elezanumab (ABT-555) / AbbVie - LARVOL DELTA

Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update. (PubMed, Int J Mol Sci) - "Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery...We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Dementia • Epilepsy • Immunology • Inflammation • Movement Disorders • Multiple Sclerosis • Neuromyelitis Optica Spectrum Disorder • Orthopedics • Pain • Parkinson's Disease • Rare Diseases

EAISE: A Safety and Efficacy Study of Intravenous (IV) Elezanumab Assessing Change in Neurologic Function in Adult Participants With Acute Ischemic Stroke (clinicaltrials.gov) - P2 | N=121 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Ischemic stroke

EAISE: A Safety and Efficacy Study of Intravenous (IV) Elezanumab Assessing Change in Neurologic Function in Adult Participants With Acute Ischemic Stroke (clinicaltrials.gov) - P2 | N=121 | Active, not recruiting | Sponsor: AbbVie | Trial primary completion date: Jan 2025 ➔ Apr 2024

Trial primary completion date • Cardiovascular • Ischemic stroke

ELASCI: Safety And Efficacy Study Of Intravenous (IV) Administration Of Elezanumab To Assess Change In Upper Extremity Motor Score (UEMS) In Adult Participants With Acute Traumatic Cervical Spinal Cord Injury (SCI) (clinicaltrials.gov) - P2 | N=54 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Orthopedics

Longitudinal Biomarker Analysis in Patients With Ischemic Stroke: Exploratory Targeted and Omics Assessments From a Phase 2a Clinical Trial (ISC 2024) - P2 | "Introduction: Elezanumab (EZB), a monoclonal antibody specific to repulsive guidance molecule A (RGMa), is under investigation to treat acute ischemic stroke... Preliminary blinded analysis of plasma markers of neurodegeneration confirm increased NfL and GFAP levels during acute stroke, which diminish over time with different temporal patterns. Final unblinded results will provide a robust natural time course of specific biomarkers of neurodegeneration including GAP43. Forthcoming analyses evaluate broad panels of proteins, mRNA, and miRNA markers."

Biomarker • Clinical • P2a data • Cardiovascular • CNS Disorders • Ischemic stroke • GFAP • NEFL

Elezanumab For Acute Ischemic Stroke: A Phase 2 Randomized, Double-blind, Placebo-controlled Neuroprotectant Trial (ISC 2024) - P2 | "Demographics are representative of the diversity of stroke survivors in these geographical areas. Elezanumab is a novel investigative therapy with protective and regenerative properties based on robust preclinical evidence. Elezanumab is currently under evaluation in clinical trials for treatment of acute neurologic damage due to spinal cord injury and ischemic stroke."

Clinical • Neuroprotectant • P2 data • Cardiovascular • CNS Disorders • Ischemic stroke • Orthopedics

Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants. (PubMed, Clin Pharmacol Drug Dev) - "All adverse events were assessed by the investigator as having no reasonable possibility of being related to the study drugs and were mild in severity. No positive immunogenicity effect was observed that impacted elezanumab exposure or safety."

Journal • PK/PD data

EAISE: A Safety and Efficacy Study of Intravenous (IV) Elezanumab Assessing Change in Neurologic Function in Adult Participants With Acute Ischemic Stroke (clinicaltrials.gov) - P2 | N=121 | Active, not recruiting | Sponsor: AbbVie | Trial primary completion date: May 2024 ➔ Jan 2025

Trial primary completion date • Cardiovascular • Ischemic stroke

Neutralizing RGMa with Elezanumab Promotes Cerebroprotection and Recovery in Rabbit Middle Cerebral Artery Occlusion. (PubMed, Transl Stroke Res) - P2 | "D: Elezanumab is efficacious in rabbit pMCAO with a 4 × larger TTI window vs. tPA (6 vs. 1.5 h, respectively). In human AIS, tPA is approved for a TTI of 3-4.5 h. Elezanumab is currently being evaluated in a clinical Ph2 study of AIS to determine the optimal dose and TTI (NCT04309474)."

Journal • Preclinical • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Multiple Sclerosis • Orthopedics • Vascular Neurology

EAISE: A Safety and Efficacy Study of Intravenous (IV) Elezanumab Assessing Change in Neurologic Function in Adult Participants With Acute Ischemic Stroke (clinicaltrials.gov) - P2 | N=121 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting | Trial completion date: May 2024 ➔ Feb 2025 | Trial primary completion date: Aug 2023 ➔ May 2024

Enrollment closed • Trial completion date • Trial primary completion date • Cardiovascular • Ischemic stroke

ELASCI: Safety And Efficacy Study Of Intravenous (IV) Administration Of Elezanumab To Assess Change In Upper Extremity Motor Score (UEMS) In Adult Participants With Acute Traumatic Cervical Spinal Cord Injury (SCI) (clinicaltrials.gov) - P2 | N=54 | Recruiting | Sponsor: AbbVie | Trial primary completion date: Aug 2023 ➔ Jul 2025

Trial primary completion date • CNS Disorders • Orthopedics

Elezanumab Decreases Neuronal Damage And Improves Functional Recovery In A Rabbit Model Of Permanent Middle Cerebral Artery Occlusion (ISC 2023) - "Elezanumab treatment was associated with improved functional recovery and reduced markers of neuronal damage. Collectively, these data support a neuroprotective role for elezanumab in this translational model of acute ischemic stroke. Elezanumab is now being tested in a Phase 2a clinical trial for acute ischemic stroke."

Preclinical • Cardiovascular • Ischemic stroke • Thrombosis • NEFL • Plasma NfL

ELASCI: Safety And Efficacy Study Of Intravenous (IV) Administration Of Elezanumab To Assess Change In Upper Extremity Motor Score (UEMS) In Adult Participants With Acute Traumatic Cervical Spinal Cord Injury (SCI) (clinicaltrials.gov) - P2 | N=54 | Recruiting | Sponsor: AbbVie | Trial completion date: May 2024 ➔ Apr 2026

Trial completion date • CNS Disorders • Orthopedics

Baseline MRI Characteristics of Multiple Sclerosis Patients Enrolled in Two Phase 2 Studies of Elezanumab (ECTRIMS 2022) - P2 | "Baseline MRI data from the two studies provided a standardized dataset to assess the MRI characteristics of the brain and cervical spinal cord in MS patients with different underlying pathologies and their relationship with clinical measures."

Clinical • P2 data • CNS Disorders • Multiple Sclerosis

Phase 1 Evaluation of Elezanumab (anti-RGMa mAb) in Healthy and MS Participants. (PubMed, Ann Neurol) - P1 | "The elezanumab pharmacokinetic profile supports monthly, or bi-monthly, administration of up to 1800mg with the option of a loading dose of 3600mg. Elezanumab partitioning into CSF is within the range expected for mAbs. Reduced CSF levels of free RGMa levels demonstrate central nervous system target binding of elezanumab with an apparent maximal effect at 1800mg IV. Exposure-associated increases in CSF IL-10, an anti-inflammatory cytokine with neuroprotective/neurorestorative properties, support potential pathway modulation in MS participants."

Journal • P1 data • CNS Disorders • Immune Modulation • Inflammation • Multiple Sclerosis • IL10

Delayed administration of elezanumab, a human anti-RGMa neutralizing monoclonal antibody, promotes recovery following cervical spinal cord injury. (PubMed, Neurobiol Dis) - "Significant recovery in grip and trunk/core strength, locomotion and gait, and spontaneous voiding ability was found in rats treated with elezanumab either immediately post-injury or at 3 h post-SCI, and improvements in specific gait parameters were found when elezanumab was delayed to 24 h post-injury. We also developed a new locomotor score, the Cervical Locomotor Score, a simple and sensitive measure of trunk/core and limb strength and stability during dynamic locomotion."

Journal • CNS Disorders • Orthopedics

Phase 2a Study Of Elezanumab In Patients With Acute Ischemic Stroke (ISC 2022) - P2 | "This phase 2 study will evaluate safety and efficacy of elezanumab, a novel therapeutic intervention to improve neurological recovery after acute ischemic stroke."

Clinical • P2a data • Cardiovascular • CNS Disorders • Epilepsy • Ischemic stroke • Migraine

ELASCI: Safety And Efficacy Study Of Intravenous (IV) Administration Of Elezanumab To Assess Change In Upper Extremity Motor Score (UEMS) In Adult Participants With Acute Traumatic Cervical Spinal Cord Injury (SCI) (clinicaltrials.gov) - P2; N=54; Recruiting; Sponsor: AbbVie; Trial primary completion date: Apr 2022 ➔ Aug 2023

Trial primary completion date • CNS Disorders • Orthopedics

[VIRTUAL] Study Design and Baseline Characteristics in Phase 2 Studies of Elezanumab, a Potential Neurorestorative Therapy for Multiple Sclerosis (AAN 2021) - P2 | "RADIUS-R and RADIUS-P are phase 2 studies investigating safety and efficacy of elezanumab, including ecologically valid physical activity measured with wireless biosensors."

P2 data • CNS Disorders

[VIRTUAL] Safety and efficacy of elezanumab in relapsing and progressive forms of multiple sclerosis: Results from two phase 2 studies, RADIUS-R and RADIUS-P (ECTRIMS 2021) - P2 | "12-month elezanumab exposure was safe and well-tolerated but did not improve physical function or reverse disability in participants with relapsing or progressive forms of MS. Investigations of elezanumab in other neurologic indications are ongoing."

Clinical • P2 data • CNS Disorders • Fatigue • Infectious Disease • Multiple Sclerosis • Nephrology • MRI

RADIUS-P: A Study to Assess the Safety and Efficacy of Elezanumab When Added to Standard of Care in Progressive Forms of Multiple Sclerosis (clinicaltrials.gov) - P2; N=123; Completed; Sponsor: AbbVie; Active, not recruiting ➔ Completed; N=90 ➔ 123

Clinical • Enrollment change • Trial completion • CNS Disorders • Multiple Sclerosis

RADIUS-R: A Study to Assess the Safety and Efficacy of Elezanumab When Added to Standard of Care in Relapsing Forms of Multiple Sclerosis (clinicaltrials.gov) - P2; N=208; Completed; Sponsor: AbbVie; Active, not recruiting ➔ Completed

Clinical • Trial completion • CNS Disorders • Multiple Sclerosis • MRI

Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models. (PubMed, Neurobiol Dis) - "Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases."

Clinical • Journal • CNS Disorders • Immunology • Multiple Sclerosis • Ocular Inflammation • Ophthalmology • Optic Neuritis

EAISE: A Safety and Efficacy Study of Intravenous (IV) Elezanumab Assessing Change in Neurologic Function in Adult Participants With Acute Ischemic Stroke (clinicaltrials.gov) - P2; N=120; Recruiting; Sponsor: AbbVie; N=80 ➔ 120; Trial primary completion date: Nov 2021 ➔ Aug 2023

Clinical • Enrollment change • Trial primary completion date • Cardiovascular • Ischemic stroke • MRI

ELASCI: Safety And Efficacy Study Of Intravenous (IV) Administration Of Elezanumab To Assess Change In Upper Extremity Motor Score (UEMS) In Adult Participants With Acute Traumatic Cervical Spinal Cord Injury (SCI) (clinicaltrials.gov) - P2; N=54; Recruiting; Sponsor: AbbVie; Trial completion date: Mar 2023 ➔ May 2024

Clinical • Trial completion date • CNS Disorders • Complement-mediated Rare Disorders • Orthopedics