Treatment Effect of Neflamapimod Enriched When Excluding High P-Tau181 Level Patients

Stephen Gomperts, MD, PhD

An additional prespecified analysis of the phase 2a AscenD-LB (NCT04001517) trial newly published in Neurology showed that patients with dementia with Lewy bodies (DLB) without elevated plasma phosphorylated tau at position 181 (ptau181) levels were more responsive to neflamapimod (EIP Pharma) compared to those with such elevation. These findings suggest an association between ptau181 levels at baseline and patient response to treatment, highlighting the significance of this biomarker in clinical trials.

During the 16-week treatment period, improvements in all end points were higher among neflamapimod-treated patients who were below the 2.2 pg/mL of ptau181 cutoff at baseline (below cutoff, n = 45; above cutoff, n = 40), compared with those above it. Participants below the cutoff showed significant improvement compared with placebo in an Attention Composite measure (+0.42; 95% CI, 0.07–0.78; P = .023, Cohen's d effect size = .78), the Clinical Dementia Rating Scale Sum of Boxes (-0.60; 95% CI, -1.04 to -0.06; P = .031, d = .74), the Timed Up and Go test (-3.1 sec; 95%CI, -4.7 to -1.6; P <.001, d = .74), and International Shopping List Test-Recognition (+1.4; 95% CI, 0.2–2.5, P = .024, d = 1.00).

"In the AscenD-LB study, treatment with oral neflamapimod at a dose of 40mg 3-times-per-day was associated with significant improvements of dementia severity and functional mobility compared to placebo. After the study was completed, multiple reports were published that showed that the blood-based biomarker plasma ptau181 can identify patients with DLB who harbor Alzheimer disease related copathology, which is associated with a greater degree of brain atrophy and associated neuronal loss,” senior author Stephen Gomperts, MD, PhD, director of the Lewy Body Dementia Unit at the Massachusetts General Hospital said in a statement.¹ “Therefore, as prespecified in the protocol, we reanalyzed the effects of neflamapimod 40mg TID in the AscenD-LB dataset, stratifying the sample according to pretreatment levels of plasma ptau181.”

AscenD-LB was a phase 2a double-blind, placebo-controlled, 16-week treatment study assessing neflamapimod among 91 patients with mild to moderate DLB. In the prespecified analysis and at the conclusion of the study, pretreatment plasma ptau181 levels were assessed in patients who had at least 1 on-study efficacy measure and grouped based on a cutoff of 2.2 pg/mL. Each subgroup treated with neflamapimod 40mg TID, the higher and more clinically active of 2 doses studied, had outcomes assessed using the Mixed Models for Repeated Measures.

“These new results show that while the effects of 16 weeks of treatment with neflamapimod were non-significantly different from placebo in patients with abnormally elevated plasma ptau181, neflamapimod was associated with a statistically significant benefit in patients with normal pretreatment levels of plasma ptau181, with a treatment effect size of at least 0.7 for each of the measures of dementia severity, attention, recognition memory, and functional mobility," Gomperts said in a statement.¹

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. Published in September 2022 in the journal of Nature Communications, previous findings of the study with the therapy demonstrated improvements in functional mobility and the dementia rating-scale despite not showing an effect on the primary end point, a cognitive-test battery. The treatment was well-tolerated with no treatment discontinuations associated with the study drug.²

In November 2019, the FDA granted fast track status to neflamapimod for the treatment of DLB.³ Then recently in January 2023, the National Institutes of Health's National Institute on Aging awarded EIP Pharma a $21 million grant to assess neflamapimod in a phase 2b clinical trial in DLB (NCT05869669) with funds to be disbursed over the course over the trial as the costs are incurred.⁴

READ MORE: Memory Consolidation in Epilepsy Enhanced During Sleep With Deep Brain Stimulation

"The results support our long-standing thesis that the key to treating chronic neurodegenerative disease is to intervene early in the disease process, ahead of the patient having extensive neuronal loss in the brain," lead author John Alam, MD, chief executive officer of CervoMed said in a statement.¹ "In the near term, we believe the exclusion of patients with abnormal levels of plasma ptau181 in our ongoing phase 2b clinical trial of neflamapimod in patients with DLB will substantively increase the probability of success in that clinical trial. In the long-term, blood-based biomarkers such as plasma ptau181 hold the potential to implement a personalized medicine approach to treating the major neurodegenerative diseases to enhance the value delivered to patients."

REFERENCES
1. CervoMed Announces Publication in Neurology® Results Showing a Blood Test at Study Entry Identified Patients Who Demonstrated Substantial Response to Neflamapimod in Dementia with Lewy Bodies. News Release. Published September 6, 2023. Accessed September 7, 2023. https://ir.cervomed.com/news-releases/news-release-details/cervomed-announces-publication-neurologyr-results-showing-blood
2. Jiang Y, Alam JJ, Gomperts SN, et al. Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration. Nat Commun. 2022;13(1):5308. Published 2022 Sep 21. doi:10.1038/s41467-022-32944-3
3. EIP Pharma Announces U.S. FDA Grants Fast-Track Designation to Neflamapimod as a Treatment for Dementia with Lewy Bodies (DLB). News Release. EIP Pharma. Published November 7, 2019. Access September 8, 2023. https://www.eippharma.com/news/eip-pharma-announces-u-s-fda-grants-fast-track-designation-to-neflamapimod-as-a-treatment-for-dementia-with-lewy-bodies-dlb/
4. National Institute on Aging (NIA) awards $21M grant to support key phase 2b study of EIP Pharma’s neflamapimod in dementia with Lewy bodies. News Release. EIP Pharma. Published January 18, 2023. Accessed September 8, 2023. https://www.eippharma.com/news/national-institute-on-aging-nia-awards-21m-grant-to-support-key-phase-2b-study-of-eip-pharmas-neflamapimod-in-dementia-with-lewy-bodies/