EC5026 (STEP Study) - Parkinson's Disease Clinical Trial

EC5026 (STEP Study) - Parkinson's Disease Clinical Trial

NCT Number: NCT07142044 Status: Recruiting Sponsor: EicOsis Human Health Inc. Phase: Phase 1 Start Date: 2025 Estimated Completion: 2026

Trial Overview

The STEP Study (Safety, Tolerability and Exploratory Efficacy of EC5026 in Parkinson's Disease) is evaluating EC5026, an oral fatty acid amide hydrolase (FAAH) inhibitor developed by EicOsis Human Health Inc., for the treatment of Parkinson's disease["@step_trial"]. This first-in-human study represents a significant milestone in the development of endocannabinoid-based neuroprotective therapies for neurodegenerative disorders.

Background and Rationale

Parkinson's disease affects approximately 10 million people worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms (bradykinesia, resting tremor, rigidity) and non-motor symptoms (cognitive decline, sleep disorders, autonomic dysfunction). Current treatments primarily address symptom management through dopaminergic replacement (levodopa) or dopamine receptor agonists, but no disease-modifying therapies exist that can halt or slow neuronal loss.

EC5026 (STEP Study) - Parkinson's Disease Clinical Trial

NCT Number: NCT07142044 Status: Recruiting Sponsor: EicOsis Human Health Inc. Phase: Phase 1 Start Date: 2025 Estimated Completion: 2026

Trial Overview

The STEP Study (Safety, Tolerability and Exploratory Efficacy of EC5026 in Parkinson's Disease) is evaluating EC5026, an oral fatty acid amide hydrolase (FAAH) inhibitor developed by EicOsis Human Health Inc., for the treatment of Parkinson's disease["@step_trial"]. This first-in-human study represents a significant milestone in the development of endocannabinoid-based neuroprotective therapies for neurodegenerative disorders.

Background and Rationale

Parkinson's disease affects approximately 10 million people worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms (bradykinesia, resting tremor, rigidity) and non-motor symptoms (cognitive decline, sleep disorders, autonomic dysfunction). Current treatments primarily address symptom management through dopaminergic replacement (levodopa) or dopamine receptor agonists, but no disease-modifying therapies exist that can halt or slow neuronal loss.

The endocannabinoid system has emerged as a promising therapeutic target for Parkinson's disease. The system comprises:

• Endocannabinoids: Anandamide (AEA) and 2-arachidonoylglycerol (2-AG)
• Cannabinoid Receptors: CB1 (primarily neuronal) and CB2 (primarily immune)
• Metabolic Enzymes: FAAH (anandamide degradation) and MAGL (2-AG degradation)

EC5026 Compound

EC5026 is a selective, brain-penetrant FAAH inhibitor developed by EicOsis, a company specializing in endocannabinoid modulation therapies. The compound belongs to the carboxylate class of FAAH inhibitors, which offer improved safety profiles compared to earlier urea-based inhibitors that demonstrated off-target toxicity in clinical trials.

| Attribute | Details |
|-----------|---------|
| Compound Name | EC5026 |
| Mechanism | Fatty Acid Amide Hydrolase (FAAH) inhibitor |
| Company | EicOsis Human Health Inc. |
| Phase | Phase 1 |
| Indication | Parkinson's Disease |
| NCT Number | NCT07142044 |
| Route | Oral |
| Status | Recruiting |
| Study Design | Single and multiple ascending dose |

Study Objectives

Primary Objectives

Secondary Objectives

Exploratory Objectives

Study Design

Phase 1 Design

The STEP study employs a standard Phase 1 design typical of first-in-human studies:

• Sequential cohorts receiving increasing single doses
• Dose escalation based on safety review
• Intensive PK/PD sampling

• Daily dosing for 7-14 days
• Assessment of steady-state pharmacokinetics
• Evaluation of accumulation and tolerability

Patient Population

Inclusion Criteria:

• Adults aged 40-80 years
• Diagnosis of Parkinson's disease per UK Brain Bank criteria
• Hoehn and Yahr stage 1-3
• Stable PD medication for ≥4 weeks
• Montreal Cognitive Assessment (MoCA) score ≥24

• Atypical parkinsonism or secondary parkinsonism
• Prior neurosurgical intervention (DBS, lesioning)
• Significant psychiatric comorbidity
• History of substance abuse
• Current cannabinoid use

Endpoints

Primary Endpoints:

• Incidence and severity of adverse events
• Changes in vital signs, ECGs, and laboratory values
• Dose-limiting toxicities (DLTs)

• Plasma PK parameters (Cmax, Tmax, AUC, half-life)
• CSF PK parameters
• FAAH activity in peripheral blood mononuclear cells (PBMCs)
• Plasma anandamide and PEA levels

• MDS-UPDRS Parts I-IV scores
• PD Questionnaire-39 (PDQ-39)
• Unified Dyskinesia Rating Scale (UDysRS) - for dyskinesia assessment

Mechanism of Action

FAAH Inhibition

EC5026 inhibits fatty acid amide hydrolase (FAAH), the primary enzyme responsible for hydrolyzing anandamide and other fatty acid amides in the central nervous system. FAAH is a membrane-bound serine hydrolase expressed predominantly in neurons and astrocytes, with lower expression in microglia.

By inhibiting FAAH, EC5026:

Neuroprotective Pathways

FAAH inhibition in Parkinson's disease may provide protection through multiple mechanisms:

• Anti-inflammatory: Reduced microglial activation and cytokine production (TNF-α, IL-1β, IL-6)
• Anti-excitotoxic: Modulated glutamate release through presynaptic CB1 receptors
• Anti-oxidant: Enhanced mitochondrial function and reduced oxidative stress
• Anti-aggregative: Decreased alpha-synuclein aggregation and propagation
• Pro-autophagic: Restored autophagy-lysosome pathway function

Preclinical Evidence

Parkinson's Disease Models

EC5026's development is supported by extensive preclinical evidence in PD models:

6-OHDA Lesion Model:

• Protected dopaminergic neurons in substantia nigra
• Improved forelimb use in cylinder test
• Reduced levodopa-induced dyskinesias
• Decreased microglial activation in striatum

• Preserved tyrosine hydroxylase (TH) positive neurons
• Maintained striatal dopamine levels
• Improved rotarod performance
• Reduced inflammatory markers (Iba-1, CD68)

• Reduced alpha-synuclein phosphorylation at Ser129
• Decreased protein aggregation in substantia nigra
• Improved motor function
• Lowered inflammatory cytokine levels

• Enhanced neuroprotection in LRRK2 G2019S knock-in mice
• Reduced phospho-LRRK2 staining in dopaminergic neurons
• Improved mitochondrial complex I activity

Safety Pharmacology

• hERG Channel: No significant inhibition at therapeutic concentrations
• Off-target Screening: Minimal binding to other enzymes and receptors
• Genotoxicity: Negative in Ames test and in vitro micronucleus
• Rodent Toxicology: Well-tolerated at doses up to 200 mg/kg for 28 days

Competitive Landscape

FAAH Inhibitors in Development

| Compound | Company | Phase | Indication | Status |
|----------|---------|-------|------------|--------|
| EC5026 | EicOsis | Phase 1 | PD | Recruiting |
| PF-04457845 | Pfizer | Phase 2 | OA/Pain | Terminated |
| BIA 10-2476 | Bial | Phase 1 | Pain | Terminated |

Comparison with Other PD Therapeutics

| Approach | Mechanism | Status | Limitation |
|----------|-----------|--------|------------|
| FAAH Inhibitors (EC5026) | Endocannabinoid modulation | Phase 1 | Unproven in humans |
| LRRK2 Inhibitors (DNL151) | Kinase inhibition | Phase 1/2 | Limited efficacy |
| GDNF Infusion | Neurotrophic factor | Phase 2 | Invasive delivery |
| Gene Therapy (AAV-GAD) | GABA production | Approved | Surgical risk |
| Alpha-synuclein Antibodies | Immunotherapy | Phase 3 | Limited benefit |

Expected Outcomes and Timeline

Study Timeline

• 2025: Trial initiation and SAD cohort enrollment
• 2026: MAD cohorts and preliminary results
• 2026-2027: Phase 2 planning and regulatory consultation

Potential Outcomes

Positive Scenarios:

• Clear target engagement (FAAH inhibition, anandamide elevation)
• Acceptable safety profile supporting further development
• Preliminary efficacy signals warranting Phase 2

• Insufficient target engagement at safe doses
• Adverse effects limiting escalation
• Lack of efficacy signal

Broader Implications

Regardless of outcome, the STEP study will provide valuable information about:

Related Pages

• [FAAH Inhibitor Therapy](/therapeutics/faah-inhibitor-therapy)
• [Endocannabinoid System in Neurodegeneration](/mechanisms/endocannabinoid-system-neurodegeneration)
• [Parkinson's Disease Overview](/diseases/parkinsons-disease)
• [Anandamide Signaling Pathway](/mechanisms/anandamide-signaling-neurodegeneration)
• [Neuroinflammation in Parkinson's Disease](/mechanisms/neuroinflammation-parkinsons-disease)
• [Alpha-Synuclein Therapeutic Approaches](/therapeutics/alpha-synuclein-therapeutic-approaches)

References