Experimental ALS Therapies QRL-201 and Neflamapimod Advance in Clinical Trials
Two experimental ALS therapies showed promise in recent clinical developments. Interim Phase 1/2 data suggest the antisense oligonucleotide QRL-201 restores a critical nerve protein and may slow disease decline, with a Phase 3 trial planned for 2027. Meanwhile, the oral therapy neflamapimod has been selected for testing in the UK's EXPERTS-ALS platform study, with first results expected this spring.
Approximately 35,000 people in the United States live with amyotrophic lateral sclerosis (ALS), with about 5,000 new diagnoses each year, according to the Centers for Disease Control and Prevention. A recent CDC study estimates cases will rise by 10% by the year 2030. In about 90% of ALS cases, there is no family history of the disease — a form known as sporadic ALS — while approximately 10% to 15% of patients carry a genetic variant that causes familial ALS.
Two experimental therapies for ALS have recently advanced in clinical development, offering new avenues for a condition that currently has limited treatment options.
Interim data from the Phase 1/2 ANQUR trial (NCT05633459) suggest that the experimental therapy QRL-201 successfully reached its biological target and showed early signs of slowing disease progression in people with sporadic ALS. The trial is testing the safety and preliminary efficacy of multiple doses of QRL-201, an antisense oligonucleotide given as an injection into the spinal canal. The treatment is designed to restore levels of Stathmin-2 (STMN2), a protein essential for nerve stability and repair that becomes depleted when the TDP-43 protein malfunctions — a hallmark of most ALS cases.
Results from the ANQUR trial, which enrolled 69 adults with sporadic ALS, showed that QRL-201 reached its intended target in the spinal cord and motor cortex, with STMN2 levels increasing above the estimated therapeutic target. The treatment also corrected the splicing of STMN2's messenger RNA. In the group of patients treated with the lower dose, there was a significant reduction in phosphorylated neurofilament heavy chain, a biomarker of nerve cell damage. Patients also showed a trend toward slower worsening on the ALS Functional Rating Scale-Revised (ALSFRS-R), a measure of daily function.
An additional post-hoc analysis that excluded patients with very high levels of neurofilament light chain — which is linked to faster disease progression — showed a statistically significant slowing of ALSFRS-R decline after about six months with QRL-201 compared with a placebo. The treatment was reported as safe and well tolerated, with most side effects being mild or moderate. Based on these findings, developer Quralis is moving forward with an open-label extension study that has been approved in Canada, and a pivotal Phase 3 trial is scheduled for 2027.
Separately, the oral therapy neflamapimod has been selected for inclusion in the EXPERTS-ALS platform study, a U.K. initiative designed to rapidly evaluate multiple potential treatments for ALS simultaneously. The platform study is sponsored by Sheffield Teaching Hospitals NHS Foundation Trust and funded by the U.K.'s National Institute for Health and Care Research and several ALS-focused charities. Its primary goal is to determine whether investigational therapies can reduce levels of neurofilament light chain (NfL), a marker of nerve damage, allowing researchers to assess potential within a few months using a small group of patients.
Neflamapimod, developed by U.S. biotech company Cervomed, targets the alpha isoform of p38 MAP kinase, a protein involved in inflammation and synapse dysfunction — two processes thought to drive ALS progression. The therapy has previously shown a favorable safety profile and early signs of effectiveness in trials involving people with dementia with Lewy bodies, another neurological disorder marked by synaptic abnormalities. A Phase 3 trial in that indication is expected to begin later this year.
In the neflamapimod arm of EXPERTS-ALS, approximately 35 adults with ALS will be treated for 18 to 24 weeks. The main goal is to determine whether the therapy lowers NfL levels, which could indicate reduced nerve cell damage. Researchers will also evaluate clinical measures of disease activity and survival as secondary outcomes. If initial results are encouraging, the arm may be expanded to include up to 80 adults with ALS.
The EXPERTS-ALS platform is currently testing three other therapies already approved for different indications: the antidiabetes drug metformin, the calcium channel blocker nifedipine, and the Parkinson's treatment ropinirole. The study is being conducted at 11 centers across the U.K., with plans to expand to 17 sites. New treatments are evaluated and added to the platform every three to six months.