Parkinson’s disease: Transitioning from symptom control to disease modification
Parkinson’s disease (PD) is entering a pivotal phase. For decades, treatment has centred on dopamine replacement to manage motor symptoms. That approach remains foundational and commercially important. However, scientific advances are shifting the field toward biologically defined subtypes, biomarker-guided development, and therapies designed to slow or alter disease progression. The next era of competition will not be defined solely by improved symptom control, but by the ability to demonstrate measurable impact on underlying neurodegeneration.
Globally, PD is the fastest-growing major neurodegenerative disorder. Prevalence is projected to more than double by 2050, reaching an estimated 25 million people, largely driven by ageing populations. Clinically, PD is characterised by bradykinesia (slowness of movement), accompanied by tremor and/or rigidity. Over time, postural instability, cognitive impairment, sleep disturbances, constipation, depression, and autonomic dysfunction frequently emerge. Approximately 10%–15% of cases are linked to genetic mutations such as LRRK2 or GBA1, though most cases are considered sporadic.
Biologically, PD is marked by the accumulation of misfolded alpha-synuclein protein within neurons. These aggregates form Lewy bodies, disrupt cellular trafficking, impair mitochondrial function, and activate inflammatory pathways, ultimately leading to the loss of dopamine-producing neurons in the substantia nigra. Dopamine depletion drives the classical motor symptoms. While diagnosis remains primarily clinical, the field is increasingly moving toward biologically defined disease frameworks using molecular biomarkers. This shift is important for research and future therapy selection, though symptomatic treatment remains the dominant clinical reality today.
Current standard: Advancing symptomatic control
Dopamine replacement with levodopa continues to anchor PD treatment. However, long-term oral levodopa use is associated with motor fluctuation periods when medication effect wears off (“OFF” time) and dyskinesias (involuntary movements). As a result, much of current innovation focuses on stabilising dopaminergic stimulation, rather than introducing entirely new mechanisms.
One major advancement is continuous subcutaneous levodopa delivery. Recently approved and late-stage systems such as Vyalev (ABBV-951) and ND0612 provide steady infusion of levodopa throughout the day. Continuous delivery reduces peaks and troughs in plasma levels, thereby decreasing OFF time and smoothing motor control. Strategically, these platforms compete on convenience, device design, and pharmacokinetic stability, rather than molecular novelty, representing meaningful quality-of-life improvements for patients with advanced disease.
Another area of differentiation is receptor-selective dopamine agonism. Traditional dopamine agonists stimulate multiple receptor subtypes and are associated with neuropsychiatric adverse effects, including impulse control disorders. Tavapadon, a selective D1/D5 partial agonist, aims to provide motor benefit with improved tolerability by targeting specific receptor subtypes. This reflects a broader movement toward precision modulation of dopaminergic tone, rather than broad stimulation.
Adjunctive therapies that reduce OFF time such as COMT inhibitors, MAO-B inhibitors, and adenosine A2A antagonists also remain important components of combination regimens. Across the symptomatic landscape, the competitive axis is increasingly defined by durability of effect, reduction in fluctuations, and simplification of treatment regimens.
Despite this progress, symptomatic optimisation alone is unlikely to transform long-term disease trajectory. As delivery systems mature, differentiation based purely on motor benefit may plateau, intensifying focus on therapies that address the underlying biology of neurodegeneration.
The shift toward disease modification
Disease-modifying therapies (DMTs) aim to slow neuronal loss, rather than simply compensate for dopamine deficiency. In PD, this represents a major scientific and regulatory challenge, as progression is gradual and heterogeneous. There are still no regulatory-approved DMTs for PD, however, multiple programmes are aiming to generate the kind of long-duration data that demonstrates a slowing of disease progression.
Therapeutic modalities span monoclonal antibodies, small-molecule kinase inhibitors, substrate reduction therapies, and gene therapies. The leading biological targets include:
• Alpha-synuclein aggregation: preventing or clearing toxic protein clumps
• LRRK2 signalling: modulating kinase activity linked to genetic and sporadic PD
• Glucocerebrosidase (GBA1) dysfunction: addressing lysosomal impairment
• Neuroinflammation and mitochondrial dysfunction: reducing secondary drivers of degeneration
Despite multiple late-stage failures of anti-alpha-synuclein antibodies in PD, continued investment in immunotherapies and aggregation inhibitors reflects sustained confidence in alpha-synuclein biology. Among the most advanced programmes, prasinezumab is a monoclonal antibody targeting the C-terminus of aggregated alpha-synuclein, designed to neutralise extracellular species and limit cell-to-cell spread. Exidavnemab (BIIB054) selectively binds soluble alpha-synuclein aggregates, which are believed to represent the most neurotoxic conformations. Together, these agents are viewed as important bellwethers for whether targeting extracellular or propagating alpha-synuclein can translate into measurable slowing of clinical decline in PD.
In parallel, active immunisation strategies are emerging. ACI-7104.056, an alpha-synuclein vaccine, is designed to stimulate a patient’s own immune system to generate a sustained, polyclonal antibody response against pathological alpha-synuclein species. Early clinical data has demonstrated favourable safety and tolerability, along with robust antibody generation and evidence of target engagement, supporting continued development. If successful, vaccination could offer a more durable and potentially scalable approach to modifying alpha-synuclein pathology compared with passive antibody therapies.
Several late-stage trials are expected to report results between 2025 and 2027, marking the first true test of biological disease modification in PD.
Regenerative and restorative approaches
Beyond slowing progression, a longer-term ambition is functional restoration by rebuilding or stabilising dopaminergic circuitry, rather than merely protecting what remains. These strategies move beyond classical disease modification and instead aim to replace lost neurons, enhance their survival, or directly correct underlying genetic drivers of degeneration.
Cellular replacement strategies are leading the regenerative push in PD. Bemdaneprocel, the most advanced cell therapy in clinical development, uses induced pluripotent stem cell (iPSC)-derived dopaminergic neurons implanted into the putamen to restore physiologic dopamine production, with the aim of durable engraftment and sustained functional benefit. In contrast, ANPD001 takes a personalised, autologous approach, generating dopaminergic neurons from a patient’s own induced pluripotent stem cells to potentially minimise immune rejection and reduce the need for chronic immunosuppression. Both approaches seek not just symptomatic relief, but structural rebuilding of dopaminergic circuitry.
Complementing cell therapy, gene- and RNA-based strategies aim to enhance neuronal resilience or correct underlying molecular drivers. AB-1005 delivers glial-derived neurotrophic factor (GDNF) via an adenoviral vector to promote dopaminergic neuron survival, while PR001 targets GBA1-associated PD through gene replacement to restore lysosomal function. At the RNA level, ION464 is an antisense oligonucleotide designed to reduce alpha-synuclein protein production upstream. Together, these programmes reflect a shift toward biologic stabilisation, and potentially partial restoration, of neural networks, moving beyond chronic pharmacologic management toward targeted, durable intervention.
These strategies attempt not merely to delay decline, but to restore dopaminergic circuitry. While still early and surgically intensive, they represent a potential paradigm shift from chronic pharmacologic management to biologic stabilisation or partial reversal of deficits.
Biomarkers as enablers of DMT development
Historically, PD diagnosis and trial enrolment have relied on clinical criteria. The emergence of alpha-synuclein seed amplification assays (SAAs) is beginning to change that paradigm. These assays detect misfolded alpha-synuclein in cerebrospinal fluid, sometimes before motor symptoms manifest. In 2024, the FDA issued a Letter of Support encouraging their use for clinical trial enrichment, though they are not yet validated as surrogate endpoints.
Other biomarker tools include:
• DAT-SPECT imaging: assessing dopaminergic neuron integrity
• Neurofilament light chain (NfL): a blood-based marker of neuronal injury
• Genetic markers: such as LRRK2 or GBA1 mutations, enabling targeted enrolment
• Skin biopsy assays: detecting peripheral synuclein deposition
Biomarkers serve three main functions: earlier detection, biologically defined patient stratification, and measurement of drug–target interaction. Their integration is essential for reducing trial heterogeneity and potentially shortening development timelines. However, regulatory validation of progression biomarkers remains a key bottleneck.
Strategic outlook
In the near term, continuous levodopa systems and receptor-selective agents will intensify competition within symptomatic management, improving consistency, tolerability, and convenience areas of clear clinical value.
Over the next decade, however, leadership in PD will likely depend on demonstrating credible disease modification. Success will require biomarker-defined enrolment, long-duration studies, and regulatory acceptance of mechanistic endpoints. Health systems may also need to invest in diagnostic infrastructure to support earlier identification and precision treatment pathways.
Together, this positions Parkinson’s disease as an evolving field, from a syndrome managed through dopamine replacement to a biologically characterised condition with an emerging disease-modifying pipeline. Symptomatic innovation remains essential, but the ultimate transformation will hinge on preserving neurons, slowing progression, and potentially restoring function.
About the author
Ivo Carre, PhD, is a senior business analyst at Lifescience Dynamics in London, with a doctorate in Neuroscience from the UKDRI and over two years of biopharma consulting experience. He has supported various clients across several indications, including oncology, neurology, and rare diseases, with expertise in competitive intelligence, market research, and market access.
