Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024;11(3):549-557.
doi: 10.14283/jpad.2024.36.

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies

Affiliations
Clinical Trial

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies

N D Prins et al. J Prev Alzheimers Dis. 2024.

Abstract

Background: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated.

Objectives: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB.

Design: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed.

Setting: 22 clinical sites in the US and 2 in the Netherlands.

Participants: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT).

Intervention: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks.

Measurements: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT).

Results: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively.

Conclusion: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Keywords: Neflamapimod; clinical trial; dementia with Lewy bodies (DLB); p38 MAPK.

PubMed Disclaimer

Conflict of interest statement

John Alam and Kelly Blackburn are employees of, and Amanda Gardner and Hui-May Chu are contractors to CervoMed (formerly known as EIP Pharma, Inc), the commercial entity that is developing neflamapimod as a treatment for DLB and other degenerative disease of the brain. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Neflamapimod improves beta functional connectivity on EEG (A) Corrected Amplitude Envelope Correlation (AECc, median & interquartile range are shown) in the beta band (13–30 Hz) significantly increased with neflamapimod TID (n=6) vs. all placebo (n=17, p=0.033) and vs. placebo TID (n=6, p=0.01). (B) Lower beta (13–20 Hz) AECc changes in the neflamapimod 40mg TID group. Grayscale: p<0.05, based on FDR-corrected permutation t-tests. Color bands represent 2 × SEM. X-axis represents EEG electrodes (10–20 system).
Figure 2
Figure 2
NEffects of 12 weeks neflamapimod treatment on the basal forebrain in patients with Early AD, assessed by MRI A. Nucleus of basalis of Meynert (NbM) volume. NbM volume was statistically significantly higher at the end of treatment compared to baseline (EOT, mean 3.1% higher vs. baseline, p=0.026). B. Functional dynamic connectivity. Neflamapimod was also associated with a statistically significantly higher functional dynamic connectivity between the NbM and deep grey matter (DGM) at EOT (mean 11% higher vs. baseline, p=0.04).
Figure 3
Figure 3
Overview of RewinD-LB Phase 2b study of neflamapimod in Early DLB.

References

    1. Lee G, Cummings J, Decourt B, Leverenz JB, Sabbagh M. Clinical drug development for dementia with Lewy bodies: past and present. Exp. Opin Invest Drugs. 2019;28:11. doi: 10.1080/13543784.2019.1681398. - DOI - PMC - PubMed
    1. Fritz N E, Kegelmeyer D A, Kloos A D, Linder S, Park A, Kataki M, Adeli A, Agrawal P, Scharre D W, Kostyk S K. Motor performance differentiates individuals with Lewy body dementia, Parkinson’s and Alzheimer’s disease. Gait & posture. 2016;50:1–7. doi: 10.1016/j.gaitpost.2016.08.009. - DOI - PubMed
    1. McKeith IG, Rowan E, Askew K, Naidu A, et al. More severe functional impairment in dementia with lewy bodies than Alzheimer disease is related to extrapyramidal motor dysfunction. Am J of Geriatr Psychiatry. 2006;14:582–588. doi: 10.1097/01.JGP.0000216177.08010.f4. - DOI - PubMed
    1. Rongve A, Soennesyn H, Skogseth R, Oesterhus R, Hortobagyi T, Ballard C, Auestad BH, Aarsland D. Cognitive decline in dementia with Lewy bodies: a 5-year prospective cohort study. BMJ Open. 2016;6:e010357. doi: 10.1136/bmjopen-2015-010357. - DOI - PMC - PubMed
    1. Karantzoulis S, Galvin J. Update on Dementia with Lewy Bodies. Curr Transl Geriatr Exp Gerontol Rep. 2013;2:196–204. doi: 10.1007/s13670-013-0053-6. - DOI - PMC - PubMed

Publication types