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New Drug Pipeline for Parkinson’s Treatment: Update on Drug Trials

In recent years, the landscape of Parkinson’s disease (PD) research has witnessed remarkable progress, offering new hope to the estimated 10 million people worldwide living with this neurodegenerative condition. As we approach mid-2025, several promising drug candidates are advancing through clinical trials, targeting various aspects of the disease’s complex pathophysiology. This article provides an update on the most significant developments in the Parkinson’s drug pipeline.

Disease-Modifying Therapies: The Holy Grail

“The most exciting frontier in Parkinson’s research remains the pursuit of disease-modifying therapies (DMTs) – treatments that could slow, halt, or potentially reverse disease progression rather than merely managing symptoms.”, stated by Early access Care.

Alpha-Synuclein Targeting Approaches

Alpha-synuclein, the protein that accumulates in toxic aggregates within the brains of Parkinson’s patients, continues to be a primary target. Several monoclonal antibodies designed to clear these aggregates are showing promise:

• PD-STAT (Prasinezumab): Following mixed Phase 2 results in 2023, this Roche/Prothena antibody entered an adaptive Phase 2b trial with refined patient selection criteria. Early data suggests it may reduce motor symptom progression in patients with specific genetic profiles.

• BIIB054 (Cinpanemab): After initial setbacks, Biogen’s reformulated version has demonstrated improved brain penetration and is currently in Phase 2 trials with results expected by year’s end.

• ABBV-0805: AbbVie’s candidate, which targets oligomeric forms of alpha-synuclein, has progressed to Phase 2 after showing favorable safety profiles and biomarker changes in Phase 1.

GLP-1 Receptor Agonists

Originally developed for diabetes, GLP-1 receptor agonists have emerged as surprising contenders for neuroprotection in Parkinson’s:

• Semaglutide for PD: Following positive results from the Phase 2 PD-STAT trial in 2024, showing approximately 30% slower clinical decline compared to placebo, this once-weekly injectable has advanced to Phase 3 trials.

• NLY01: This PegBio/Neuraly GLP-1 receptor agonist specifically designed to cross the blood-brain barrier has shown encouraging Phase 2 results, with particular benefits in non-motor symptoms.

Genetic Approaches: Precision Medicine

For the 10-15% of PD cases with known genetic causes, targeted approaches are advancing rapidly:

• LRRK2 Inhibitors: Denali Therapeutics’ DNL151 (BIIB122) has shown promising Phase 2 results in LRRK2 mutation carriers, with significant reductions in LRRK2 kinase activity and stabilization of certain motor functions.

• GBA-Targeted Therapies: Sanofi’s venglustat, despite earlier setbacks, has been repositioned with a new trial design specifically for GBA mutation carriers, with interim Phase 2 data showing encouraging trends in cognitive outcomes.

• Gene Therapy: Voyager Therapeutics’ VY-AADC, delivering the AADC enzyme directly to the putamen via surgical intervention, has advanced to a pivotal Phase 3 trial after demonstrating sustained motor improvement in Phase 2.

Novel Symptomatic Treatments

While the search for disease-modifying therapies continues, significant advances in symptomatic treatment options are improving quality of life for patien ts:

• ND0612: This subcutaneous levodopa/carbidopa delivery system by NeuroDerm has completed Phase 3 trials with positive results, providing continuous dopaminergic stimulation and reducing “off” time by an average of 2.8 hours daily.

• Tavapadon: Cerevel’s selective D1/D5 dopamine receptor partial agonist has shown favorable outcomes in Phase 3 trials for early-stage PD, offering potentially fewer dyskinetic side effects than traditional therapies.

• KarXT: Karuna Therapeutics’ muscarinic receptor modulator has shown promise in addressing both motor symptoms and psychosis in PD without the adverse effects of traditional antipsychotics.

Non-Motor Symptom Targeted Therapies

Recognition of the significant burden of non-motor symptoms has led to dedicated development programs:

• Nelotanserin: This selective 5-HT2A inverse agonist has demonstrated efficacy in reducing visual hallucinations in PD psychosis in Phase 2b studies.

• AXS-05: Axsome’s dextromethorphan/bupropion combination has shown significant improvement in PD depression symptoms in Phase 2 trials.

• ENT-01: Enterin’s synthetic squalamine compound, targeting alpha-synuclein in the enteric nervous system, has shown promising results for constipation and is being evaluated for potential broader benefits.

Challenges and Future Directions

Despite these advances, significant challenges remain. Trial design continues to evolve, with increased emphasis on biomarkers, digital assessment tools, and patient stratification. The heterogeneity of Parkinson’s disease suggests that combination therapies may ultimately prove most effective.

The Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI) has expanded its longitudinal study, providing invaluable data that is helping to refine trial design and patient selection.

Conclusion

The Parkinson’s drug development pipeline has never been more robust, with multiple promising approaches advancing through clinical trials. Disease-modifying therapies remain the ultimate goal, but improved symptomatic treatments are also making significant impacts on patients’ lives. As our understanding of the complex pathophysiology of Parkinson’s continues to deepen, there is growing optimism that the next five years may see transformative new treatment options emerge for this challenging condition.

With increased collaboration between researchers, industry, and patient advocacy organizations, the pace of innovation continues to accelerate, offering genuine hope for the millions affected by Parkinson’s disease worldwide.

Tribune Online