Targeting Synaptic Dysfunction to Treat Neurodegenerative Disease
EIP Pharma is pursuing a new mechanism that is based on our understanding of how stress to the neuron, including that due to inflammation, amyloid plaques or alpha synuclein deposits (i.e., Lewy bodies), drives the neurodegenerative process.
Scientific evidence has shown that the enzyme p38 alpha is a driver of neurological disease progression. Chronic activation of p38 alpha in the brain interferes with how neurons signal to one another – this is called synaptic dysfunction. Synaptic dysfunction leads to memory loss, executive function defects and other cognitive deficits, and if left untreated will result in neuron death over time.
We are developing an oral therapy, neﬂamapimod, that inhibits the enzyme p38 alpha. We believe that if neflamapimod is given in the early stages of neurological disease, it may reverse synaptic dysfunction and improve neuron health. EIP is investigating neflamapimod as a disease modifying therapy for neurodegenerative diseases. Our lead indication is Dementia with Lewy bodies and neflamapimod has also been evaluated in early-stage Alzheimer’s disease. In addition, pre-clinical data supports the potential role of neflamapimod in recovery after stroke, where efficient synaptic function is essential for establishing new neuronal connections during the recovery process.
EIP Pharma licensed neﬂamapimod in 2014. Prior to licensing, a full chronic toxicology program of neflamapimod had been completed by the originator company, as well as extensive phase 1 clinical trials and early phase evaluation in patients with rheumatoid arthritis.
After demonstrating the ability of neﬂamapimod to reverse synaptic dysfunction in animal models, the existing development experience allowed EIP Pharma to go directly to phase 2a clinical trials in patients with early-stage Alzheimer’s disease. The company then moved into a phase 2b study in Alzheimer’s disease and a phase 2a study in patients with Dementia with Lewy bodies. EIP Pharma owns six issued US patents on the administration of neﬂamapimod to treat Alzheimer’s disease, cognitive disorders, acute neurologic injury, including acute ischemic stroke, and other central nervous system (CNS) disorders, neflamapimod formulation and has ﬁled for additional US and international patents.
We have evidence from a phase 2a study (ASCEND-LB) in patients with mild to moderate DLB that neflamapimod has a significantly positive effect on cognition and motor function. We also have evidence from a phase 2b study (REVERSE-SD) in early Alzheimer’s disease that neflamapimod positively impacts the markers of the disease, establishing proof of neuronal target engagement for the drug. Results also suggest a positive effect on cognition in patients who have a certain drug level in their blood.
We have evidence from a phase 2a study (ASCEND-LB) in patients with mild to moderate DLB that neflamapimod has a significantly positive effect on cognition and motor function. We also have evidence from a phase 2b study (REVERSE-SD) in early Alzheimer's disease that neflamapimod positively impacts the markers of the disease, establishing proof of neuronal target engagement for the drug. Results also suggest a positive effect on cognition in patients who have a certain drug level in their blood.Treatment & Results
"The data from the trial of neflamapimod in DLB are very encouraging, setting the stage for more extensive testing. There are no approved treatments for DLB, the second most common cause of neurodegenerative dementia, and there is an urgent need to find therapies for this severe and progressive disorder."
Jeffrey L. Cummings, MD, ScD, Joy Chambers-Grundy Professor of Brain Science and Director of the Chambers-Grundy Center for Transformative Science, UNLV School of Integrated Health Sciences
“The demonstrated positive effects on the AscenD-LB study’s primary endpoint, cognition, and as well as on a number of secondary endpoints, establishes proof-of-concept for neflamapimod as a possible treatment for patients with dementia with Lewy bodies. If these findings are confirmed in phase 3 clinical studies, neflamapimod could potentially become the first approved therapy for this devastating disease,” said Stephen Gomperts, MD, PhD, Director of the Lewy Body Dementia Unit and Assistant Professor of Neurology at Massachusetts General Hospital, and an investigator in the AscenD-LB study. “DLB is not only the second most common neurodegenerative dementia but is also associated with substantial reduction of patient quality of life and high caregiver burden.”
“It is exciting to see efficacy of potential new drugs for Lewy Body Dementia,” said Marwan Sabbagh, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health. “It is a huge area of unmet need.”