Cavion, Denali Therapeutics, F. Hoffmann-La Roche, Impel Neuropharma, Intec, Ipsen, Kyowa Kirin Hakko, Lundbeck A/S, Merck, Merz, Mitsubishi Tanabe Neuropharma, Neurocrine Biosciences, NeuroDerm Ltd, Noven, Parkinson Study Group, Prexton Therapeutics, Revance Therapeutics, Saccadous, Supernus, and US WorldMeds, and has received speaker honoraria from Acorda Therapeutics, Britannia, the American Academy of Neurology, The International Parkinson's Disease and Movement Disorders Society, Kyowa Kirin Hakko, Neurocrine Biosciences, Pallidan Labs, US WorldMeds, and the World Parkinson Congress. He is compensated for services as editor in chief of Clinical Neuropharmacology and serves without compensation on the editorial boards of the Journal of Neural Transmission , Translational Neurodegeneration , and the Journal of Parkinson's Disease . His employers have received clinical research grant support from Acorda Therapeutics, Amneal, Aptinyx, Biotie, Bukwang, Cerevel, Denali Therapeutics, Impax Labs, The Michael J. Fox Foundation for Parkinson's Research, Pharma 2B, F. Hoffmann-La Roche, Revance, Sunovion, Sun Pharma, and Supernus. C.H.W. has received research support from Neuraly, Sanofi, Biogen, and Roche; consulting fees from Acadia, Kyowa, and Sunovion; and honoraria for speaking engagements from Adamas, Amneal, Kyowa, and Neurocrine. D.G.G. has received grant funding from Parkinson's UK; compensation for consulting services to Acorda Therapeutics and the Glasgow Memory clinic; and honoraria from Bial, UCB Pharma, and GE Healthcare. B.B. is an employee of and owns stock in Acorda Therapeutics, Inc., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Reliable and sensitive biomarkers are needed for enhancing and predicting Parkinson's disease (PD) diagnosis., Objective: To investigate comprehensive metabolomic profiling of biochemicals in CSF and serum for determining diagnostic biomarkers of PD., Methods: Fifty subjects, symptomatic with PD for ≥5 years, were matched to 50 healthy controls (HCs). We used ultrahigh-performance liquid chromatography linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring relative concentrations of ≤1.5 kDalton biochemicals. A reference library created from authentic standards facilitated chemical identifications. Analytes underwent univariate analysis for PD association, with false discovery rate-adjusted p-value (≤0.05) determinations. Multivariate analysis (for identifying a panel of biochemicals discriminating PD from HCs) used several biostatistical methods, including logistic LASSO regression., Results: Comparing PD and HCs, strong differentiation was achieved from CSF but not serum specimens. With univariate analysis, 21 CSF compounds exhibited significant differential concentrations. Logistic LASSO regression led to selection of 23 biochemicals (11 shared with those determined by the univariate analysis). The selected compounds, as a group, distinguished PD from HCs, with Area-Under-the-Receiver-Operating-Characteristic (ROC) curve of 0.897. With optimal cutoff, logistic LASSO achieved 100% sensitivity and 96% specificity (and positive and negative predictive values of 96% and 100%). Ten-fold cross-validation gave 84% sensitivity and 82% specificity (and 82% positive and 84% negative predictive values). From the logistic LASSO-chosen regression model, 2 polyamine metabolites (N-acetylcadaverine and N-acetylputrescine) were chosen and had the highest fold-changes in comparing PD to HCs. Another chosen biochemical, acisoga (N-(3-acetamidopropyl)pyrrolidine-2-one), also is a polyamine metabolism derivative., Conclusions: UHPLC-MS/MS assays provided a metabolomic signature highly predictive of PD. These findings provide further evidence for involvement of polyamine pathways in the neurodegeneration of PD., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest pertinent to this research report., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

MRI has been used to develop biomarkers for movement disorders such as Parkinson disease (PD) and other neurodegenerative disorders with parkinsonism such as progressive supranuclear palsy and multiple system atrophy. One of these imaging biomarkers is neuromelanin (NM), whose integrity can be assessed from its contrast and volume. NM is found mainly in certain brain stem structures, namely, the substantia nigra pars compacta (SNpc), the ventral tegmental area, and the locus coeruleus. Another major biomarker is brain iron, which often increases in concert with NM degeneration. These biomarkers have the potential to improve diagnostic certainty in differentiating between PD and other neurodegenerative disorders similar to PD, as well as provide a better understanding of pathophysiology. Mapping NM in vivo has clinical importance for gauging the premotor phase of PD when there is a greater than 50% loss of dopaminergic SNpc melanized neurons. As a metal ion chelator, NM can absorb iron. When NM is released from neurons, it deposits iron into the intracellular tissues of the SNpc; the result is iron that can be imaged and measured using quantitative susceptibility mapping. An increase of iron also leads to the disappearance of the nigrosome-1 sign, another neuroimage biomarker for PD. Therefore, mapping NM and iron changes in the SNpc are a practical means for improving early diagnosis of PD and in monitoring disease progression. In this review, we discuss the functions and location of NM, how NM-MRI is performed, the automatic mapping of NM and iron content, how NM-related imaging biomarkers can be used to enhance PD diagnosis and differentiate it from other neurodegenerative disorders, and potential advances in NM imaging methods. With major advances currently evolving for rapid imaging and artificial intelligence, NM-related biomarkers are likely to have increasingly important roles for enhancing diagnostic capabilities in PD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Patients with Parkinson's disease often suffer from OFF symptoms disrupting their daily routines and adding to disabilities. Despite polypharmacy and adjustments to medication schedules, they often do not experience consistent relief from their motor symptoms. As the disease progresses, impaired gastric emptying may evolve, making it even more challenging for dopaminergic drugs to provide consistent results. This review focuses on a group of drugs that have the pharmacokinetic advantage of a much earlier onset of action by virtue of their non-oral routes of absorption. We compare the current marketed options: subcutaneous apomorphine, sublingual apomorphine, and inhaled levodopa. Subcutaneous apomorphine is the speediest to take effect, whereas sublingual apomorphine offers the longest clinical effect. Inhaled levodopa has the most favorable side effect profile among the three options. An inhaled form of apomorphine is currently under development, having passed safety and efficacy studies. Each of these drugs has unique characteristics for the user, including different side effect profiles and onset of action. The best choice for a patient will depend on individual needs and circumstances. In this review, we explore those nuances to allow clinicians to select the best option for their patients.

Background: While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery. ND0612 is in development as a combination product providing continuous levodopa/carbidopa via a minimally invasive, subcutaneous delivery system for PD patients experiencing motor response fluctuations. We present pharmacokinetic results from a series of studies that analyzed plasma concentrations after SC levodopa delivery with ND0612 to inform the clinical development program., Methods: We performed a series of six Phase I and II studies to characterize the pharmacokinetics of levodopa and carbidopa derived from ND0612 infusion with/without adjunct oral therapy of the same ingredients. These studies were conducted in healthy volunteers and in PD patients experiencing motor response fluctuations while on their current levodopa therapy regimen., Results: Taken together, the results demonstrate dose-proportionality dependent on rate of subcutaneous levodopa infusion leading to stable and sustained plasma concentrations of levodopa. Subcutaneous infusion of ND0612 administered with oral levodopa/carbidopa maintained near-constant, therapeutic levodopa plasma concentrations, thereby avoiding the troughs in levodopa plasma concentrations that are associated with OFF time in PD. The data generated in this series of studies also confirmed that a levodopa/carbidopa dose ratio of 8:1 would be the most reasonable choice for ND0612 development., Conclusions: This series of clinical pharmacokinetic studies have demonstrated that ND0612, administered continuously with a levodopa concentration of 60 mg/ml combined with carbidopa 7.5 mg/ml, and complemented with oral levodopa/carbidopa, is suitable for 24 h continuous administration in patients with PD. The stable plasma concentrations of levodopa achieved predict utility of ND0612 as a parenteral formulation for achieving clinically useful delivery of levodopa for PD patients., Competing Interests: Author PL reports advisory roles for Abide, Acorda Therapeutics, Adamas, Biogen, Cavion, Denali, Intec Pharma, Jazz Pharmaceuticals, Lundbeck, Neurocrine, Mitsubishi NeuroDerm Ltd., Prexton, Revance, Sage, and US WorldMeds; lecture fees from US WorldMeds, Acorda, American Academy of Neurology, and Kyowa Hakko Kirin. Research grant support from Abide, Acorda, Amneal, Lundbeck, Michael J. Fox Foundation for Parkinson's Research, Mitsubishi NeuroDerm Ltd., Parkinson Study Group; National Institute of Neurological Disorders and Stroke, Pharma 2B, Revance, Hoffmann-La Roche; Sunovion, and Sun Pharma. Author FS reports honoraria and consulting fees from Britannia Pharmaceuticals, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Orion, NeuroDerm, Novartis, Teva, Pfizer and Zambon. Authors YC and IP report consultancy for NeuroDerm. Authors LA and RC are employed by NeuroDerm. Author NG serves as consultant to Sionara, NeuroDerm, Pharma2B, Denali, Neuron23 and Abbvie, Sanofi-Genzyme and Biogen. He receives royalties from Lysosomal Therapeutics (LTI) and payment for lectures at Abbvie, Sanofi-Genzyme and Movement Disorder Society. He received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the European Union and the Israel Science Foundation as well as from Teva NNE program, Biogen and Ionis. He receives support from the Sieratzki Family Foundation and the Aufzien Academic Center in Tel-Aviv University. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 LeWitt, Stocchi, Arkadir, Caraco, Adar, Perlstein, Case and Giladi.)

Introduction : The most widely used pharmacological treatment for Parkinson's disease is levodopa, the precursor for dopamine formation in the brain. Over time, the effectiveness of levodopa declines, and patients experience motor fluctuations, or OFF periods. A levodopa formulation administered via a capsule-based oral inhaler provides a new delivery mechanism for levodopa that provides rapid relief of OFF periods. Areas covered : CVT-301 is a dry powder formulation designed to supply levodopa to the systemic circulation via pulmonary absorption. The technology, pharmacokinetics, efficacy, and safety data of this formulation are presented. Expert opinion : Oral inhalation is a novel method of administration for levodopa that bypasses the gastrointestinal tract, allowing levodopa to enter the systemic circulation rapidly and more reliably than oral medications. Gastrointestinal dysfunction, a common feature of Parkinson's disease, can lead to impaired absorption of oral medications. Pulmonary delivery rapidly elevates levodopa plasma concentrations to provide relief of OFF periods for patients receiving oral levodopa.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data., Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression., Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019., Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years., Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity., Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years)., Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD., Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but a major treatment challenge is that over time, many patients experience periods of return of PD symptoms intermittently through the day, known as OFF periods. OFF periods typically manifest as a return of motor symptoms but can also involve non-motor symptoms and these periods can disrupt good control despite optimization of the oral levodopa regimen. OFF periods emerge in large measure due to a shortening of the duration of clinical benefit from oral levodopa, thought to be related to a progressive loss of dopamine neurons and their ability to store and release levodopa-derived dopamine over many hours. The problem is further compounded by impaired absorption of oral levodopa due to gastroparesis and other factors limiting its uptake in the small intestine, including competition for uptake by meals and their protein content. On-demand therapies are now available for the treatment of OFF episodes in PD and are administered intermittently, on an as-needed basis, on top of the patient's maintenance medication regimen. To be useful, an on-demand medication should take effect more rapidly and reliably than oral levodopa. Options for on-demand therapy for OFF periods have recently increased with the approval of levodopa inhalation powder and sublingual apomorphine as alternatives to the older option of subcutaneous apomorphine injection, each of which avoids the gastrointestinal tract and its potential for absorption delay. On-demand therapy is now available for patients experiencing episodic or intermittent need for rapid and reliable onset of benefit. On-demand therapy may also provide an alternative to more invasive treatment such as infusion of levodopa/carbidopa intestinal gel and for patients whose OFF episodes are not controlled despite deep brain stimulation.

Background: Hypokinetic dysarthria and dysphagia are known features of Parkinson's disease; however, self-perception of their handicapping effects on emotional, physical, and functional aspects of quality of life over disease duration is less understood., Objective: 1) Based upon patient self-perception, to determine the relationship of the handicapping effects of dysphagia and dysphonia with time since diagnosis in individuals with Parkinson's disease; 2)To determine if there is a relationship between voice and swallowing handicap throughout the course of Parkinson's disease., Method: 277 subjects completed the Dysphagia Handicap Index and the Voice Handicap Index. Subjects were divided into three groups based on disease duration: 0-4 years, 5-9 years, and 10 + years., Results: Subjects in the longer duration group identified significantly greater perceptions of voice and swallowing handicap compared to the shorter duration groups. There was a significant positive correlation between the DHI and VHI., Conclusion: Self-perception of swallowing and voice handicap in Parkinson's disease are associated with later stages of disease and progress in a linear fashion. Self-perception of voice and swallowing handicap parallel each other throughout disease progression in Parkinson's disease. Individuals may be able to compensate for changes in voice and swallowing early while sensory perceptual feedback is intact. Results support early targeted questioning of patient self-perception of voice and swallowing handicap as identification of one problem indicates awareness of the other, thus creating an opportunity for early treatment and maintenance of swallowing and communication quality of life for as long as possible.

Introduction: CVT-301 (Inbrija®) is a levodopa inhalation powder for on-demand treatment of OFF episodes in Parkinson's disease patients treated with carbidopa/levodopa. Safety and efficacy results of a 12-month, dose-level blinded extension study of a phase 3 trial (SPAN℠-PD) of CVT-301 are presented., Methods: Patients were receiving oral carbidopa/levodopa and adjunctive CVT-301 treatment, blinded to dose (60 mg or 84 mg, N = 325). Study visits occurred every 3 months. Pulmonary function was assessed by spirometry. Other safety assessments included dyskinesia and adverse events (AEs). Secondary objectives of the study included maintenance of improvement assessments for occurrence of an ON state during the 60-min post-dose period, change in total daily OFF time, and Patient Global Impression of Change (PGIC)., Results: Most frequent AEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%). Severe AEs (>1 event) were cough (1.9%) and dyskinesia (0.6%). Twelve-month mean changes from baseline for FEV 1 , FVC, and DL CO were -0.092 L, -0.097 L, and -0.922 mL/min/mmHg, respectively. At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the 84 mg dose. Percentage of patients self-reported as improved by PGIC was 65.5-91.9% over 12 months., Conclusion: CVT-301 was generally well-tolerated. Twelve-month decline in pulmonary function was consistent with a prior PD control group. Exploratory efficacy results showed CVT-301 maintained improvement at achieving ON states in patients experiencing OFF episodes, decreasing daily OFF time, and maintaining improvement in PGIC., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Compared to other neurodegenerative diseases, Parkinson's disease (PD) is distinctive in terms of marked symptomatic variability and prognosis, as well as for the wide variety of symptomatic treatment options. Despite several decades of advances in medications and neurosurgical approaches, there remains an unmet need for symptomatic motor control. Better control of tremor, gait and balance, posture, dexterity, and communication skills are major challenges for better therapeutics of the PD movement disorder. Non-motor symptoms (NMS), which often precede motor impairments, add complexity to the burden of PD and its management. Recognized by James Parkinson MD two centuries ago, and despite 21st century neurological advances, a range of NMS plague the patient's journey, from prodromal to palliative stages. Characterizing the clinical phenotype of the entire non-motor profile of PD is challenging. Further research and understanding are needed for discovering biomarkers of certain NMS, such as dementia, fatigue, pain, sleep, and apathy. More work is needed to gather a robust evidence base for guiding treatment of troubling NMS, which exert a major impact on quality of life for people with PD and their caregivers., (Copyright © 2020. Published by Elsevier Ltd.)

Laboratory and clinical experience have pointed to the value of targeting motor pathways emerging from the striatum to treat problems arising in advanced Parkinson's disease (PD). These pathways are selectively populated with a subtype of adenosine binding sites (A 2A receptors) that offer a target for improving PD symptomatology. Several compounds were developed that possess high selectivity and potency for blocking this receptor. Three of these compounds - istradefylline, preladenant, and tozadenant - were chosen for clinical development programs that culminated in Phase 3 multicenter randomized clinical trials. Each of these drugs exert virtually no off-target neurochemical effects. Clinical trials with these drugs focused upon reducing OFF time when administered adjunctly to levodopa and other antiparkinsonian medications. Despite promising Phase 2 data, preladenant did not show efficacy when tested in a randomized placebo-controlled Phase 3 clinical trial. Reports of hematological toxicity necessitated ceasing an ongoing Phase 3 investigation of tozadenant. Following a challenging approval process, based on the results of randomized clinical trials carried out in the U.S. and Japan, istradefylline received approval in these countries for treatment of OFF episodes., (Copyright © 2020. Published by Elsevier Ltd.)

Parkinson disease (PD) is often associated with postural instability and gait dysfunction that can increase the risk for falls and associated consequences, including injuries, increased burden on healthcare resources, and reduced quality of life. Patients with PD have nearly twice the risk for falls and associated bone fractures compared with their general population counterparts of similar age. Although the cause of falls in patients with PD may be multifactorial, an often under-recognized factor is neurogenic orthostatic hypotension (nOH). nOH is a sustained decrease in blood pressure upon standing whose symptomology can include dizziness/lightheadedness, weakness, fatigue, and syncope. nOH is due to dysfunction of the autonomic nervous system compensatory response to standing and is a consequence of the neurodegenerative processes of PD. The symptoms associated with orthostatic hypotension (OH)/nOH can increase the risk of falls, and healthcare professionals may not be aware of the real-world clinical effect of nOH, the need for routine screening, or the value of early diagnosis of nOH when treating elderly patients with PD. nOH is easily missed and, importantly, healthcare providers may not realize that there are effective treatments for nOH symptoms that could help lessen the fall risk resulting from the condition. This review discusses the burden of, and key risk factors for, falls among patients with PD, with a focus on practical approaches for the recognition, assessment, and successful management of OH/nOH. In addition, insights are provided as to how fall patterns can suggest fall etiology, thereby influencing the choice of intervention., Competing Interests: Conflict of Interests Robert A. Hauser has consulted for Acadia Pharmaceuticals, Acorda Therapeutics, Adamas Pharmaceuticals, AlphaSights, Amneal Pharmaceuticals, Inc., ApoPharma Inc., Aptis Partners LLC, Clinical SCORE LLC., CNS Ratings LLC, Compass Group, Decision Resource Group, Dedham Group, Defined Health, Enterin Inc., Ernest and Young S.L., Extera Partners LLC., Gerson Lehman Group Inc., Global Kinetics Corporation, Guidepoint Global, Health Advances, Impax Lab, Impel Neuropharma, IntraMed Educational Group, IQVIA, International Stem Cell Corporation, Jazz Pharmaceuticals, Kashiv Pharma, L.E.K Consulting, Lundbeck A/S, Lundbeck LLC, Med IQ, Medscape, Mitsubishi Tanabe Pharma America, Michael J. Fox Foundation, Morgan, Lewi, and Bockius LLP, Neuro Challenge Foundation for Parkinson's, Neurocrea LLC, Neurocrine Biosciences Inc, Neurocrine Continental, Inc., Northwestern University, Orbees Inc., Orion, Parkinson's Foundation, Partners Healthcare, Penn Technology Partnership, Perception OpCo, Prescott Medical Communications Group, Prilenia Therapeutics LLC, Parkinson’s Study Group, Regenera Pharma, Scion Neurostim LLC, Seelos Therapeutics, Slingshot Insights, Sunovion Pharmaceuticals Inc., Teva Pharmaceuticals, US World Meds, and WebMD. He has received research support from AbbVie Inc., Acorda Therapeutics, AstraZeneca, Axovant Sciences, Biogen Inc., Cavion, Enterin Inc., Impax Laboratories LLC, Intec Pharma Ltd, Jazz Pharmaceuticals, NeuroDerm Ltd., Lundbeck, Michael J. Fox Foundation for Parkinson’s Research, F. Hoffman-La Roche, Dart NeuroScience LLC, Prexton Therapeutics, Revance Therapeutics Inc., and Sunovion Pharmaceuticals, and grant support from the Parkinson’s Foundation. Steve Kymes is employed by Lundbeck and owns stock in Lundbeck. Peter A. LeWitt has served as a consultant and has been an investigator in clinical trials sponsored by Impax Laboratories Inc. He has also served as a consultant or advisor for Acorda, Britannia, Concit, Dexcel, Depomed, Insightec, Intec, Ipsen, Merck, Merz, NeuroDerm, Noven, Parkinson Study Group, Pfizer, ProStrakan, Teva, and US WorldMeds and has received speaker honoraria from the International Parkinson's Disease and Movement Disorders Society, Lundbeck, US WorldMeds, and the World Parkinson Congress. He is compensated for services as editor in chief of Clinical Neuropharmacology and serves without compensation on the editorial boards of Journal of Neural Transmission, Translational Neurodegeneration, and Journal of Parkinson's Disease. The Parkinson's Disease and Movement Disorders Program, which he directs, has received clinical research grant support (for conducting clinical trial and other research) from Acorda, Adamas, Biotie, Great Lakes Neurotechnologies, Kyowa, Michael J. Fox Foundation for Parkinson's Research, Pharma 2B, and US WorldMeds., (Copyright: © 2019 LeWitt et al.)

The expanding landscape of options for Parkinson's disease (PD) therapeutics calls for novel ways to improve delivery of treatments to counteract neurodegeneration or enhance symptomatic control. This unmet need is particularly relevant for opportunities in gene therapy, which, in recent PD clinical trials, has required invasive neurosurgical approaches into the CNS. One of the promising techniques to bring new therapies into the brain for PD therapeutics involves an evolving technology, focused ultrasound. Focused ultrasound has been used to alleviate tremor by thermal ablation with high-energy sonication. Using similar equipment but much lower sonication energy, focused ultrasound assisted with micro-bubbles can temporarily open the blood-brain barrier at specific brain targets to facilitate real-time magnetic resonance-guided delivery of therapeutic agents. To explore the current status and future of focused ultrasound in transvascular therapeutics for PD, a November 2018 workshop reviewed its accomplishments and challenges. This report summarizes key points of discussion and provides further background to the promising roles focused ultrasound offers. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Introduction: Dopamine replacement via levodopa (LD) remains the most effective treatment for Parkinson's disease (PD), yet its use is often associated with motor complications within several years of continued use. The Accordion Pill ® (AP-CD/LD) is a novel drug delivery system based on gastric retention of multilayer films containing immediate-release (IR) carbidopa (CD) and immediate- and controlled-release LD. The AP-CD/LD was designed to improve the consistency of LD in the bloodstream while offering patients with PD more consistent symptom management., Methods: This phase 2, multicenter, open-label, two-way randomized crossover study included 4 cohorts of participants with PD, each receiving AP-CD/LD (50/250 mg, 50/375 mg or 50/500 mg) twice daily in one treatment period and an active comparator in the other treatment period. Pharmacokinetics (PK) and efficacy were evaluated for AP-CD/LD vs IR-CD/LD. Treatment-emergent adverse events (TEAEs) and patient- and investigator-reported measures were also evaluated., Results: Compared with IR-CD/LD, treatment with either AP-CD/LD dose resulted in more stable LD plasma concentrations in both fluctuating and non-fluctuating PD patients, and significantly decreased C max (57.1% and 66.8% decreases among fluctuating and non-fluctuating patients, respectively). Both AP doses significantly improved standard measures of motor symptoms: (daily OFF time, total ON time, and good ON time), as well as patient- and investigator-assessed measures, versus IR-CD/LD. The safety and tolerability profile of AP-CD/LD was consistent with the known properties of IR-CD/LD., Conclusions: AP technology demonstrated effective controlled-release PK performance and reduced motor response fluctuations in advanced PD patients. A phase 3 randomized controlled trial is currently underway., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Although commercially available levodopa (LD) formulations include carbidopa (CD) or benserazide for gastrointestinal L-aromatic amino acid decarboxylase inhibition, little is known how manipulating CD delivery affects the pharmacokinetics of LD. Our research systematically evaluated the peripheral and central pharmacokinetics of LD during continuous subcutaneous CD delivery., Methods: We conducted pharmacokinetic experiments in pigs, mice, and humans to characterize effects of continuous subcutaneous CD delivery co-administered with LD as compared with oral LD/CD administration on LD pharmacokinetics. The porcine and human studies compared peripheral LD pharmacokinetic parameters (area under the curves [AUCs], peak plasma concentrations [Cmax], and plasma elimination half-life [t1/2]) and the mouse studies compared brain LD and dopamine concentrations., Results: In the pig, supplementary subcutaneous CD delivery significantly increased the LD t1/2 and AUC versus LD/CD alone and versus additional oral CD administration. In mice, administration of supplementary subcutaneous CD substantially increased mean plasma concentrations of both LD and CD versus oral LD/CD alone at all time points. These increases were mirrored by increased brain dopamine levels for at least the 7 hours of study. In healthy human subjects, continuous subcutaneous CD administration, 3.33 mg/h x24h, increased the plasma LD t1/2, Cmax, and AUC by 17.4%, 40.5%, and 22.3%, respectively (P < 0.003)., Conclusions: This series of studies demonstrates that small continuous dosing of subcutaneous CD has an unexpected effect on LD pharmacokinetics greater than the extent of decarboxylase inhibition achieved by additional oral CD administration.

Background: Patients with Parkinson's disease chronically treated with levodopa commonly have delayed or unpredictable onset of its benefits after oral intake. In this study, we assessed the safety and efficacy of CVT-301, a self-administered levodopa oral inhalation powder, for the treatment of patients with Parkinson's disease during off periods., Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, patients were recruited at 65 sites in Canada, Poland, Spain, and the USA. Eligible participants were patients with Parkinson's disease aged 30-85 years, who had daily off periods of 2 h or longer and showed an improvement of 25% or greater in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score from off to on state after use of an oral levodopa plus a dopa-decarboxylase inhibitor combination. Patients were assigned (1:1:1) with a computer-generated randomisation code, in fixed blocks of six, to either CVT-301 60 mg, CVT-301 84 mg, or placebo. Spirometry results and modified Hoehn and Yahr disease stage at screening were used for stratification of treatment groups. Patients, the sponsor, and site personnel were masked to treatment assignment. Each study dose consisted of two capsules administered with an inhaler. Patients were instructed to use the study drug as needed for off periods, and could self-administer up to five doses per day. The primary endpoint was the change in UPDRS motor score from predose to 30 min postdose, assessed at week 12 during an in-clinic off period, in the CVT-301 84 mg group compared with the placebo group. Analysis was by intention to treat. Safety was assessed in all patients who received at least one dose of experimental treatment. This trial is registered with ClinicalTrials.gov, number NCT02240030., Findings: Between Dec 4, 2014, and Aug 26, 2016, 351 patients were enrolled and randomly assigned to receive CVT-301 60 mg (115 patients), CVT-301 84 mg (120 patients), or placebo (116 patients). Of these, 339 received the assigned study treatment (CVT-301 60 mg, n=113; CVT-301 84 mg, n=114; placebo, n=112) and 290 completed the study (CVT-301 60 mg, n=96; CVT-301 84 mg, n=97; placebo, n=97). The least-squares mean difference in UPDRS motor score change from predose to 30 min postdose was -5·91 (SE 1·50, 95% CI -8·86 to -2·96) for the placebo group and -9·83 (1·51; -12·79 to -6·87) for the CVT-301 84 mg group (between-group difference -3·92 [-6·84 to -1·00]; p=0·0088). Treatments were safe and well tolerated. Severe adverse events were reported by 2 (2%) of 112 patients in the placebo group, 7 (6%) of 113 in the CVT-301 60 mg group, and 5 (4%) of 114 in the CVT-301 84 mg group, with no severe adverse event occurring in more than one patient in any treatment group. 11 (3%) of 339 patients had 19 serious adverse events (three [3%] of 112 patients in placebo, six [5%] of 113 in CVT-301 60 mg, and two [2%] of 114 in CVT-301 84 mg). Of these, hypotension and atrial fibrillation were assessed by investigators to be possibly related to the study drug., Interpretation: CVT-301 can improve UPDRS motor scores of patients with Parkinson's disease during in-clinic off periods, with few severe or serious adverse events. The long-term safety and efficacy of CVT-301 need to be investigated in future studies., Funding: Acorda Therapeutics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)