AXER-204 in Participants With Chronic Spinal Cord Injury

Study Overview
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Brief Summary
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This two-part trial will assess the safety, tolerability, pharmacokinetics, and efficacy of AXER-204 administered by lumbar puncture and slow bolus infusion. Part 1 will evaluate the safety, tolerability, and pharmacokinetics of single ascending doses of AXER-204. Part 2 will evaluate the safety, tolerability, pharmacokinetics, and efficacy of repeated doses AXER-204 in comparison to placebo.

Detailed Description
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AXER-204 is a human fusion protein that acts as a soluble decoy/trap for the myelin-associated inhibitors of axonal growth known as Nogo-A, MAG, and OMgp. AXER-204 and a surrogate protein used in early preclinical studies have been found to promote axon growth and recovery of function in animal models of spinal cord injury. Part 1 of the trial is a multicenter, open-label, single ascending dose study in participants with chronic cervical spinal cord injury. Four cohorts of 6 participants each are planned, with participants within each cohort expected to receive the same dose of AXER-204. Part 2 is a multicenter, randomized, double-blind, placebo-controlled, repeat dose study in chronic cervical spinal cord injury participants. Approximately 32 participants will be randomized (ratio 1:1) to receive repeated doses of AXER-204 or placebo (a phosphate buffered saline formulation). The dose level and dose frequency will be dependent upon outcomes from Part 1.

Official Title
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A Multicenter, Two Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of AXER-204 in Subjects With Chronic Spinal Cord Injury

Conditions
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Chronic Spinal Cord Injury

Intervention / Treatment
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* Drug: AXER-204
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Traumatic spinal cord injury that occurred ≥ 1 year ago Cervical spinal cord injury with serious neurologic deficit as evidenced by 1) bilateral ISNCSCI UEMS between 4 and 36 points inclusive, and 2) bilateral GRASSP Prehension Ability score between 4 and 17 points inclusive Confirmation by MRI of the following: Chronic SCI (persistent spinal cord lesion) For AIS grade of A without sensory or motor zone of partial preservation extending at least two levels caudal to the level of injury, no apparent transection of the cord CSF space spanning the lesion Key Exclusion Criteria: Penetrating injury to the cord or spinal cord trauma caused by ballistic injury including gunshot that did not penetrate the spinal cord History of stroke, cerebrovascular injury, or elevated intracranial pressure Contraindications for lumbar puncture Requiring mechanical ventilatory assistance of any type Body mass index (BMI) ≥ 35 kg/m2 or body weight <50 kg History of life threatening allergic or immune-mediated reaction to vaccines, or biologic drugs, at any time or any life threatening allergic or immune-mediated reaction within the past 12 months Subjects fitted with an implanted pump or port for delivery of therapeutics to the CSF Uncontrolled medical condition including but not limited to cardiovascular disease, sleep apnea, obstructive lung disease, severe neuropathic or severe chronic pain, severe autonomic dysreflexia Participation in any other investigational drug or device trial within 30 days or within 5 half-lives of the investigational drug or any past participation in a SCI cellular therapy trial. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1 is open-label single-ascending dose. Part 2 is double-blind, placebo-controlled, repeat dose.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AXER-204<br>Part 1 - Single ascending doses; Part 2 - Repeated dose | Drug: AXER-204<br>* human NoGo Trap fusion protein<br>* Other names: human Nogo Receptor decoy;|
| Placebo Comparator: Placebo<br>Part 2 only - Repeated dose | Drug: Placebo<br>* Phosphate buffered saline formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization or prolongation of existing hospitalization, results in a significant disability/incapacity or congenital anomaly, or is a medically important event. | Up to Day 29 for Part 1 and Day 253 for Part 2 | 
| Area Under the Concentration-Time Curve From Time 0 to Time of the Last Measurable Concentration (AUClast) of AXER-204 in Serum |  | Part 1: pre-dose and 1 h, 6 h, 12 h, and 24 h post-dose, Day 4, 8, 15, and 29, Part 2: pre-dose and 4 h post-dose on days 1, 21, 42, 63, and 104; and on Study Days 169 and 253. | 
| Cmax in Serum |  | Part 1: pre-dose and 1 h, 6 h, 12 h, and 24 h post-dose, Day 4, 8, 15, and 29, Part 2: pre-dose and 4 h post-dose on days 1, 21, 42, 63, and 104; and on Study Days 169 and 253. | 
| Tmax in Serum |  | Part 1: pre-dose and 1 h, 6 h, 12 h, and 24 h post-dose, Day 4, 8, 15, and 29, Part 2: pre-dose and 4 h post-dose on days 1, 21, 42, 63, and 104; and on Study Days 169 and 253. | 
| t1/2 in Serum |  | Part 1: pre-dose and 1 h, 6 h, 12 h, and 24 h post-dose, Day 4, 8, 15, and 29, Part 2: pre-dose and 4 h post-dose on days 1, 21, 42, 63, and 104; and on Study Days 169 and 253. | 
| Clearance From Serum |  | Day 1 pre-dose up to Day 29 in Part 1, Pre-dose up to Day 253 in Part 2 | 
| Volume of Distribution | Volume of distribution calculated from serum exposure data | Part 1: pre-dose and 1 h, 6 h, 12 h, and 24 h post-dose, Day 4, 8, 15, and 29, Part 2: pre-dose and 4 h post-dose on days 1, 21, 42, 63, and 104; and on Study Days 169 and 253. | 
| Area Under the Concentration-Time Curve From Time 0 to Time of the Last Measurable Concentration (AUClast) of AXER-204 in CSF |  | Part 1: pre-dose, post-dose at 24 h, 72 h, Days 8 and 29, Part 2: pre-dose on Days 1, 21, 42, 63, and 104, and on Day 253. | 
| Cmax of AXER-204 in CSF |  | Part 1: pre-dose, post-dose at 24 h, 72 h, Days 8 and 29, Part 2: pre-dose on Days 1, 21, 42, 63, and 104, and on Day 253. | 
| Tmax of AXER-204 in CSF |  | Part 1: pre-dose, post-dose at 24 h, 72 h, Days 8 and 29, Part 2: pre-dose on Days 1, 21, 42, 63, and 104, and on Day 253. | 
| t1/2 of AXER-204 in CSF |  | Part 1: pre-dose, post-dose at 24 h, 72 h, Days 8 and 29, Part 2: pre-dose on Days 1, 21, 42, 63, and 104, and on Day 253. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in International Standards for Neurological Classification of SCI (ISNCSCI) Bilateral Upper Extremity Motor Score (UEMS) | The ISNCSCI bilateral Upper Extremity Motor Score (UEMS) is determined by examining the muscle function within each of the 5 myotomes encompassing arm and hand function on each side of the body. A score ranging from 0 to 5 can be given to each myotome tested resulting in a maximum score of 50. Higher values indicate greater strength. | Baseline to Day 169 | 
| Change in Graded Redefined Assessment of Strength, Sensation and Prehension (GRASSP) Bilateral Prehension Performance Score | The GRASSP Bilateral Prehension Performance Score is determined based on performance of four tasks with each hand with scores ranging from 0 to 5 for each task resulting in a maximum score of 40. Higher scores indicate better function. | Baseline to Day 169 | 
| Change in Version III of the Spinal Cord Independence Measure (SCIM III) Self-care | The SCIM III questionnaire self-care score assesses activities of daily living including feeding, bathing, dressing, and grooming. The self-care score ranges 0-20 with higher scores correspond to better ability to carry out these self-care activities. | Baseline to Day 169 | 
| Patient Global Impression of Change (PGIC) Responder Rate | The PGIC instrument captures the patient's overall evaluation of response to treatment. Specifically, the PGIC asks: Since beginning this clinical trial, how would you describe the overall change (if any) related to your chronic spinal cord injury? The patient is asked to report the degree to which they have changed since entering the treatment period using a 7-point Likert scale (1='Much worse', 2='Worse', 3='A little worse', 4='No change', 5='A little better', 6='Better', 7='Much better') and If better or worse, what has changed?. Patients that have evaluation results including Much better, Better, or A little better are considered Responders. | Day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myelin-associated inhibitor, Nogo-A, MAG, OMgp, Nogo Receptor