Neflamapimod Reduces Plasma GFAP in Dementia With Lewy Bodies, Showing Correlation With Clinical Improvement

Newly presented data from a phase 2b trial (NCT05869669) revealed that treatment with investigational neflamapimod (CervoMed) led to reduced plasma glial fibrillary acidic protein (GFAP) and increased amyloid-ß (Aß)42/40 ratio in those with dementia with Lewy bodies (DLB). More importantly, these biomarker changes, along with downward trends in neurofilament light (NfL), correlated with positive changes in clinical outcomes, further strengthening neflamapimod as a potential treatment for DLB.^1,2

The latest analyses came from the extension of the phase 2 Rewind-LB trial, presented in 2 sessions at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) conference, held December 1-4 in San Diego, California. The extension, which tested a new batch of neflamapimod capsules (DP Batch B), included 159 patients with DLB who had a Clinical Dementia Rating (CDR) score of 0.5 or 1.0 at baseline. Patients with Alzheimer disease (AD) co-pathology, as assessed by plasma phosphorylated tau 181 levels, were excluded from the trial.

In the original 16-week, double-blind period, treatment with the first batch of neflamapimod (DP Batch A) led to no difference vs placebo in plasma GFAP levels (placebo: +5.4; DP Batch A: +2.0). In contrast, from the start of the extension to week 32 of the extension, there was a significant reduction in plasma GFAP levels in participants who received DP Batch B (median change, –16.0; IQR: –35 to 6.7; P <.0001).

In participants who received placebo during the randomized period and then switched to DP Batch B in the extension, plasma GFAP declined significantly more during 32 weeks of DP Batch B treatment than during 16 weeks of placebo (difference −23.5 pg/mL, P = 0.016). In this same group, the reduction in plasma GFAP associated with neflamapimod treatment was positively correlated with change in CDR-sum of boxes score over the 32 weeks of the extension phase (r = .35; P = .036).

"The biomarker data presented at CTAD reinforces the results of our previous Phase 2a study and demonstrates a significant correlation between the reduction of plasma GFAP and the slowing of clinical progression in people with DLB," John Alam, chief executive officer at CervoMed, said in a statement.¹ "These results highlight the utility of biomarkers such as plasma GFAP and the Aβ42/40 ratio in DLB and suggest that neflamapimod may be acting on the underlying disease process. Together, these findings further strengthen our confidence as we move toward our upcoming Phase 3 trial."

During the randomized phase, there were no apparent treatment effects with DP Batch A on NfL, a biomarker of neuroaxonal damage (DP Batch A: +4.6; Placebo: 2.3). As patients entered the extension to receive DP Batch B, there was a minor trend towards a reduction in plasma NfL levels, with decreases of –3.7 for Batch B vs increases of 1.2 for Batch A. Of note, NfL levels were only minimally elevated at study entry, which provided insufficient signal to definitively demonstrate treatment effects of NfL in this context.

The authors concluded that plasma GFAP is a viable biomarker for detecting treatment effects in dementia with Lewy bodies, based on the variability and effect sizes observed in the study. Using the measured standard deviation of roughly 30 pg/mL, they estimate that future trials would need about 24 to 41 participants per group to reliably detect clinically meaningful GFAP reductions, depending on the magnitude of change and desired statistical power.

In contrast, the authors find that plasma NfL is not a practical biomarker for treatment-response studies in DLB. Because the elevation in NfL is small and variability remains high, hundreds of participants would be required to detect the modest changes seen with therapy, making NfL far less sensitive than GFAP for clinical trial endpoints in this population.

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Neflamapimod is currently headed toward a phase 3 trial, which is expected to be a global, randomized, double-blind, placebo-controlled study of nearly 300 patients with DLB. The study, anticipated to initiate in the second half of 2026, will use change in CDR-SB as the primary end point, consistent with the RewinD-LB trial, as well other secondary outcomes, including biomarkers of neurodegeneration such as GFAP. The design of the phase 3 study and the registrational path for neflamapimod were done in coordination with the FDA, as the agency provided feedback for the next steps.³

Similar to Rewind-LB, the phase 3 study is expected to exclude patients with historical evidence of AD co-pathology based on brain imaging or cerebrospinal fluid analysis. The trial will further select participants without AD co-pathology using a validated blood plasma test; individuals with plasma ptau181 levels of at least 21.0 pg/mL at screening will be excluded.

Prior to Rewind-LB, the agent was studied in the phase 2 AscenD-LB trial (NCT04001507). Overall, the study met its primary end point, with neflamapimod-treated patients showing cognitive improvement on the Neuropsychological Test Battery (NTB). In this double-blind, placebo-controlled trial, patients were randomized to the investigational agent or placebo for 16 weeks, receiving twice-daily dosing if they weighed 80 kg or less and three-times-daily dosing if they weighed more than 80 kg.⁴

Patients receiving the three-times-daily regimen demonstrated the greatest cognitive benefit, with a significant NTB improvement compared with twice-daily dosing or placebo (effect size d = 0.52; P = .015). Additional secondary measures, including neuropsychiatric symptoms, mobility, and global clinical ratings, also showed significant or favorable trends in those treated with neflamapimod.

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REFERENCES
1. CervoMed Presents New Plasma Biomarker Data That Indicates Neflamapimod Broadly Improves Neuroinflammation and Neurodegeneration in Dementia with Lewy Bodies (DLB). News release. December 2, 2025. Accessed December 2, 2025. https://www.stocktitan.net/news/CRVO/cervo-med-presents-new-plasma-biomarker-data-that-indicates-lpz2r5694r0l.html
2. Alam JJ, Chu H, Gardner A, Kelly B, Teunissen CE. Neflamapimod Significantly Lowers Plasma GFAP and Correlates with Clinical Benefit in Dementia with Lewy Bodies: Results from the RewinD-LB Trial. Presented at: CTAD 2025; December 1-4; San Diego, CA. Abstract P071.
3. CervoMed Announces Alignment with FDA on Registration Path for Neflamapimod in Dementia with Lewy Bodies. News release. CervoMed. November 4, 2025. Accessed December 2, 2025. https://ir.cervomed.com/news-releases/news-release-details/cervomed-announces-alignment-fda-registration-path-neflamapimod
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 December 2, 2025. 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​