Clinical Trials in Parkinson's Disease

Overview

Parkinson's disease (PD) is the second most common neurodegenerative disorder after [Alzheimer's disease](/diseases/alzheimers-disease), affecting approximately 10 million people worldwide. Clinical trials for PD span a wide spectrum from disease-modifying therapies targeting alpha-synuclein and [LRRK2](/entities/lrrk2) to symptomatic treatments addressing motor and non-motor symptoms. This page provides a comprehensive overview of active and recent clinical trials, organized by mechanism and phase of development. Understanding the trial landscape is essential for researchers, clinicians, patients, and caregivers seeking to stay informed about emerging treatments. [@kalia2015]

Disease-Modifying Therapies

Disease-modifying therapies aim to slow or halt the progression of Parkinson's disease rather than merely treating symptoms. The main targets under investigation include alpha-synuclein aggregation, LRRK2 kinase activity, and glucocerebrosidase (GBA) function. These approaches represent the most promising avenues for changing the trajectory of PD, as current treatments only address symptoms and become less effective over time. [@poewe2017]

Alpha-Synuclein Targeting

Alpha-synuclein is a small protein that forms Lewy bodies in PD brains. The hypothesis that alpha-synuclein aggregation drives neurodegeneration has led to multiple immunotherapy approaches. Both active vaccines and passive antibody treatments are in development, aiming to reduce or prevent the formation of toxic aggregates.

Overview

Parkinson's disease (PD) is the second most common neurodegenerative disorder after [Alzheimer's disease](/diseases/alzheimers-disease), affecting approximately 10 million people worldwide. Clinical trials for PD span a wide spectrum from disease-modifying therapies targeting alpha-synuclein and [LRRK2](/entities/lrrk2) to symptomatic treatments addressing motor and non-motor symptoms. This page provides a comprehensive overview of active and recent clinical trials, organized by mechanism and phase of development. Understanding the trial landscape is essential for researchers, clinicians, patients, and caregivers seeking to stay informed about emerging treatments. [@kalia2015]

Disease-Modifying Therapies

Disease-modifying therapies aim to slow or halt the progression of Parkinson's disease rather than merely treating symptoms. The main targets under investigation include alpha-synuclein aggregation, LRRK2 kinase activity, and glucocerebrosidase (GBA) function. These approaches represent the most promising avenues for changing the trajectory of PD, as current treatments only address symptoms and become less effective over time. [@poewe2017]

Alpha-Synuclein Targeting

Alpha-synuclein is a small protein that forms Lewy bodies in PD brains. The hypothesis that alpha-synuclein aggregation drives neurodegeneration has led to multiple immunotherapy approaches. Both active vaccines and passive antibody treatments are in development, aiming to reduce or prevent the formation of toxic aggregates.

| Drug | Company | Mechanism | Phase | Status |
|------|---------|-----------|-------|--------|
| Prasinezumab | Roche/Genentech | Anti-α-Syn Antibody | Phase 2 | Active |
| Cinpanemab | Biogen | Anti-α-Syn Antibody | Phase 2 | Completed |

Prasinezumab (PRX002) is a monoclonal antibody designed to bind aggregated alpha-synuclein and promote its clearance. The PASADENA Phase 2 trial showed signals of efficacy in slowing motor progression, particularly in patients with earlier disease. Cinpanemab (BIIB054) similarly targets alpha-synuclein aggregates but did not meet its primary endpoint in the SPARK trial, though biomarker evidence of target engagement was observed. [@prasinezumab2022]

LRRK2 Inhibitors

LRRK2 (leucine-rich repeat kinase 2) is one of the most common genetic causes of PD. Mutations in LRRK2 cause increased kinase activity, leading to neuronal dysfunction. LRRK2 inhibitors represent a precision medicine approach for the approximately 5-10% of PD patients with LRRK2 mutations, though the drugs may also benefit sporadic PD.

| Drug | Company | Mechanism | Phase | Status |
|------|---------|-----------|-------|--------|
| DNL151 | Denali/Biogen | LRRK2 Inhibitor | Phase 1b | Completed |
| BIIB122 | Denali/Biogen | LRRK2 Inhibitor | Phase 2 | Recruiting |

DNL151 (also known as BIIB122) has completed Phase 1b studies showing target engagement and is now advancing to Phase 2 trials. The development of LRRK2 inhibitors represents an important example of genetic insights leading to targeted therapeutic development. [@denali2023]

Symptomatic Treatments

Motor Symptoms

Motor symptoms including tremor, bradykinesia, rigidity, and postural instability remain the hallmark of PD. Treatment options include dopamine precursors (levodopa), dopamine agonists, MAO-B inhibitors, and COMT inhibitors. Deep brain stimulation provides an important surgical option for patients with motor complications.

| Treatment | Mechanism | Typical Use |
|-----------|-----------|-------------|
| Levodopa/Carbidopa | Dopamine precursor | First-line |
| Pramipexole | D2/D3 agonist | First-line |
| Rasagiline | MAO-B inhibitor | Early/mid disease |
| Deep Brain Stimulation | Neural modulation | Advanced disease |

Non-Motor Symptoms

Non-motor symptoms including cognitive impairment, depression, anxiety, sleep disorders, and autonomic dysfunction significantly impact quality of life. These symptoms are increasingly recognized as important therapeutic targets, as they often precede motor symptoms and can be more disabling than motor issues in advanced disease.

Genetic Subtypes

GBA-PD

Glucocerebrosidase (GBA) mutations are the most common genetic risk factor for PD, accounting for approximately 5-10% of cases. [GBA](/entities/gba) deficiency leads to lysosomal dysfunction and alpha-synuclein accumulation. Several therapies targeting GBA function are in development.

| Drug | Company | Mechanism | Phase | Status |
|------|---------|-----------|-------|--------|
| Venglustat | Sanofi | GCase Activator | Phase 2 | Completed |
| LTI-03 | Luc Therapeutics | GCase Activator | Phase 1 | Recruiting |

Venglustat (GZ161) is a glucosylceramide synthase inhibitor that reduces substrate accumulation in cells with GBA mutations. Although the primary endpoint was not met, subgroup analyses suggested potential benefit in certain patient populations. [@venglustat2022]

LRRK2-PD

LRRK2-PD represents a distinct genetic subtype with potentially different pathophysiology. Clinical trials increasingly stratify patients by LRRK2 mutation status to assess treatment effects.

Neuroprotective Strategies

Several trials have investigated neuroprotective agents aimed at preserving surviving [neurons](/entities/neurons). These approaches target various pathways including oxidative stress, mitochondrial dysfunction, and neuroinflammation.

| Drug | Company | Mechanism | Phase | Status |
|------|---------|-----------|-------|--------|
| Inosine | University of Pennsylvania | Urate Elevation | Phase 3 | Completed |
| Isradipine | NINDS | Calcium Channel Blocker | Phase 3 | Completed |
| CoQ10 | Parkinson Study Group | Mitochondrial Support | Phase 3 | Completed |

Inosine supplementation to raise urate levels showed promise in early studies but the Phase 3 SURE-PD3 trial did not meet its primary endpoint. Isradipine, a calcium channel blocker, also did not show significant neuroprotection in the STEADY-PD trial. These negative results highlight the challenges of neuroprotection in established disease. [@neuroprotective2023]

Gene Therapy Approaches

Gene therapy offers the potential for long-lasting treatment through viral vector delivery of therapeutic genes. Targets include genes involved in dopamine synthesis and neuroprotection.

| Drug | Company | Mechanism | Phase |
|------|---------|-----------|-------|
| AAV2-GAD | Neurologix | GAD Gene Therapy | Phase 2 |
| AADC | PTC Therapeutics | AADC Gene Therapy | Phase 1 |

AAV2-GAD delivers the glutamic acid decarboxylase gene to the subthalamic nucleus, increasing GABA production and modulating abnormal neural activity. Results have shown improvement in motor symptoms, though the approach remains experimental. [@aavgad2021]

Recent Trial Results

Prasinezumab (PASADENA)

Cinpanemab (SPARK)

Biomarkers and Endpoints

Clinical Endpoints

• Primary Endpoint: MDS-UPDRS Parts II+III (Motor)
• Secondary Endpoints: Non-motor symptoms (NMS Scale), Quality of Life (PDQ-39)
• Imaging: DaTscan for dopamine transporter imaging

Biomarkers

• α-Synuclein RT-QuIC in CSF: Detects misfolded alpha-synuclein
• [Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL): Marker of neuronal damage
• Dopamine transporter imaging (DaTscan): Measures dopaminergic integrity

See Also

• [Parkinson's Disease](/diseases/parkinsons-disease) — Main disease page](/proteins/parkin)
• [Alpha-Synuclein](/proteins/alpha-synuclein) — Target protein](/proteins)
• [LRRK2](/genes/lrrk2) — Target gene](/genes)
• [Deep Brain Stimulation](/therapeutics/deep-brain-stimulation) — Surgical treatment](/therapeutics)
• [Parkinson Drug Pipeline](/clinical-trials/drug-pipeline) — Industry overview

External Links

• [Michael J. Fox Foundation](https://www.michaeljfox.org/) — Research and patient resources](/resources)
• [Parkinson's Progression Markers Initiative](https://www.ppmi-info.org/) — Biomarker study](/proteins/parkin)
• [ClinicalTrials.gov](https://clinicaltrials.gov/) — Trial database

Individual Trial Pages

Detailed pages for specific clinical trials:

• [Valacyclovir for HSV-1-Positive Parkinson's Disease — Phase 2 trial testing antiviral therapy for HSV-1 reactivation targeting](/clinical-trials/valacyclovir-hsv1-pd)

Alpha-Synuclein Targeting

• [Prasinezumab PASADENA Trial — Anti-α-Syn antibody](/entities/prasinezumab)](/entities)
• [Cinpanemab SPARK Trial — Anti-α-Syn antibody](/genes/ar)](/genes)
• [ACI-35 Alpha-Synuclein Vaccine — A](/institutions/ucl)ctive immunization

LRRK2 Inhibitors

• BIIB122 LRRK2 Inhibitor Trial — LRRK2 kinase inhibition
• DNL151 LRRK2 Trial — LRRK2 kinase inhibition

GBA-Targeted Therapies

• Venglustat GBA Trial — GCase activator
• LTI-03 GBA Trial — GCase activator

GLP-1 and Metabolic Therapies

• Exenatide PD Trial — GLP-1 receptor agonist
• Liraglutide PD Trial — GLP-1 receptor agonist
• Cilofexor GLP-1 Trial — FXR inhibitor

Disease-Modifying Trials

• Ambroxol ASPro-PD Trial — GCase activator
• Inosine SURE-PD3 Trial — Urate elevation
• Pi3K/Akt Activator PD Trial — Neuroprotection

Symptomatic Treatments

• Apomorphine PD Trial — Dopamine agonist
• Abbv-951 (Prodopas) Trial — Continuous levodopa delivery
• ROI-A Trial — A2A receptor antagonist
• Inclisiran Lewy Bodies Trial — PCSK9 targeting
• CUE1 Device Trial — Non-invasive vibrational cueing for gait

Failed Approaches (Learning from)

• Azilect ADAGIO Trial — MAO-B inhibitor (not disease-modifying)
• CoQ10 QE3 Trial — Mitochondrial support (failed)
• Creatine PD Trial — Neuroprotection (failed)

References