Amyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND) in which the motor neurons are gradually lost. As these neurons deteriorate, patients experience muscle weakness, twitching, and atrophy, eventually losing the ability to move, speak, swallow, or breathe independently. A recent review of available data estimated that ALS affects approximately five people per 100,000 in the US.
Only five to 10 percent of cases are inherited, with the vast majority arising sporadically. Regardless of origin, the disease typically progresses rapidly, with most patients surviving just two to five years after diagnosis. Although, there are notable exceptions, including the physicist Stephen Hawking who was diagnosed with a form of MND at 21 and died in 2018 at the age of 76.
A new treatment from CervoMed is now being tested through the UK’s EXPERTS-ALS Platform, which is designed to rapidly evaluate potential therapies for slowing disease progression. The therapy, known as neflamapimod, is an oral small molecule that targets p38 alpha kinase, a protein that regulates axonal transport and becomes overactive in stressed or aging neurons.
Why target p38 in ALS?
One of the hallmarks of ALS is the accumulation of abnormal protein clumps in neurons. Across both sporadic and familial ALS, nearly all patients exhibit TDP-43 (TAR DNA-binding protein 43) proteinopathy, a condition in which the TDP-43 protein misfolds and aggregates in neurons. This misbehavior disrupts essential cellular functions, contributing to the progressive loss of motor neurons.
By inhibiting p38-alpha, neflamapimod interrupts this pathological cascade and protects motor neurons.
—James Shorter, University of Pennsylvania
“By phosphorylating TDP-43 at specific residues, p38-alpha biases TDP-43 toward pathological aggregation instead of normal physiological condensation, which can promote cytoplasmic mislocalization,” James Shorter, a biochemist at the University of Pennsylvania and a leading researcher on the project, explained to DDN. “By inhibiting p38-alpha, neflamapimod interrupts this pathological cascade and protects motor neurons.”
John Alam, CEO of CervoMed, added that, “Overactive p38-alpha disrupts axonal transport, a process that is especially important in motor neurons,” he explained. “By inhibiting p38-alpha, you can restore that transport and help neurons function more normally.”
Research in cell and animal models shows that blocking p38-alpha can both reduce TDP-43 clumping and restore neuronal function. Similarly, patient-derived motor neurons and human induced pluripotent stem cell (iPSC)-derived motor neurons also responded positively to p38-alpha inhibition. “Wherever we tested it, it was protective,” emphasized Shorter.
Beyond preventing further damage, Shorter also said that neflamapimod may offer modest functional improvement. By halting the TDP-43 pathology early and restoring axonal transport, neurons may regain some efficiency, providing a potential small reversal of ALS-related deficits alongside disease stabilization.
Testing neflamapimod in patients
Building on these preclinical results, CervoMed will be advancing neflamapimod into the clinic through the EXPERTS-ALS Platform. The platform is a UK-based initiative designed to accelerate ALS drug development by providing access to well-characterized patient populations and standardized outcome measures. Unlike traditional trials, EXPERTS-ALS does not require a placebo arm for each study, allowing researchers to evaluate potential therapies more quickly while still comparing results against robust historical and ongoing control data.
With nearly 35 years in clinical development, Alam noted that ALS is a particularly challenging area for trials, especially for smaller biotech companies. Patients are severely ill, heterogeneous, and widely dispersed, making recruitment and study design difficult compared with diseases like cancer. “Having a platform like EXPERTS-ALS fundamentally accelerates drug development,” he said. Funded by the UK government and charities, the platform provides infrastructure, investigators, and resources that make trials faster and more efficient.
Having a platform like EXPERTS ALS fundamentally accelerates drug development.
—John Alam, Cervomed
Shorter also praised the infrastructure, noting that it allows rapid progression from early signals to later-phase testing. “The deep integration of translational neuroscience and clinical expertise here is remarkable,” he said. “It’s a model that could speed up ALS research globally.”
A key measure in the trial is neurofilament light chain (NfL), a protein released into the blood when neurons are damaged. Elevated NfL levels closely track with motor neuron injury in ALS, making it a sensitive marker of disease activity. “NfL is currently the most direct biomarker we have for monitoring ALS-related axonal damage,” Alam explained. “While it’s not measuring TDP-43 directly, NfL levels reflect something arguably even more important — the actual damage that TDP-43 is causing to motor neurons and their axons.”
There’s a strong precedent for using NfL as a surrogate marker. In the tofersen trial for patients with SOD1 (Superoxide Dismutase 1)-linked ALS, treatment led to roughly 50 percent reductions in NfL, even before noticeable clinical improvements. That result helped establish NfL as a practical early benchmark, signaling that a drug is hitting its target and potentially slowing neuronal damage. “That has set the game,” said Shorter, “giving a great benchmark for all other therapeutics to go up against.”
The trial is aiming for a 30 percent reduction in NfL levels, which would indicate a meaningful therapeutic effect and help guide progression to later-stage trials.
Lessons from other neurodegenerative diseases
Before entering ALS trials, neflamapimod was tested in dementia, including dementia with Lewy bodies (DLB), where it targets the same p38-alpha pathway to restore neuronal function. Clinical studies have shown that the drug can improve cognitive and motor function, demonstrating both safety and early signs of efficacy.
Across Phase 1 and 2 trials involving more than 800 participants, neflamapimod was generally well tolerated and demonstrated signals of efficacy. In the 91-patient Phase 2a AscenD-LB trial, the drug improved cognitive function and functional mobility. The subsequent 159-patient Phase 2b RewinD-LB trial, which included a 16-week double-blind phase followed by a 32-week open-label extension, confirmed these benefits — enhancing cognition, daily function, and key blood biomarkers of neurodegeneration, particularly in patients without Alzheimer’s co-pathology.
The work underpinning these studies was recently recognized by the Queen Elizabeth Prize for Higher and Further Education, awarded to Newcastle University for its outstanding contributions to understanding and treating dementia, including DLB.
Looking ahead
The inclusion of neflamapimod in the EXPERTS-ALS Platform represents a promising step forward in ALS research. By targeting the p38-alpha pathway, the drug addresses a fundamental mechanism of neuronal dysfunction, with the potential not only to slow disease progression, but also to modestly restore motor function. While ALS remains a devastating disease with urgent unmet needs, the combination of a targeted therapy and an efficient platform trial approach offers hope that meaningful clinical advances may soon be within reach.
