NCT Number: NCT07142044
Status: Recruiting
Sponsor: EicOsis Human Health Inc.
Phase: Phase 1
Start Date: 2025
Estimated Completion: 2026
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. 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)
In Parkinson's disease, endocannabinoid signaling is dysregulated, with reduced anandamide levels in the cerebrospinal fluid of PD patients compared to healthy controls. This deficiency may contribute to increased neuroinflammation, reduced neuroprotection, and impaired synaptic plasticity. FAAH inhibition represents a strategy to restore endocannabinoid tone by preventing anandamide breakdown, thereby enhancing CB1 and CB2 receptor signaling without the psychotropic effects associated with direct cannabinoid receptor agonists.
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 |
- Safety and Tolerability: Evaluate the safety and tolerability of single and multiple ascending doses of EC5026 in adults with Parkinson's disease
- Maximum Tolerated Dose: Determine the maximum tolerated dose (MTD) or recommended Phase 2 dose
- Pharmacokinetics: Characterize the pharmacokinetic profile of EC5026 in plasma and cerebrospinal fluid
- Target Engagement: Assess FAAH inhibition in peripheral (plasma) and central (CSF) compartments
- Pharmacodynamics: Measure anandamide and related fatty acid amide levels as biomarkers of target engagement
- Preliminary Efficacy: Explore preliminary efficacy signals using Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores
- Biomarker Development: Establish biomarkers for predicting therapeutic response
- Disease Mechanisms: Explore effects on neuroinflammation markers and other disease-relevant pathways
- CSF Pharmacokinetics: Characterize drug levels in cerebrospinal fluid to confirm brain penetration
The STEP study employs a standard Phase 1 design typical of first-in-human studies:
-
Single Ascending Dose (SAD) Phase:
- Sequential cohorts receiving increasing single doses
- Dose escalation based on safety review
- Intensive PK/PD sampling
-
Multiple Ascending Dose (MAD) Phase:
- Daily dosing for 7-14 days
- Assessment of steady-state pharmacokinetics
- Evaluation of accumulation and tolerability
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
Exclusion Criteria:
- Atypical parkinsonism or secondary parkinsonism
- Prior neurosurgical intervention (DBS, lesioning)
- Significant psychiatric comorbidity
- History of substance abuse
- Current cannabinoid use
Primary Endpoints:
- Incidence and severity of adverse events
- Changes in vital signs, ECGs, and laboratory values
- Dose-limiting toxicities (DLTs)
Secondary Endpoints:
- Plasma PK parameters (Cmax, Tmax, AUC, half-life)
- CSF PK parameters
- FAAH activity in peripheral blood mononuclear cells (PBMCs)
- Plasma anandamide and PEA levels
Efficacy Endpoints:
- MDS-UPDRS Parts I-IV scores
- PD Questionnaire-39 (PDQ-39)
- Unified Dyskinesia Rating Scale (UDysRS) - for dyskinesia assessment
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:
- Increases Anandamide Levels: Elevates synaptic and extracellular anandamide concentrations by 5-50 fold, depending on dose and brain region
- Enhances CB1 Receptor Signaling: Sustained CB1 activation provides neuroprotection against excitotoxicity, oxidative stress, and protein aggregation
- Modulates CB2 Receptor Activity: CB2 activation on immune cells reduces neuroinflammation and promotes microglial phenotype switching from pro-inflammatory (M1) to anti-inflammatory (M2)
- Preserves Synaptic Function: CB1-mediated modulation of glutamate release reduces excitotoxicity while maintaining normal synaptic transmission
- Promotes Neurotrophic Support: Enhanced endocannabinoid signaling supports BDNF release and neurogenesis
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
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
MPTP Model:
- Preserved tyrosine hydroxylase (TH) positive neurons
- Maintained striatal dopamine levels
- Improved rotarod performance
- Reduced inflammatory markers (Iba-1, CD68)
Alpha-Synuclein Transgenic Models:
- Reduced alpha-synuclein phosphorylation at Ser129
- Decreased protein aggregation in substantia nigra
- Improved motor function
- Lowered inflammatory cytokine levels
LRRK2 Models:
- Enhanced neuroprotection in LRRK2 G2019S knock-in mice
- Reduced phospho-LRRK2 staining in dopaminergic neurons
- Improved mitochondrial complex I activity
- 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
| 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 |
| 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
- 2025: Trial initiation and SAD cohort enrollment
- 2026: MAD cohorts and preliminary results
- 2026-2027: Phase 2 planning and regulatory consultation
Positive Scenarios:
- Clear target engagement (FAAH inhibition, anandamide elevation)
- Acceptable safety profile supporting further development
- Preliminary efficacy signals warranting Phase 2
Challenges:
- Insufficient target engagement at safe doses
- Adverse effects limiting escalation
- Lack of efficacy signal
Regardless of outcome, the STEP study will provide valuable information about:
- FAAH as Therapeutic Target: Validating or challenging FAAH inhibition for neurodegenerative diseases
- Endocannabinoid Modulation: Understanding the role of the endocannabinoid system in PD
- Biomarker Development: Establishing pharmacodynamic markers for future trials
- Clinical Development Framework: Informing development of next-generation FAAH inhibitors