Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The authors confirm that the data supporting the findings of this study are available within the cited references and the supplementary materials.
References
Acorda Therapeutics (2018) Inbrija® (levodopa inhalation powder): US prescribing information. 2018. https://www.inbrija.com/. Accessed 4 Apr 2020.
Chou KL, Stacy M, Simuni T, Miyasaki J, Oertel WH, Sethi K, Fernandez HH, Stocchi F (2018) The spectrum of “off” in Parkinson’s disease: What have we learned over 40 years? Parkinsonism Relat Disord 51:9–16. https://doi.org/10.1016/j.parkreldis.2018.02.001
Dewey RB, Hutton JT, LeWitt PA, Factor SA (2001) A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol 58:1385–1392. https://doi.org/10.1001/archneur.58.9.1385
Edwards DA, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew ML, Mintzes J, Deaver D, Lotan N, Langer R (1997) Large porous particles for pulmonary drug delivery. Science 276(5320):1868–1871. https://doi.org/10.1126/science.276.5320.1868
European Medicines Agency (2019) Inbrija® (levodopa inhalation powder): EU summary of product characteristics. 2019. https ://www.ema.europa.eu/. Accessed 18 Jan 2022.
Farbman ES, Waters CH, LeWitt PA, Rudzińska M, Klingler M, Lee A, Qian J, Oh C, Hauser RA (2020) A 12-month, dose-level blinded safety and efficacy study of levodopa inhalation powder (CVT-301, Inbrija) in patients with Parkinson’s disease. Parkinsonism Relat Disord 81:144–150. https://doi.org/10.1016/j.parkreldis.2020.10.029
Glenardi G, Handayani T, Barus J, Mangkuliguna G (2022) Inhaled levodopa (CVT-301) for the treatment of Parkinson disease: a systematic review and meta-analysis of randomized controlled trials. Neurol Clin Pract 12:139–148. https://doi.org/10.1212/CPJ.0000000000001143
Grosset DG, Dhall R, Gurevich T, Kassubek J, Poewe WH, Rascol O, Rudzinska M, Cormier J, Sedkov A, Oh C (2020) Inhaled levodopa in Parkinson’s disease patients with OFF periods: a randomized 12-month pulmonary safety study. Parkinsonism Relat Disord 71:4–10. https://doi.org/10.1016/j.parkreldis.2019.12.012
Gupta HV, Lyons KE, Pahwa R (2019) Old drugs, new delivery systems in Parkinson’s disease. Drugs Aging 36:807–821. https://doi.org/10.1007/s40266-019-00682-9
Hauser RA (2009) Levodopa: past, present, and future. Eur Neurol 62:1–8. https://doi.org/10.1159/000215875
Hauser RA, Isaacson SH, Ellenbogen A, Safirstein BE, Truong DD, Komjathy SF, Kegler-Ebo DM, Zhao P, Oh C (2019) Orally inhaled levodopa (CVT-301) for early morning OFF periods in Parkinson’s disease. Parkinsonism Relat Disord 64:175–180. https://doi.org/10.1016/j.parkreldis.2019.03.026
Hauser RA, LeWitt PA, Comella CL (2021) On demand therapy for Parkinson’s disease patients: opportunities and choices. Postgrad Med 133:721–727. https://doi.org/10.1080/00325481.2021.1936087
Healy AM, Amaro MI, Paluch KJ, Tajber L (2014) Dry powders for oral inhalation free of lactose carrier particles. Adv Drug Deliv Rev 75:32–52. https://doi.org/10.1016/j.addr.2014.04.005
Inbrija (levodopa inhalation powder) (2020) Prescribing information. Acorda Therapeutics Inc; 2020. https://www.inbrija.com/prescribing-information.pd. Accessed 30 Sep 2020
Isaacson SH, Pagan FL, Lew MF, Pahwa R (2022) Should “on-demand” treatments for Parkinson’s disease OFF episodes be used earlier? Clin Park Relat Disord 7:100161. https://doi.org/10.1016/j.prdoa.2022.100161
LeWitt PA, Hauser RA, Grosset DG, Stocchi F, Saint-Hilaire MH, Ellenbogen A, Leinonen M, Hampson NB, DeFeo-Fraulini T, Freed MI, Kieburtz KD (2016) A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord 31:1356–3165. https://doi.org/10.1002/mds.26611
LeWitt PA, Pahwa R, Sedkov A, Corbin A, Batycky R, Murck H (2018) Pulmonary safety and tolerability of inhaled levodopa (CVT-301) administered to patients with Parkinson’s disease. J Aerosol Med Pulm Drug Deliv 31:155–161. https://doi.org/10.1089/jamp.2016.1354
LeWitt PA, Hauser RA, Pahwa R, Isaacson SH, Fernandez HH, Lew M, Saint-Hilaire M, Pourcher E, Lopez-Manzanares L, Waters C, Rudzínska M, Sedkov A, Batycky R, Oh C, SPAN-PD Study Investigators (2019) Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol 18:145–154. https://doi.org/10.1016/S1474-4422(18)30405-8
Lipp MM, Batycky R, Moore J, Leinonen M, Freed MI (2016) Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson’s disease. Sci Transl Med 8:360ra136. https://doi.org/10.1126/scitranslmed.aad8858
Lipp MM, Hickey AJ, Langer R, LeWitt PA (2021) A technology evaluation of CVT-301 (Inbrija): an inhalable therapy for treatment of Parkinson’s disease. Expert Opin Drug Deliv 18:1559–1569. https://doi.org/10.1080/17425247.2021.1960820
Olanow CW, Stocchi F (2018) Levodopa: a new look at an old friend. Mov Disord 33:859–866. https://doi.org/10.1002/mds.27216
Olanow CW, Factor SA, Espay AJ, Hauser RA, Shill HA, Isaacson S, Pahwa R, Leinonen M, Bhargava P, Sciarappa K, Navia B, Blum D, CTH-300 study investigators (2019) Apomorphine sublingual film for off episodes in Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 study. Lancet Neurol 19:135–144. https://doi.org/10.1016/S1474-4422(19)30396-5
Olanow CW, Poewe W, Rascol O, Stocchi F (2021) On-demand therapy for OFF episodes in Parkinson’s disease. Mov Disord 36:2244–2253. https://doi.org/10.1002/mds.28726
Poewe W, Espay AJ (2020) Long duration response in Parkinson’s disease: levodopa revisited. Brain 143:2332–2335. https://doi.org/10.1093/brain/awaa226
Safirstein BE, Ellenbogan A, Zhao P, Henney HR, Kegler-Ebo DM, Oh C (2020) Pharmacokinetics of inhaled levodopa administered with oral carbidopa in the fed state in patient with Parkinson’s disease. Clin Ther 42:1034–1046
Santos-García D, de Deus FT, Bartolomé CC, Painceiras MJF, Castro ES, Canfield H, Miró CM, Jesús S, Aguilar M, Pastor P, Planellas L, Cosgaya M, Caldentey JG, Caballol N, Legarda I, Hernández-Vara J, Cabo I, Manzanares LL, Aramburu IG, Rivera MAÁ, Mayordomo VG, Nogueira V, Puente V, García-Soto JD, Borrué C, Vila BS, Sauco MÁ, Vela L, Escalante S, Cubo E, Padilla FC, Castrillo JCM, Alonso PS, Losada MGA, Ariztegui NL, Gastón I, Kulisevsky J, Estrada MB, Seijo M, Martínez JR, Valero C, Kurtis M, de Fábregues O, Ardura JG, Redondo RA, Ordás C, Díaz LML, McAfee D, Martinez-Martin P, Mir P, Coppadis Study Group (2022) Motor fluctuations development is associated with non-motor symptoms burden progression in Parkinson’s disease patients: a 2-year follow-up study. Diagnostics (basel) 12:1147. https://doi.org/10.3390/diagnostics12051147
Schwab RS, Amador LV, Lettvin JY (1951) Apomorphine in Parkinson’s disease. Trans Am Neurol Assoc 56:251–253
Shpiner DS, Bette S, Di Luca DG (2019) Margolesky J (2019) CVT-301 for the treatment of Parkinson’s disease. Expert Rev Neurother 19:603–611. https://doi.org/10.1080/14737175.2019.1621748
Thach A, Jones E, Pappert E, Pike J, Wright J, Gillespie A (2021) Real-world assessment of the impact of “OFF” episodes on health-related quality of life among patients with Parkinson’s disease in the United States. BMC Neurol 21:46. https://doi.org/10.1186/s12883-021-02074-2
Vijiaratnam N, Foltynie T (2020) Therapeutic strategies to treat or prevent Off episodes in adults with Parkinson’s disease. Drugs 80:775–796. https://doi.org/10.1007/s40265-020-01310-2
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Wolfgang H. Jost is or was a consultant and/or speaker for the following companies: Abbvie, Bial, Desitin, Esteve, Stada, UCB, Zambon. Jaime Kulisevsky is or was a consultant and/or speaker for the following companies: Abbvie, Bial, Kyowa Kirin, Stada, UCB, Zambon, AC Immune, SOM Biotech. In the past 2 years, Dr. LeWitt has served as a consultant or advisor for the following pharmaceutical firms: Amneal, Aptinyx, Bukwang, Jazz, Kyowa Kirin, Mitsubishi Tanabe NeuroDerm, Neurorine Biosciences, Scion Neurostim, Sunovion, and Supernus, and received speaker honoraria from Amneal, Kyowa Kirin, Palidan, and Supernus.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jost, W.H., Kulisevsky, J. & LeWitt, P.A. Inhaled levodopa for threatening impending OFF episodes in managing Parkinson’s disease. J Neural Transm 130, 821–826 (2023). https://doi.org/10.1007/s00702-023-02636-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-023-02636-3