Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is a progressive disease and one of the most common types of dementia after Alzheimer’s disease. In this disease, a protein known as alpha-synuclein builds up to form structures called Lewy bodies within the neurons in the parts of the brain that control cognition, behavior and movement. Patients with DLB incur higher healthcare costs, have longer hospitalizations, report lower quality of life, and have caregivers with higher levels of distress when compared with patients with AD at similar stages of disease. There are no treatments for DLB that have been approved by the US FDA or European Medicines Agency. EIP Pharma is developing a drug, neflamapimod, to reverse and potentially slow the synaptic dysfunction that contributes to this neurological decline. Results from a phase 2 study showed that neflamapimod improves cognitive function in patients with mild to moderate DLB.

The Role of Synaptic Dysfunction in Dementia with Lewy Bodies

The brain has billions of neurons, and each one connects to other neurons in the brain through synaptic connections. Evidence suggests that synaptic dysfunction results from a combination of excessive inflammation and the toxicity of alpha synuclein. In DLB, the synaptic dysfunction that is responsible for symptoms occurs in a specific part of the brain called the basal forebrain and impacts a specific type of nerve called cholinergic neurons. The resulting cholinergic dysfunction then is thought to cause the decline in attention, judgement, reasoning and other symptoms associated with DLB, including mobility impairment. Synaptic dysfunction in the basal forebrain is reversible in animal models, suggesting that therapeutics targeting basal forebrain cholinergic dysfunction have the potential to reverse the cognitive and motor impairments in DLB.

p38 alpha – A Driver of Synaptic Dysfunction

p38 alpha is an enzyme that is activated in neurons in times of stress and disease. While p38 alpha plays an important role in protecting cells from acute injury, chronically activated p38 alpha activity within neurons can damage synapses and contribute to alpha-synuclein-associated toxicity. If untreated, synaptic dysfunction will progress and result in neuron loss.

EIP Pharma is developing an oral p38 alpha inhibitor, neflamapimod, to reverse synaptic dysfunction and improve the cognitive deficits associated with DLB. In animal studies, neflamapimod reverses disease progression and increases the number of cholinergic neurons in the basal forebrain, findings that suggest that neflamapimod has disease-modifying potential in DLB. A phase 2a exploratory placebo-controlled clinical study (named “AscenD-LB”) evaluating neflamapimod in patients with mild-to-moderate DLB has been conducted and the results indicate that neflamapimod has significant positive effects, compared to placebo, on outcomes on the gold-standard dementia rating scale (Clinical Dementia Rating Sum of Boxes, CDR-SB) and on a measure of functional mobility (Timed Up and Go, TUG, test). In addition, at the higher of two doses evaluated in the study, neflamapimod showed significant improvement, compared to placebo, on a cognitive test battery that assessed attention and executive function. The results from this trial were published in the journal Nature Communications in September 2022. (view the publication – https://www.nature.com/articles/s41467-022-32944-3

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