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Over the past decade, researchers have developed a greater understanding of the relative contributions of the environment, genetic, and epigenetic influences on the onset and progression of Parkinson’s disease (PD). New strategies have emerged that seek to modulate inflammatory cellular mediators, mitochondrial function, and/or halt the accumulation of synuclein and neuromelanin (1–3).
In August 2024, German-based Centogene NV released new data from the landmark Rostock International Parkinson’s Disease (ROPAD) Consortium Study which aimed to characterize the genetics of PD to better understand disease progression, diagnosis, and treatment for patients (4). The study identified that approximately 15% of 12,580 patients studied harboured genetic variants that present new opportunities for genetic testing and the development of innovative therapies such as cell and gene therapies (CGTs) (5).
Editor’s Note: This article was published in Pharmaceutical Technology Europe’s November/December2024 print issue.
New formulations and novel non-biological drugs
More than 10 million people worldwide are living with PD, and it is now classed as the fastest-growing neurological condition in the world (6,7). Several companies such as NeuroDerm (a Tanabe Pharma company), Cerevel (an AbbVie company), and Swiss-based Contera Pharma A/S are working on non-biological agents with immediate or long-duration action to improve the symptoms of PD (8–10) (Table I). In October 2024, the US Food and Drug Administration (FDA) finally approved AbbVie’s Vyalev (foscarbidopa and foslevodopa), the first 24-hour infusion of levodopa-based therapy for motor fluctuations in adults with advanced PD (11). This single infusion helps reduce the pill burden whereby PD patients may take more than 20 tablets a day to control their symptoms. AbbVie gained approval for the drug, under the trade name Produodopa, from the European Commission (EC) in January 2024 (12). In May 2024, Portuguese BIAL Holding S/A launched a novel sublingual film formulation Kynmobi (apomorphine hydrochloride) in Germany, for the intermittent treatment of off episodes in adult patients with PD who are not sufficiently controlled by oral anti-Parkinson medication (13).
Pharma companies are actively pursuing the development of drugs that target novel pathways involved in the underlying mechanism of PD (Table I). These include BIAL’s BIA 28-6156, a small-molecule activator of glucocerebrosidase (GCase), a lysosomal enzyme involved in the breakdown of glycosphingolipids and UK-based Neurolixis’ NLX-112 (befiradol), a novel 5-HTA1A receptor agonist that has completed a Phase IIa proof-of-concept trial for dyskinesia in PD (14–16).
Table I: Innovative non-biological drugs under clinical development for Parkinson’s disease (PD).
Innovative biological therapies are progressing through trials
Several companies are looking to harness biologics to halt the accumulation of detrimental proteins such as alpha-synuclein (a-syn), which has been implicated in the pathology of PD (Table II). US-based AC Immune is evaluating ACI-7104 in Phase II, a monoclonal antibody (mAb) that has been shown to inhibit the accumulation of a-syn aggregates in preclinical animal models and the brain tissue of PD patients (17). An alternative approach is the use of adeno-associated virus (AVV) vectors to deliver genes that selectively modulate the production of proteins such as glutamic acid decarboxylase (GAD) to increase gamma-aminobutyric acid (GABA) levels, or glial cell line-derived neurotrophic factor (GDNF) to boost dopamine levels. In January 2024, Asklepios BioPharmaceuticals (AskBio, a subsidiary of Bayer AG) released positive data with its AAV2-GDNF showing that the one-time bilateral delivery of AB-1005 gene therapy was well-tolerated, and no serious adverse events (AEs) were observed (18). In October 2024, US-based MeiraGTx Holdings released positive top-line data from its clinical bridging study with MGT-GAD-025, an AAV-GAD, resulted in a significant and clinically meaningful improvement in Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) from baseline to Week 26 in patients with idiopathic PD (IPD) (19).
Table II: Cell and gene therapies under clinical development for the treatment of Parkinson’s disease (PD).
Cell-based therapy is expected to provide an alternative route to treat PD through the surgical injection of autologous induced pluripotent stem cell (iPSC)-derived dopamine neurons into the putamen, the brain region affected in PD. Denmark/China-based iRegene is evaluating chemically induced human dopaminergic neuron precursors derived from iPSCs to treat moderate to severe PD; the company entered clinical development with its gene therapy NouvNeu001 in the second half of 2023 (20). Similarly, Massachusetts-based BlueRock Therapeutics (a subsidiary of Bayer AG) has released promising Phase I follow-up data from its safety trial with its cell-based therapy bemdaneprocel (MSK-DA01) (21). Alternatively, Australia-based Living Cell Technologies (LCT) is developing an alginate-coated capsule containing clusters of neonatal porcine choroid plexus cells that contains a range of factors that support nerve cell functions and protective enzymes that are crucial for nerve growth and healthy functioning in PD patients (22).
Future developments in PD
Since 2019, the number of active clinical trials for PD has remained relatively consistent, with more than 136 trials per year. However, the proportion of disease-modifying to symptomatic therapies has been increasing during the past five years, and the diversity of drug targets across both symptomatic and disease-modifying drugs has also increased. Interestingly, the number of trials investigating drugs aiming to improve non-motor symptoms has expanded and several drugs are now being developed to target inflammation, a key driver of PD progression (23). But despite these significant advances, many drugs still fail to transition from Phase II to Phase III.
National and international organizations and foundations, such as Cure Parkinson’s, the American and European Parkinson’s Disease Association, Michael J. Fox Foundation, National Parkinson’s Foundation, and Parkinson’s UK, have an important role in raising awareness, supporting patients, and funding PD research. Pharma companies including Bayer, Biogen, Genzyme, GlaxoSmithKline, Sanofi, and Pfizer have made multi-million-dollar strategic investment investments, and several life-changing therapies, including CGTs, are steadily progressing through the clinic. If successful, these therapies could help rewire the PD brain circuits and fundamentally change the way patients are treated over the next decade (24).
References
1. Elsworth, J.D. Parkinson’s Disease Treatment: Past, Present, and Future. J Neural Transm (Vienna). 2020 May;127(5):785-791.
2. Pajares. M.; Rojo, A.I.; Manda, G.; Boscá, L.; Cuadrado, A. Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications. Cells. 2020 Jul 14;9(7):1687.
3. Abeliovich, A.; Hefti, F.; Sevigny, J. Gene Therapy for Parkinson‘s Disease Associated with GBA1 Mutations. J Parkinsons Dis. 2021 11(s2): S183-S188.
4. Westenberger, A.; Skrahina, V.; Usnich, T.; et al. Relevance of Genetic Testing in the Gene-targeted Trial Era: The Rostock Parkinson’s Disease study. Brain 2024. 147(8) 2652-2667.
5. Centogene. Introducing the ROPAD Consortium: Unlocking Real-world Genetic Insights to Accelerate Treatment Access for Parkinson’s Disease. Webinar. October 2024.
6. Parkinson’s Foundation. Statistics. parkinson.org (accessed 30 Oct. 2024).
7. BBC News. New Parkinson’s Drug Produodopa to be Available on NHS. 16 Feb. 2024.
8. NeuroDerm Ltd. ND0612 (accessed 30 Oct. 2024).
9. Cerevel Therapeutics. Cerevel Therapeutics Announces Positive Topline Results for Tavapadon in Phase 3 Adjunctive Trial for People Living with Parkinson’s Disease | Cerevel Therapeutics. News Release. 18 Apr. 2024.
10. Contera Pharma A/S. Contera Pharma Reports Topline Results from its Phase IIb Clinical Trial ASTORIA, evaluating JM-010 for the Treatment of Parkinson’s Disease Dyskinesia. News Release. 21 May 2024.
11. AbbVie. U.S. FDA Approves VYALEV (foscarbidopa and foslevodopa) for Adults Living with Advanced Parkinson’s Disease. News Release. 17 Oct. 2024.
12. AbbVie. AbbVie Launches PRODUODOPA (foslevodopa/foscarbidopa) for People Living with Advanced Parkinson’s Disease in the European Union. News Release. 9 Jan. 2024.
13. Bial. Bial launches Kynmobi in Germany. News Release. 3 May 2024.
14. Bial. BIA 28-6156. Bial.com. (accessed 30 Oct. 2024).
15. Cavion. Cavion to Present Results of Phase 2 Essential Tremor Clinical Trial in Platform Presentation at the American Academy of Neurology. News Release. 24 Apr. 2019.
16. Neurolixis. Successful NLX-112 Clinical Results were Discussed in an Interview with the Parkinson’s UK Foundation. 15 Jan. 2024.
17. AC Immune. ACI-7104: Updates on Clinical Progress. 2024.
18. AskBio. AskBio Phase Ib Trial of AB-1005 Gene Therapy in Patients with Parkinson’s Disease Meets Primary Endpoint. News Release. 4 Jan. 2024.
19. MeiraGTx. MeiraGTx Announces Positive Data from Randomized, Sham-controlled Clinical Bridging Study of AAV-GAD for the Treatment of Parkinson’s Disease. News Release 15 Oct. 2024.
20. Cai M.; Wei, J.; Ren, X.; et al. NouvNeu001, A Phase 1 Stage Chemically Induced Human Dopaminergic Progenitor Cell Therapy for the Treatment of Mid- to Late-stage Parkinson’s Disease. 2024 International Conference. Abstract Number 700.
21. BlueRock Therapeutics. BlueRock’s Phase I Study with Bemdaneprocel in Patients with Parkinson’s Disease Meets the Primary Endpoint. News Release. 28 Aug. 2023.
22. LCT. NTCELL. Accessed 30 Oct. 2024.
23. Cure Parkinson’s. Parkinson’s Drug Therapies in the Clinical Trial Pipeline: 2024 Update. News Release. August 2024.
24. Kingwell, K. Gene Therapy Zeroes in on Parkinson’s Disease Brain Circuits. Nat Rev Drug Discov. 2024 Jan;23(1):20.
About the author
Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.
Article details
Pharmaceutical Technology Europe
Vol. 36, No. 10
November/December 2024
Pages: 16–18
Citation
When referring to this article, please cite it as Barton, C. European Biotechs Unlocking Parkinson’s Disease. Pharmaceutical Technology Europe, 2024, 36 (10), 16–18.