Clinical Trial Identifier: NCT05931575
Status: Recruiting
Sponsor: Technical University of Munich
Phase: Phase IIa (early phase)
Intervention: Fasudil hydrochloride (ROCK inhibitor) vs placebo
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.
- 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
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
Both isoforms are abundantly expressed in the substantia nigra and play critical roles in PD pathogenesis.
In Parkinson's Disease, ROCK is chronically overactivated through multiple mechanisms:
- Loss of dopaminergic signaling: Dopamine normally inhibits ROCK activity; its loss leads to disinhibition
- Oxidative stress: Reactive oxygen species directly activate ROCK
- Neuroinflammation: Pro-inflammatory cytokines (TNF-α, IL-1β) activate ROCK
- Alpha-synuclein aggregation: Oligomeric alpha-synuclein triggers ROCK activation
- Mitochondrial dysfunction: ATP depletion activates AMPK, which in turn activates ROCK
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 |
Fasudil is a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor that has shown several neuroprotective properties relevant to Parkinson's Disease:
-
Antioxidant protection:
- Upregulates Nrf2 pathway
- Increases glutathione peroxidase activity
- Reduces lipid peroxidation
- Protects dopaminergic neurons from 6-OHDA and MPTP toxicity
-
Mitochondrial protection:
- Preserves mitochondrial membrane potential
- Inhibits mitochondrial permeability transition
- Enhances complex I activity
- Reduces apoptotic cytochrome c release
-
Neurite outgrowth:
- Promotes axonal regeneration via LIM kinase/cofilin pathway
- Enhances dendritic spine formation
- Stimulates synaptic plasticity
-
Neurogenesis:
- Promotes neural progenitor cell proliferation
- Supports differentiation into dopaminergic neurons
- Enhances survival of new neurons
-
Microglial modulation:
- Shifts microglia from M1 (pro-inflammatory) to M2 (protective) phenotype
- Reduces iNOS and COX-2 expression
- Decreases pro-inflammatory cytokine release
-
Peripheral immunity:
- Modulates T-cell responses
- Reduces peripheral inflammation crossing BBB
-
Alpha-synuclein modulation:
- Attenuates alpha-synuclein aggregation in PD models
- Promotes clearance of aggregated species
- Inhibits oligomer formation
-
Autophagy enhancement:
- Activates autophagy-lysosomal pathway
- Enhances misfolded protein clearance
- Improves proteasome function
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.
- Known safety profile: Extensive clinical experience in >1 million patients
- Established manufacturing: FDA/EMA approved manufacturing processes
- Known pharmacokinetics: Well-characterized absorption, distribution, metabolism, excretion
- Established dosing: Safe dose ranges established
- Cost reduction: Typical development costs reduced by ~$1.5 billion
- Faster timeline: Can advance directly to Phase II
| 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 |
- 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
Primary Objectives:
- Safety and tolerability assessment
- Dose-finding (two dosage arms)
- Preliminary efficacy signal detection
Secondary Objectives:
- Pharmacokinetic profiling
- Target engagement (ROCK activity inhibition)
- Exploratory efficacy endpoints
Primary Endpoints:
- Adverse event incidence and severity
- Vital signs and laboratory parameters
- Electrocardiogram changes
Secondary Endpoints:
- 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
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
Beyond disease modification, ROCK inhibition may provide:
- Improved motor function
- Reduced non-motor symptoms
- Neuroprotective effects independent of symptomatic relief
- NCT05931575 - Safety, Tolerability and Symptomatic Efficacy of the ROCK-Inhibitor Fasudil in Patients With Parkinson's Disease
- Fasudil in Parkinson's Disease: From Bench to Bedside (2023)
- ROCK Inhibition as a Therapeutic Target in Neurodegeneration (2022)
- Alpha-synuclein Aggregation Inhibitors in Clinical Development (2024)
- Rho-ROCK Pathway in Dopaminergic Neuron Survival (2021)