Neflamapimod Demonstrates Positive Impact on Cholinergic Degenerative Process in Alzheimer Disease

John Alam, MD

New exploratory data from the phase 2 AscenD-LB trial (NCT04001417) showed that treatment with neflamapimod (EIP Pharma) was associated with increasing Nucleus basalis of Meynert (NbM) volume and NbM-deep gray matter (DGM) dynamic connectivity in patients with early Alzheimer disease (AD). These findings were presented at the 2023 International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders (AD/PD).^1,2

In the study, 15 patients were assigned to 40-mg neflamapimod capsules and followed up after 12 weeks. At the end of treatment, NbM volume, the largest cluster of cholinergic neurons in the basal forebrain, was increased by a mean of 3.1%, from 469 mm3 to 483 mm3 (P = .03). Specifically, 8 of the 15 patients treated saw increases of at least 3%.

Neflamapimod is designed to inhibit p38MAP kinase alpha (p38a), which is expressed in neurons under conditions of stress and disease, and has been thought to play a role in inflammation-induced synaptic toxicity, leading to synaptic dysfunction. In the presentation, investigators discussed how NbM structural alteration is an upstream event for AD progression in the brain, and that functional changes in NbM connectivity correlate with memory function in preclinical studies of AD. Thus, the main goal of the analysis was to assess the effects of the agent on NbM in early AD using structural and functional MRI.

Patients included in the analysis were between 60 and 85 years old with MCI due to AD or mild AD, had elevated C-PiB PET amyloid plaque load, and had Mini-Mental State Examination scores between 20 and 28. At the end of the 12-week period, patients demonstrated a mean decrease of 0.7% (IQR, –1.7% to 0.6%) in brain volume and 11% (IQR, –3.7% to 25.2%) increase in NbM-DGM (P = .043). Specifically, 6 of 13 participants demonstrated increases of at least 10% in NbM-DGM. Notably, there was no change in static connectivity throughout this time.

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"The data presented this weekend at AD/PD 2023 continue to support the thesis that inhibiting p38 MAP kinase alpha (p38α) activity has a positive impact on the cholinergic degenerative process and that functional and structural MRI assessments of the NbM may have utility as biomarkers for therapeutic effects when patients are treated with neflamapimod," John Alam, MD, chief executive officer, EIP Pharma, said in a statement.¹ "We are encouraged by these findings and are pleased to share these important results with the medical and scientific community."

AscenD-LB was originally a phase 2, double-blind, proof-of-concept study that randomly assigned patients with Lewy body dementia (LBD) to either 40-mg neflamapimod capsules or matching placebo. Presented at the 14th Clinical Trials on Alzheimer’s Disease Conference (CTAD), 2021, data revealed that patients with plasma phosphor-tau 181 levels of less than 2.2 mg/mL—indicating the presence of nonmixed, pure LBD pathology—showed significantly greater efficacy outcomes when treated with the therapy than those with higher levels. Above all, the findings supported the notion that neflamapimod has potent and specific activity against basal forebrain cholinergic dysfunction, the underlying disease processes of LBD.³

Dosing regimen was based on weight, with participants weighing less than 80 kg receiving capsules twice-daily (BID) and those weighing greater than or equal to 80 kg received capsules thrice daily (TID). At baseline, 53% (22 of 41) of placebo and 54% (22 of 42) of the neflamapimod participants in the efficacy population had plasma p-tau181 less than 2.2 pg/mL, which predicts a lack of AD copathology. patients without copathology demonstrated better efficacy outcomes, with effect size ranging from 0.56 to 0.78 for major efficacy end points for the comparison of 40-mg TID vs placebo in patients.

Neflamapimod remains the first treatment with potential impact on cognition, function, and motor function in patients with DLB. EIP Pharma previously announced that the study met its primary end point of demonstrating an improvement in cognition as assessed by the NTB (effect size d = 0.52; P = .015). Significant improvements (P <.05) or trends (P <.01) were evident on multiple secondary clinical end points as well.⁴

REFERENCES
1. EIP Pharma announces presentation of neuroimaging data exhibiting potential effects of neflamapimod on cholinergic structure and function at AD/PD 2023. News release. April 3, 2023. Accessed April 4, 2023. https://www.biospace.com/article/releases/eip-pharma-announces-presentation-of-neuroimaging-data-exhibiting-potential-effects-of-neflamapimod-on-cholinergic-structure-and-function-at-ad-pd-2023/
2. Lin C, Noteboom S, Bet M, et al. Effects of p38a kinase inhibitor on basal forebrain volume in Alzheimer’s disease. Presented at: 2023 AD/PD Conference; March 28 to April 1; Gothernburg, Sweden.
3. Alam J, Gomperts SN, Lemstra AW, et al. Impact of Alzheimer disease related co-pathology on treatment effects of the oral p38a kinase inhibitor neflamapimod in mild-to moderate dementia with Lewy bodies (DLB). Presented at CTAD 2021; November 9-12. Poster LP14
4. EIP Pharma announces positive phase 2 results for neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB). News release. EIP Pharma. October 6, 2020. Accessed April 4, 2023. https://www.prnewswire.com/news-releases/eip-pharma-announces-positive-phase-2-results-for-neflamapimod-in-mild-to-moderate-dementia-with-lewy-bodies-dlb-301146415.html