Novel Soluble Epoxide Hydrolase Inhibitor for Neuropathic Pain in Patients With Spinal Cord Injury

EC5026 has been shown to be effective in preclinical pain models of pain, including inflammatory and neuropathic pain subtypes. Three Phase 1 studies of EC5026 have been conducted in healthy volunteers; a Phase 1a Single Ascending Dose (SAD) study, a Phase 1a Fed-Fasted study, and a Phase 1b Multiple Ascending Dose (MAD) study. The Phase 1b MAD study evaluated the safety, tolerability, and PK of 2 sequential ascending dose regimens of oral EC5026, administered once daily for 7 consecutive days, in healthy volunteers. The present study will evaluate the safety and tolerability, as well as target engagement and pharmacodynamics, of EC5026 administered as multiple doses in subjects with neuropathic pain due to traumatic or non-traumatic (degenerative) spinal cord injury.

Inclusion criteria

Each subject must meet all of the following criteria to be enrolled in this study:

• Male and female subjects must be 18 and older.
• Subjects must be willing to provide written informed consent to participate in the study.
• Subjects must be able to provide own transportation to study site every day for the duration of the study.
• Subjects with either a traumatic or a non-traumatic SCI may be eligible to enroll in this study. For subjects with complete or incomplete traumatic spinal cord injuries (tSCI), or complete non-traumatic spinal cord injury: Subjects must have a complete or incomplete T6 or below tSCI, or complete non-traumatic SCI of at least 12 months duration, with below-level neuropathic pain identified by the International Spinal Cord Injury Pain (ISCIP) classification criteria. Importantly, subjects must not be ventilator-dependent as detailed in Exclusion Criteria 1. For subjects with degenerative partial spinal cord injuries (pSCI): Subjects must have an incomplete, non-traumatic, SCI at any level secondary to degenerative spinal disorders such as disc degeneration, spinal stenosis, or spondylosis, with associated chronic neuropathic pain. The injury and the associated pain must be of at least 12 months duration. Neuropathic pain should meet the ISCIP classification criteria. Importantly, subjects must not be ventilator-dependent as detailed in Exclusion Criteria 1.
• Subjects must have completed a minimum of 6 of the 7 daily assessments for average and worst daily pain prior to final screening, using an 11-point numerical rating scale (NRS) for average daily pain intensity, and the arithmetic average daily SCI neuropathic pain score must be ≥4 and ≤9, with a standard deviation less than or equal to 1.2. Daily pain assessment screenings will be done over the phone with the study coordinator after informed consent is obtained.
• Subjects must have failed at least 2 classes of medications for their neuropathic pain due to SCI (classes may include antidepressants, antiepileptics, opioids, anti-inflammatories, topical treatments, etc.).
• Subjects must be in overall stable condition, as determined by pre-study medical history, physical examination, clinical laboratory tests, and 12 lead ECG measurements
• Subjects must have normal or not clinically significant clinical laboratory test results, as determined by the study investigator, including coagulation panel, blood cell counts, comprehensive metabolic panel analytes, and creatinine clearance (60 cm3/min or greater). Clinical laboratory tests results that are consistent with known, stable comorbidities will be allowed as long as the comorbidities do not represent an exclusion criteria per se.
• Subjects must have a negative screening for HIV, Hepatitis C, and Hepatitis B within 30 days of randomization.
• Subjects must have a normal hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes screening study.
• Subjects must have a negative urinary drug screen (UDS) for illicit drugs (marihuana/THC are allowed) and serum ethanol level <80 mg/dL.
• Male subjects who are not surgically sterile (vasectomized) and their female sexual partners must agree to use contraception during the study period and for 2 months afterward.
• Male subjects must not donate sperm during the study and for 12 months after receiving the last dose of study drug.
• Female subjects must be non-pregnant, non-lactating, and either postmenopausal for at least 1 year, or surgically sterile (bilateral tubal ligation ('clipping or tying tubes' or hysterectomy) for at least 3 months, or they must agree to use two forms of highly effective contraception method (less than 1 pregnancy per 100 people using the method for one year), from 28 days and/or their last confirmed menstrual period prior to study enrollment (whichever is longer) until 2 months after clinic discharge. Postmenopausal status will be defined as follow: minimum 1 year; amenorrhea duration of 12 consecutive months and a serum FSH value >40 IU/L; postmenopausal status must be confirmed by an FSH test at Screening). Highly effective contraception methods include: Intra-uterine device (IUD) containing either copper or levonorgestrel (e.g., Mirena®), and/or barrier methods of contraception, including condoms (external or internal) and diaphragm ('cap'). Hormonal methods of contraception (with the exception of hormonal IUD) are not permitted within this study. Female participants will refrain from using hormonal contraceptives for at least 28 days prior to study entry until the end of the study period. Participants/Participant's partner(s) must also use a barrier form of contraception, from the first dose of study drug through until 2 months after the last dose. For all females of childbearing potential, the pregnancy test result must be negative at Screening and Pre-Study Baseline (Day -1).
• Subjects must be able to speak, read, and understand English sufficiently to allow comprehension and completion of all study assessments.

Exclusion criteria

Subjects meeting any of the following criteria will be excluded from the study:

• Ventilator-dependent subjects, with the exception of nocturnal use of CPAP or BiPAP.
• Subjects with pain that is not present every day (chronic) or where the pain description does not have a classic neuropathic phenotype.
• Subjects with other chronic neuropathic pain conditions, including painful diabetic neuropathy, HIV-associated neuropathic pain, chemotherapy or ethanol-associated neuropathy.
• Subjects with other pain syndromes that may confound assessment or self-evaluation of the SCI neuropathic pain.
• Subjects with only negative symptoms, defined as numbness without clear evidence of spontaneous pain, either constant or episodic.
• Non-opioid pain medications will be allowed if at a fixed stable dose for more than 1 month prior to Screening with no anticipation of the dose changing during the study, and if they do not interfere with the subject's ability to rate pain as per Investigator's discretion. Allowed non-opioid medications include gabapentin, pregabalin, duloxetine, acetaminophen, ibuprofen, celecoxib, meloxicam, other antidepressants including amitriptyline and other antiepileptics, as well as topical capsaicin and topical lidocaine.
• Subjects using opioid medications will be required to be on a dose of 60 morphine milligrams equivalents (MME) per day or less, and with a stable dose for at least four (4) weeks prior to consent, with no anticipation of dose changing during the study.
• Subjects with active Hepatitis A, Hepatitis B and/or Hepatitis C.
• Subjects with any clinically unstable or significant cardiovascular (including acute coronary syndrome within the prior year to Screening), renal, hepatic, respiratory, gastrointestinal, hematological, endocrine, or infectious disease (including HIV infection).
• Subjects with clinically significant abnormalities on screening vital signs, laboratory tests, and/or ECG. Subjects with poor venous access will also be excluded.
• Subjects with a history of disorders of the hypothalamic-pituitary-adrenal axis, including adrenal insufficiency and Cushing's, or with a history of disorders of the hypothalamic-pituitary-gonadal axis, including hypogonadism.
• Subjects who have used any topical, oral, or intravenous exogenous corticosteroids within 12 weeks and/or intra-articular exogenous corticosteroids within 6 months prior to the start of the trial, or who plan on using them during the study.
• Subjects who have used fludrocortisone or exogenous testosterone products within 12 weeks prior to the start of the trial or who plan on using them during the study.
• Subjects who have used (within 14 of randomization) or plan on using during the duration of the study any renin-angiotensin system (RAS)-acting drugs (including angiotensin-receptor blockers, or ARBs; angiotensin-converting enzyme inhibitors, or ACE-inhibitors; and direct renin inhibitors) or mineralocorticoid receptor antagonists (such as spironolactone and eplerenone)
• Subjects who have used chemotherapy agents, or who have a personal history of cancer or cancer in first degree relatives suggestive of elevated cancer risk, other than nonmetastatic skin cancer that has been completely excised, within 5 years prior to Screening.
• Subjects with a history of bacterial, fungal, or viral infection requiring treatment with antibiotics, antifungal agents, or antivirals within 1 month prior to randomization.
• Subjects who have used (within 14 days of randomization) or plan on using during the duration of the study any prescription or over-the-counter drugs that are moderate-strong CYP3A4 inducers or inhibitors.
• Subjects who have used (within 14 days of randomization) or plan on using during the duration of the study any dietary aids, supplements, or foods that are moderate-strong CYP3A4 inhibitors (e.g., grapefruit juice).
• Subjects with difficulty in swallowing oral medications.
• Subjects with serious psychosocial comorbidities as determined by the Investigator.
• Subjects with current cognitive or major psychiatric disorders, or any other condition that could interfere with compliance with study procedures.
• Subjects with a positive drug or alcohol test (>80 mg/dL) during Screening and/or admission (a positive THC test will be allowed as long as it consists of minimal social use, per discretion of Investigator), or with a recent history of binge drinking within 1 week of randomization.
• Subjects who have used any other investigational drug within 1 month prior to enrollment. If the investigational drug is known to have a long half-life, a longer washout period will be done.
• Subjects with a presence or history of active gastrointestinal disorder, including esophageal or gastroduodenal ulceration, or renal, hepatic, or coagulant disorder within 1 month prior to enrollment.
• Subjects with a family history of significant cardiac disease (i.e., sudden death in first degree relative; myocardial infarction before the age of 50).
• Subjects with confirmed COVID-19, or suspected COVID-19 (e.g., developed symptoms of a respiratory infection such as cough, sore throat, shortness of breath, or fever, but did not get tested for COVID 19) within 30 days of randomization.
• Subjects who have received a COVID-19 vaccine within 30 days of randomization or are planning on receiving it during the study duration.
• Exclude subjects with spinal cord injury at T6 or higher with a history of neurogenic bladder.
• Exclude subjects with documented autonomic dysreflexia (AD) or a history of episodes consistent with undiagnosed AD as determined by an experienced clinician.