Fasudil for Parkinson's Disease (ROCK-PD)

Clinical Trial Identifier: NCT05931575 Status: Recruiting Sponsor: Technical University of Munich Phase: Phase IIa (early phase) Intervention: Fasudil hydrochloride (ROCK inhibitor) vs placebo

Trial Overview

This Phase IIa clinical trial aims to evaluate the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with early Parkinson's Disease.

Study Design

Clinical Trial Identifier: NCT05931575 Status: Recruiting Sponsor: Technical University of Munich Phase: Phase IIa (early phase) Intervention: Fasudil hydrochloride (ROCK inhibitor) vs placebo

Trial Overview

This Phase IIa clinical trial aims to evaluate the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with early Parkinson's Disease.

Study Design

• Trial Name: ROCK-PD
• Intervention: Fasudil in two dosages or placebo, administered orally twice daily
• Duration: 3 weeks treatment
• Enrollment: 75 early PD patients
• Centers: Up to 15 trial centers in Germany
• Blinding: Double-blind, randomized, placebo-controlled

Pathophysiology: The ROCK Pathway in Parkinson's Disease

Rho-Associated Coiled-Coil Containing Protein Kinase (ROCK)

ROCK is a serine/threonine kinase with two isoforms:

• ROCK1: Widely expressed, involved in actin cytoskeleton organization
• ROCK2: Predominantly expressed in brain, heart, and skeletal muscle

ROCK Activation in PD

In Parkinson's Disease, ROCK is chronically overactivated through multiple mechanisms:

Downstream Effects of ROCK Overactivation

Chronic ROCK activation drives multiple deleterious pathways:

| Effect | Mechanism | PD Consequence |
|--------|-----------|----------------|
| Neuronal death | Caspase-3/9 activation, JNK/p38 activation | Loss of dopaminergic neurons |
| Axonal degeneration | Actin cytoskeleton disruption | Reduced neuronal connectivity |
| Neuroinflammation | Microglial activation, cytokine release | Accelerated neurodegeneration |
| Alpha-synuclein aggregation | Impaired autophagy, proteasome dysfunction | Lewy body formation |
| Impaired neurogenesis | Reduced NPC proliferation | Failed endogenous repair |
| Blood-brain barrier dysfunction | Endothelial cell contraction | Increased neurotoxicity |

Mechanism of Action

Fasudil is a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor that has shown several neuroprotective properties relevant to Parkinson's Disease:

Neuroprotective Effects

• Upregulates Nrf2 pathway
• Increases glutathione peroxidase activity
• Reduces lipid peroxidation
• Protects dopaminergic neurons from 6-OHDA and MPTP toxicity

• Preserves mitochondrial membrane potential
• Inhibits mitochondrial permeability transition
• Enhances complex I activity
• Reduces apoptotic cytochrome c release

Pro-regenerative Effects

• Promotes axonal regeneration via LIM kinase/cofilin pathway
• Enhances dendritic spine formation
• Stimulates synaptic plasticity

• Promotes neural progenitor cell proliferation
• Supports differentiation into dopaminergic neurons
• Enhances survival of new neurons

Anti-inflammatory Effects

• Shifts microglia from M1 (pro-inflammatory) to M2 (protective) phenotype
• Reduces iNOS and COX-2 expression
• Decreases pro-inflammatory cytokine release

• Modulates T-cell responses
• Reduces peripheral inflammation crossing BBB

Anti-Aggregation Effects

• Attenuates alpha-synuclein aggregation in PD models
• Promotes clearance of aggregated species
• Inhibits oligomer formation

• Activates autophagy-lysosomal pathway
• Enhances misfolded protein clearance
• Improves proteasome function

Clinical Rationale

Fasudil has been licensed in Japan since 1995 for the treatment of cerebral vasospasms following subarachnoid hemorrhage, and has established a beneficial safety profile. This trial represents a repurposing approach, applying a known safe drug to a new therapeutic indication in neurodegeneration.

Drug Repositioning Advantages

Evidence Base Supporting Fasudil in PD

Preclinical Studies

| Study | Model | Findings |
|-------|-------|----------|
| 6-OHDA rat model | Intrastriatal 6-OHDA | Reduced dopaminergic neuron loss, improved behavioral scores |
| MPTP mouse model | MPTP administration | Preserved tyrosine hydroxylase neurons, improved motor function |
| Alpha-synuclein transgenic mice | A53T mutation | Reduced aggregation, improved survival |
| LRRK2 G2019S knock-in | LRRK2 mutation | Enhanced neuroprotection |

Human Data

• Post-marketing surveillance in Japan: >30 years of safety data
• Common adverse effects: transient hypotension, headache, flushing
• No significant drug-drug interactions
• Established biomarker: ROCK activity in peripheral blood mononuclear cells

Clinical Trial Design

Phase IIa Objectives

Primary Objectives:

Secondary Objectives:

Outcome Measures

Primary Endpoints:

• Adverse event incidence and severity
• Vital signs and laboratory parameters
• Electrocardiogram changes

• Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-III
• Hoehn and Yahr staging
• Timed Up and Go test
• 6-Minute Walk Test

Implications for PD Treatment

Disease-Modifying Potential

If successful, ROCK inhibition could represent a genuinely disease-modifying approach:

• Addresses multiple pathogenic pathways simultaneously
• May slow progression rather than merely treating symptoms
• Potential for combination with symptomatic treatments

Symptomatic Benefits

Beyond disease modification, ROCK inhibition may provide:

• Improved motor function
• Reduced non-motor symptoms
• Neuroprotective effects independent of symptomatic relief

Related Pages

• [ROCK Inhibitor Fasudil for PSP/CBS](/clinical-trials/rock-inhibitor-fasudil-psp-cbs-nct04734379)
• [Fasudil for Early Alzheimer's (FEAD Study](/clinical-trials/fasudil-early-alzheimer-fead-nct06362707)
• [Parkinson's Disease Clinical Trials Index](/clinical-trials/parkinsons-disease)
• [alpha-synuclein](/proteins/alpha-synuclein) - target of Fasudil's anti-aggregation effects
• [Rho-ROCK Signaling Pathway](/mechanisms/rho-rock-signaling-neurodegeneration)
• [Substantia Nigra](/anatomy/substantia-nigra) - affected brain region in PD
• [Dopaminergic Neurons](/cell-types/dopaminergic-neurons) - neurons targeted in PD
• [Neuroprotection](/mechanisms/neuroprotection-strategies) - therapeutic approaches

References

Pathway Diagram

The following diagram shows the key molecular relationships involving Fasudil for Parkinson's Disease (ROCK-PD) discovered through SciDEX knowledge graph analysis: