edonerpic (T-817MA) / Fujifilm Holdings - LARVOL DELTA

Edonerpic maleate enhances functional recovery from spinal cord injury with cortical reorganization in non-human primates. (PubMed, Brain Commun) - "We concluded that edonerpic MA accelerates the recovery of grasping movements after SCI, accompanied by cortical somatotopic reorganization. Since edonerpic MA enhances recovery from damage in the central nervous system at multiple levels, treatment with edonerpic MA combined with rehabilitative training may represent a novel therapy for not only stroke but also for SCI."

Journal • Cardiovascular • CNS Disorders • Orthopedics • Vascular Neurology • ACACA

Spine plasticity to restore the cortical networks of movement: a therapeutic approach to spinal cord injury. (PubMed, Brain Commun) - "This scientific commentary refers to 'Edonerpic maleate enhances functional recovery from spinal cord injury with cortical reorganization in non-human primates', by Uramaru et al. (https://doi.org/10.1093/braincomms/fcaf036)."

Journal • CNS Disorders • Orthopedics

Edonerpic maleate prevents epileptic seizure during recovery from brain damage by balancing excitatory and inhibitory inputs. (PubMed, Front Neural Circuits) - "The threshold of picrotoxin-induced epileptic seizure in recovered animals without edonerpic maleate treatment was lower than in intact animals and recovered animals with edonerpic maleate. Thus, edonerpic maleate enhances motor function recovery from brain damage by balancing excitatory and inhibitory synaptic inputs, which helps prevent epileptic seizures during recovery."

Journal • Cardiovascular • CNS Disorders • Epilepsy • Vascular Neurology • CRMP

Cognitive Functional Composite detected time-dependent worsening of cognition and function during 18-month period in a phase II clinical trial with biomarker proven Alzheimer's disease patients (CTAD 2023) - P2 | "CFC was previously demonstrated as a suitable assessment to capture clinically meaningful cognitive decline in early dementia, therefore it was used as a secondary endpoint in T817MAEU201 study (NCT04191486) to evaluate efficacy and safety of edonerpic maleate (T-817MA) in patients with early stages of Alzheimer’s disease (AD)... The CFC showed time-dependent worsening of both cognition and function, and these did not differ between intervention and placebo. The observations of CFC decline in 18 months in the placebo group is valuable for designing future clinical trials and understanding drug effects. ."

Biomarker • Clinical • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • CSF P-tau

Changes of CSF and plasma biomarkers during 18-month period in a phase II clinical trial with biomarker proven Alzheimer's disease patients (CTAD 2023) - P2 | "Clinical Trial Registry: NCT04191486; https://clinicaltrials.gov; Background: Edonerpic maleate (T-817MA) is an orally available small molecule compound which has potent neuroprotective actions... No differences in changes in CSF p-tau 181 were observed as a result of the intervention vs placebo. The observations of CNS biomarker trend in 18 months in the placebo groups during this very controlled observation interval is valuable for designing clinical trials in future and understanding drug effect. ."

Biomarker • Clinical • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Aβ42 • CHI3L1 • CSF P-tau • GFAP • NEFL • Plasma NfL

Changes in EEG theta/alpha ratio during an 18-month period in a phase II clinical trial with biomarker-confirmed Alzheimer's disease patients (CTAD 2023) - P2 | "The EEG theta/alpha ratio was explored as neurophysiological efficacy marker of T-817MA treatment in AD. Although a trend towards theta/alpha ratio stabilization was observed in the treated group, the difference with the placebo group was non-significant. Its usefulness as therapeutic marker needs further validation."

Biomarker • Clinical • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • CSF P-tau

Topline results of a Phase II Trial of Edonerpic Maleate in Patients with Early Stage Biomarker-Proven Alzheimer's Disease (CTAD 2023) - P2 | "T817MAEU201 was a well-controlled study, well balanced at baseline and excellent retention. Treatment of 448 mg of T-817MA appeared to be safe and tolerable. No changes in CSF p-tau 181 were observed as a result of the intervention vs placebo."

Biomarker • Clinical • Late-breaking abstract • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Infectious Disease • Novel Coronavirus Disease • CSF P-tau

Efficacy and Safety of T-817MA in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD (clinicaltrials.gov) - P2 | N=221 | Completed | Sponsor: FUJIFILM Toyama Chemical Co., Ltd. | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CHI3L1 • CSF Neurogranin • CSF P-tau • CSF T-tau • Plasma NfL • p-tau181

T817MA regulates mitochondrial dynamics via Sirt1 and Arc following subarachnoid hemorrhage. (PubMed, Neuroscience) - "The decreased expression of Fis-1 and Drp-1, as well as the increased expression of Arc and Sirt1 were also observed in vivo. Taken together, these data indicate that the neuroprotective agent T817MA protects against SAH-induced brain injury via Sirt1- and Arc-mediated regulation of mitochondrial dynamics."

Journal • CNS Disorders • Hematological Disorders • Metabolic Disorders • Subarachnoid Hemorrhage • Vascular Neurology • IDH2 • SIRT1

A systematic review on drugs for synaptic plasticity in the treatment of dementia. (PubMed, Ageing Res Rev) - "A total of 12 studies were selected on Levetiracetam, Masitinib, Saracatinib, BI 40930, Bryostatin 1, PF-04447943 and Edonerpic drugs. This could suggest that research on these drugs is still preliminary. Of all, three studies reported promising results on Levetiracetam, Bryostatin 1 and Masitinib."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

CRMP2 binding compound accelerates functional recovery from central nervous system damage (PubMed, Nihon Yakurigaku Zasshi) - "We found that edonerpic maleate binds to Collapsin-response mediator protein 2, a downstream molecule of Semaphorin and enhance synaptic plasticity by facilitating synaptic delivery of AMPA receptors, thereby promoting functional recovery in a rehabilitation-dependent manner after brain injury in rodents and non-human primates. Further investigations is needed to seek more appropriate drug targets from both preclinical animal studies and clinical trials, and to translate preclinical results into successful clinical trials."

Journal • Cardiovascular • CNS Disorders • Vascular Neurology • CRMP

Edonerpic maleate regulates glutamate receptors through CRMP2- and Arc-mediated mechanisms in response to brain trauma. (PubMed, Cell Death Discov) - "Furthermore, edonerpic maleate inhibited CRMP2 cleavage but increased Arc activation in vivo. In summary, our results identify edonerpic maleate as a clinically potent small compound with which to attenuate TBI-related brain damage through regulating GluRs signaling."

Journal • CNS Disorders • Vascular Neurology

Efficacy and Safety of T-817MA in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD (clinicaltrials.gov) - P2; N=200; Active, not recruiting; Sponsor: FUJIFILM Toyama Chemical Co., Ltd.; Recruiting ➔ Active, not recruiting; Trial completion date: Oct 2022 ➔ Mar 2023; Trial primary completion date: Sep 2022 ➔ Feb 2023

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CHI3L1 • CSF Neurogranin • CSF P-tau • CSF T-tau • Plasma NfL

The emerging role of the sigma-1 receptor in autophagy: Hand-in-hand targets for the treatment of Alzheimer's. (PubMed, Expert Opin Ther Targets) - "AF710B, T-817MA and ANAVEX2-73 are some of the σ-1R agonists which have shown promising results and have entered clinical trials...The future of AD treatment could involve the combined targeting the σ-1R and autophagy activation. We suggest that future studies investigate the link between autophagy the σ-1R and AD."

Journal • Alzheimer's Disease • CNS Disorders • APP

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases. (PubMed, J Med Chem) - "Evaluation of the five selective σ receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ selective orthosteric ligands or allosteric modulators."

Journal • CNS Disorders • Mental Retardation • Psychiatry

Evaluation of edonerpic maleate as a CRMP2 inhibitor for pain relief. (PubMed, Channels (Austin)) - "We observed: (i) no binding between human CRMP2 and edonerpic maleate; (ii) edonerpic maleate had no effect on CRMP2 expression and phosphorylation in dorsal root ganglion (DRG) neurons; (iii) edonerpic maleate-decreased calcium but increased sodium current density in DRG neurons; and (iv) edonerpic maleate was ineffective in reversing post-surgical allodynia in male and female mice. Thus, while CRMP2 inhibiting compounds remain a viable strategy for developing new mechanism-based pain inhibitors, edonerpic maleate is an unlikely candidate."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Novel synaptic plasticity enhancer drug to augment functional recovery with rehabilitation. (PubMed, Curr Opin Neurol) - "A novel CRMP2-binding small compound, edonerpic maleate, accelerates motor function recovery after brain damage in rodent and nonhuman primate."

Journal • Cardiovascular • Vascular Neurology

Edonerpic maleate enhances motor function recovery from the internal capsule hemorrhage in primates (Neuroscience 2018) - "These indicated that edonerpic maleate enhanced the upper limb function recovery of macaque monkeys with the internal capsule hemorrhage. Thus, edonerpic maleate is an effective accelerator of functional recovery after brain damage in primates as well as in rodents. "

CNS Disorders • Vascular Neurology

A Novel Drug-Screening Platform in Microglial Cells Identifies Potential AD Drugs. (AAIC 2017) - "...Among the screened compounds, T-817MA (edonerpic, Toyama Chemical Co., Ltd.) was active in both microglial assays... The developed assays are valuable tools to study potential AD drugs in microglial cells, which are highly relevant in several neurodegenerative diseases. Furthermore, we can evaluate drug interaction with CD33, an emerging AD target. T-817MA, currently being evaluated in AD clinical trials, was found active in both assays."

Alzheimer's Disease

Fujifilm, Alzheimer’s drug ‘T-817MA’ clinical trial [Google Translation] - "FUJIFILM Corporation...has started a Phase III clinical trial of T-817MA, a treatment for Alzheimer's disease (AD), in Europe. The study is for early AD patients with mild cognitive impairment and mild AD....The company plans to further elucidate the relationship between T-817MA and phosphorylated tau, amyloid β, and microglial cells, which are the main causative agents of AD, along with clinical development."

New P3 trial

Efficacy and Safety of T-817MA in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD (clinicaltrials.gov) - P2; N=200; Recruiting; Sponsor: FUJIFILM Toyama Chemical Co., Ltd.

Clinical • New P2 trial

CRMP2 binding compound accelerates recovery from central nervous system (Neuroscience 2019) - "Indicating edonerpic could facilitate synaptic AMPAR delivery through the regulation of actin dynamics. Thus, edonerpic-maleate, a neural plasticity enhancer, could be a clinically potent small compound to accelerate rehabilitation after damage of CNS."

Epilogue on edonerpic: It does not work in Alzheimer’s (Alzforum) - P2, N=482; "Schneider and colleagues designed another Phase 2 trial to test this in 482 AD patients, average age 72. Of those, 377 completed the study. All had been diagnosed with probable AD according to the DSM-IV criteria and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria (McKhann et al., 1984). They also had MRI or CT scan results matching the diagnosis, an MMSE score between 12 and 22, and were on donepezil or rivastigmine for at least four months."

P2 data

Safety and Efficacy of Edonerpic Maleate for Patients With Mild to Moderate Alzheimer Disease: A Phase 2 Randomized Clinical Trial. (PubMed, JAMA Neurol) - P2; "Of 822 outpatients screened, 484 met the following criteria and were randomly assigned to treatment: 55 to 85 years of age, probable Alzheimer disease, Mini-Mental State Examination scores from 12 to 22, and taking stable doses of donepezil or rivastigmine with or without memantine. Edonerpic maleate appeared to be safe and tolerable, with expected gastrointestinal symptoms occurring early but without evidence for a clinical effect among patients with mild to moderate Alzheimer disease. ClinicalTrials.gov identifier: NCT02079909."

Biomarker • Clinical • Journal • P2 data

T-817MA ENHANCED AMYLOID BETA UPTAKE OF IPSC-DERIVED MICROGLIA AND DECREASED NEUROINFLAMMATORY RESPONSE IN MOUSE BRAIN. (ADPD 2019) - "Conclusions T-817MA has efficacy on human microglial function in vitro and on neuroinflammation in vivo mice model. These results further supported that T-817MA has a potential to be a disease modifier via neuroprotection and anti-neuroinflammatory efficacy."

Preclinical