Neflamapimod Shows Promise in ALS, Lewy Body Dementia Trials

A new study will explore the impact of neflamapimod on neurofilament light levels in patients with amyotrophic lateral sclerosis (ALS), offering a potential new avenue for treatment of this devastating neurodegenerative disease. The trial, facilitated by the EXPERTS-ALS platform, aims to assess whether the drug can slow disease progression, measured by changes in these biomarkers.

Understanding Neflamapimod and its Potential

Neflamapimod is a modest-molecule drug designed to cross the blood-brain barrier and selectively inhibit the p38 MAP kinase alpha isoform. This enzyme plays a key role in driving neuroinflammation and synaptic dysfunction, processes heavily implicated in the progression of ALS and other neurodegenerative conditions. According to CervoMed CEO, John Alam, MD, the drug’s specific targeting of p38 alpha kinase sets it apart from existing ALS treatments like riluzole and edaravone, which address symptoms but don’t directly target the underlying inflammatory mechanisms. CervoMed believes this focused approach could offer a more effective way to stabilize disease progression.

The rationale behind targeting p38 alpha kinase stems from its role in the communication between nerve cells. Alam explains that inflammation has a “toxic effect on the physiology, on the function, of the nerves,” particularly impacting the nerve fiber and synaptic connections. By blocking this kinase, neflamapimod aims to correct these underlying pathological defects and protect neurons.

Previous Research and Encouraging Signals

Prior research has demonstrated neflamapimod’s ability to restore synaptic function in the basal forebrain cholinergic system, a brain region significantly affected in dementia with Lewy bodies (DLB). Phase 1 and 2 clinical trials involving patients with DLB have shown promising results, with participants demonstrating reduced dementia severity, improved functional mobility, and enhanced cognitive outcomes, alongside good tolerability.

Importantly, studies have also indicated that neflamapimod can positively influence neurofilament light levels – a blood biomarker indicative of neurodegeneration. The most significant benefits were observed in patients without co-existing Alzheimer’s disease pathologies, suggesting a potentially more targeted effect in specific ALS subtypes.

The EXPERTS-ALS Trial: Design and Objectives

The upcoming phase 2 trial will be a randomized, multicenter, open-label study involving approximately 35 patients with ALS. Participants will receive treatment for 18 to 24 weeks, during which researchers will closely monitor changes in neurofilament light chain levels. A reduction of at least 30% in these levels is considered a significant indicator of a positive impact on the underlying disease process. The study will also assess deviations from the natural progression of ALS using various clinical endpoints.

The trial is being conducted through the EXPERTS-ALS platform, a UK-based initiative funded by the National Institute for Health & Care Research. This platform is designed to accelerate drug development for ALS by efficiently testing potential therapies and prioritizing those showing the most promise for clinical trials and regulatory approval. Six additional motor neuron disease centers in the UK are joining the existing 11 involved in the platform, expanding its reach and capacity.

What the Results Could Imply

If neflamapimod demonstrates a significant reduction in neurofilament light chain levels, it could pave the way for a phase 3 clinical trial focusing on broader clinical and survival measures. Alam envisions a potential phase 3 study involving around 75 patients per arm, lasting 6 to 9 months, or potentially a year. The ultimate goal is not to reverse the damage caused by ALS, but to substantially stabilize patients at a certain stage of the disease, improving their quality of life and potentially extending their survival.

The MND Association, My Name 5 Doddie Foundation, and LifeArc are providing support for the study, highlighting the collaborative effort to combat this challenging disease. The study’s success hinges on the translational research capabilities of the EXPERTS-ALS platform, which is considered “fantastic” by Alam in its ability to accelerate the development of new therapies for neurodegenerative diseases.

The researchers will also be measuring changes in clinical endpoints, providing a comprehensive assessment of the drug’s impact on disease progression. Patient enrollment is expected to initiate by the conclude of 2026.

For more information: John Alam, MD, can be reached at [email protected].