Disease-Modifying Drugs for Parkinson's Disease: A New Wave on the Horizon?
Parkinson’s Disease, like Alzheimer’s, is a complex neurodegenerative disorder with both motor and non-motor symptoms that progressively worsen over time. While symptomatic treatments, such as dopamine replacement therapies, have been the mainstay for PD management, they do not halt the disease's progression. The race is now on to develop drugs that target the root causes of Parkinson’s, and as we shall explore, there are a variety of different therapeutic approaches in the pipeline.
Drivers of disease: Alpha-Synuclein and Beyond
The pathophysiology of Parkinson’s Disease (PD) is multifaceted and remains incompletely understood. However, several mechanisms have emerged as key contributors to disease development, with alpha-synuclein aggregation and neuroinflammation playing central roles (1).
Alpha-Synuclein Aggregation:
One of the most widely studied features of PD is the abnormal accumulation of a protein called alpha-synuclein in neurons. These aggregates contribute to the formation Lewy bodies, the pathological hallmark of PD. While the exact cause of alpha-synuclein aggregation is not fully understood, it is believed to trigger a cascade of toxic events, including mitochondrial dysfunction, synaptic failure, and cell death. The spread of these aggregates from one neuron to another may explain the progressive nature of PD. Thus, halting or reversing alpha-synuclein aggregation could potentially modify disease progression, making it a major focus of drug development.
Neuroinflammation:
Another critical aspect of PD pathophysiology is inflammation. Both the central nervous system (CNS) and peripheral immune systems contribute to a chronic inflammatory state in PD. Microglia, the resident immune cells of the CNS, are often activated in PD and may exacerbate neurodegeneration through the release of pro-inflammatory cytokines and reactive oxygen species. Inflammation, therefore, represents a viable target for disease modification, as reducing inflammation may protect neurons from further damage.
Other Mechanisms:
In addition to alpha-synuclein and inflammation, mitochondrial dysfunction, oxidative stress, and impaired lysosomal function are also thought to contribute to PD. Genetic mutations, such as those in the glucocerebrosidase (GBA) gene, have been linked to PD, further implicating lysosomal pathways in disease development.
The Current Clinical Development Landscape
In addition to the continued development of symptomatic drugs for PD, there is substantial work focusing on attempting to alter disease progression, with a range of mechanisms in late-stage clinical trials. Although no disease-modifying therapy has yet been approved for PD, the pipeline is rich with potential.
Alpha-Synuclein-Targeted Therapies:
As of January 2024, there were a total of 9 clinical trials targeting alpha-synuclein (out of a total of 60 disease modifying treatment trials). Drugs targeting alpha-synuclein aim to limit the loss of dopamine-producing neurons by reducing alpha-synuclein aggregation and subsequent formation of Lewy Bodies. An example of such a drug is prasinezumab, a monoclonal antibody developed by Roche and is currently in Phase 2. The data from clinical trials has been mixed but promising, as despite missing its primary end point in its phase 2 PASADENA study, further subgroup analysis suggests it may slow disease progression in rapidly progressing patients. Further trials are ongoing to explore this further. (2)
GLP-1 Receptor Agonists:
GLP-1R agonists, such as exenatide, originally developed for diabetes, are being repurposed for PD due to their neuroprotective effects. Based upon data that suggests there are common pathogenic pathways between Type 2 Diabetes and PD, it’s believed that GLP-1R drugs may help reduce inflammation, limit alpha-synuclein folding, enhance autophagy and support mitochondrial regeneration. As of January, there were 5 clinical trials investigating this class of drugs. Exenatide is such an example and is the most advanced candidate currently in Phase 3 trials, sponsored by the University College London. Early data suggest that it may slow motor progression in PD, making it a compelling candidate for disease modification. (3)
Kinase Inhibitors:
Traditionally used to treat cancer, these are now being investigated based on their implication in the pathobiology of PD. Several different targets are being pursued including c-Ab1 and LRRK2 (the latter being associated with genetic mutations). It is thought these drugs help reduce reactive oxidative stress, enhance mitophagy, reduce neuroinflammation and the aggregation of alpha-synuclein. As of earlier this year, there were 5 drugs in Phase 2 with disease modifying potential.
Glucocerebrosidase (GBA) Modulators:
Approximately 5-15% of PD patients have GBA mutations, making this the most common genetic risk factor for PD. Mutations in this gene can compromise production of the enzyme GCase and reduce lysosomal function. Drugs that address these mutations may be able to restore lysosomal function and reduce alpha-synuclein accumulation thereby slowing disease. Earlier in this year, there were 7 drugs focused on GBA. One such drug is BIA 28-6156, currently in Phase 2 and being developed by Bial Pharmaceuticals. Top line results are expected in 2026. (4)
Cell and Gene Therapies:
Whilst still early days, cell and gene therapies offer disease modifying potential. Cell therapies focus on transplanting healthy dopamine-producing neurons into the brain to replace those lost in Parkinson’s, potentially restoring motor function. Gene therapies, on the other hand, target the genetic mutations or pathways contributing to disease, such as increasing dopamine production or protecting neurons from alpha-synuclein toxicity. One example is Bayer/Ask Bio’s gene therapy AB-1005. Currently in Phase 2, this is expected to allow stable and continuous expression of glial cell line-derived neurotrophic factor (GDNF) in localized regions of the brain after direct neurosurgical injection. This is expected to promote the survival and morphological differentiation of dopaminergic neurons. The trial will recruit 87 patients and read out in 2027. (5)
The Emerging Role of Biomarkers
The development of reliable biomarkers is critical to advancing disease-modifying treatments for Parkinson’s Disease. Biomarkers can help identify patients earlier in the disease process, track disease progression, and assess the efficacy of new therapies.
One of the most exciting developments in PD biomarker research is the alpha-synuclein seed assay. This assay detects misfolded alpha-synuclein in cerebrospinal fluid, providing a potential tool for early diagnosis and patient stratification in clinical trials. Early detection is likely to be crucial, as disease-modifying drugs may be most effective when administered in the early stages of PD. These measures are currently being investigated as stand-alone or combined with other data sources, such as clinical symptoms and genetic tests, and may potentially redefine the disease and its staging. (6)
Other promising biomarkers include imaging techniques that assess dopamine function, inflammatory markers in cerebrospinal fluid, and genetic testing for mutations such as GBA and LRRK2. As these biomarkers become more refined, they could significantly accelerate the clinical development and approval of disease-modifying therapies for PD.
Five Key Questions for Drug Developers
As the race to develop disease-modifying therapies for Parkinson’s Disease intensifies, drug developers must address several critical questions:
- How early in the disease process should treatment begin? Given that neurodegeneration starts long before symptoms appear, early intervention may be key to success. On the other hand, if progression is slow in the early stages how can we best demonstrate a clinically meaningful impact?
- How can we best stratify patients for clinical trials? Genetic testing and other biomarkers such as alpha-synuclein assays could help identify patients most likely to benefit from specific therapies.
- What combination of therapies will provide the best outcomes? Combining disease modifying drugs that target different aspects of PD pathophysiology may be the most effective strategy.
- How can we design trials that demonstrate disease-modifying effects? Clear biomarkers and outcome measures are essential for proving that a drug alters the course of PD. Use of digital biomarkers for high sensitivity to changes in movement, or measures of non-motor symptoms may also offer promise.
- What are the long-term safety implications of these therapies? Disease-modifying treatments may need to be taken for extended periods, or require long term follow-up, making safety a paramount concern.
Contact
If you are interested in discussing any of the issues above for your company/drug development program, please contact me through my email address dniven@nivenbiopharma.com . Feel free to also visit my website at www.nivenbiopharma.com for more information.
Sources
- Parkinson’s Disease Drug Therapies in the ClinicalTrial Pipeline: 2024 Update, McFarthing et al, Journeal of Parkinson’s Disease 14, July 24
- Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease, Pagano et al, Nature Medicine, April 24
- GLP-1 Receptor Agonists: A New Treatment in Parkinson's Disease, Kalinderi et al, Int. J Mol. Sci, March 2024
- BIA 28-6156, Bial Pharmaceuticals, company website
- AskBio Initiates Recruitment to its Phase 2 Parkinson’s Disease Trial, Bayer, June 2024
- Major Shift in the Clinical Definition of Parkinson's Triggers Debate, Brooks, Medscape July 2024
