Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is a progressive disease where a protein known as alpha-synuclein builds up to form structures called Lewy bodies 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 Alzheimer’s Disease (AD). No treatments have been approved by the US FDA or European Medicines Agency for DLB.

CervoMed is developing neflamapimod to reverse and potentially slow the synaptic dysfunction that contributes to this neurological decline in DLB patients, and it is the only clinical drug candidate of which we are aware that has shown significant improvements compared to placebo in a Phase 2a clinical trial (our AscenD-LB trial) and improved outcomes (p < 0.001) on the trial’s primary endpoint in a Phase 2b evaluation (16-week Extension data from our ongoing RewinD-LB trial). We are also the only company of which we are aware that is specifically targeting the treatment of DLB patients without AD co-pathology. Compared to patients with “pure” DLB – who may represent up to 50% of the total diagnosed DLB patient population at any given time – DLB patients with AD co-pathology have significant, irreversible neuronal loss in the hippocampus, which may be assessed via imaging or biomarker evidence of amyloid and/or tau pathology. DLB without AD co-pathology, however, is primarily a disease of reversible synaptic dysfunction in the basal forebrain cholinergic system.

Based on available preclinical and clinical data, we believe if neflamapimod is given in the early stages of certain degenerative diseases of the brain, it may reverse synaptic dysfunction, improve neuron health and function, and slow further progression by delaying synaptic dysfunction and neuronal death. We believe that targeting DLB patients without AD co-pathology enhances the alignment of our development path with neflamapimod’s mechanism of action, reduces the heterogeneity of our target patient population, and thereby has the potential to improve outcomes for patients.

The Role of Synaptic Dysfunction in Dementia with Lewy Bodies

The brain has billions of neurons that connect 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, this occurs in a specific part of the brain called the basal forebrain and impacts a type of nerve called cholinergic neurons. The resulting cholinergic dysfunction 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, such as neflamapimod.

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.

CervoMed is developing an oral p38 alpha inhibitor, neflamapimod, to reverse synaptic dysfunction and improve the cognitive deficits associated with DLB. The results of CervoMed’s AscenD-LB Phase 2a exploratory placebo-controlled clinical trial evaluating neflamapimod in patients with DLB 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 (40mg TID), neflamapimod showed significant improvement, compared to placebo, on a cognitive test battery that assessed attention and executive function, with results most pronounced in patients with DLB without evidence of AD co-pathology. The results from this trial were published in the journal Nature Communications in September 2022.

In March 2025, CervoMed announced 16-week results from the Extension phase of its RewinD-LB Phase 2b clinical trial evaluating neflamapimod in patients with DLB without evidence of AD co-pathology in which a new batch of neflamapimod capsules (relative to the batch used in in the Initial phase of the study) led to increased plasma drug concentrations and demonstrated improvement (p<0.001 vs. old capsules; p=0.003 vs. placebo) on the primary outcome measure, change from baseline in CDR-SB, and a key secondary outcome measure (p=0.035 against either old capsules or placebo), Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (CGIC). In addition, compared to either old capsules or placebo, a lower incidence of falls was seen in participants receiving neflamapimod from the new batch of capsules during the Extension phase.

Scientific data for neflamapimod has been published in certain medical journals and presented to the medical and scientific community at various medical meetings.  Click below to access the data presentations.

PRESENTATIONS AND PUBLICATIONS