QRL-101 reduces motor-neuron hyperexcitability in ALS trial
Oral therapy engaged its target and showed a favorable safety profile
QRL-101, an experimental oral small molecule being developed by Quralis for amyotrophic lateral sclerosis (ALS), was found in an early clinical trial to engage its intended biological target and reduce nerve cell overactivity in people with ALS.
These results come from a proof-of-mechanism Phase 1 clinical study (NCT06714396), called QRL-101-04, that enrolled 12 adults with ALS. Participants were randomly assigned to receive a single dose of QRL-101, at one of several increasing dose levels, or a placebo. The main goal was to study how the medication moves through the body (pharmacokinetics) and what effects it has (pharmacodynamics).
Researchers also measured changes in “nerve cell excitability,” which describes how easily nerve cells fire signals. In ALS, increased excitability has been linked to faster disease progression and shorter survival. As in a previous Phase 1 clinical study (NCT06681441) in healthy adults, QRL-101 reduced nerve cell excitability compared with placebo.
Based on these findings, Quralis now plans to move QRL-101 into a Phase 2 proof-of-concept clinical trial to further test its potential benefits in people with ALS.
“This is the first time we are seeing target engagement of QRL-101 in ALS patients with a biomarker which predicts survival in ALS,” Kasper Roet, PhD, CEO and co-founder of Quralis, said in a company press release. “We look forward to advancing the clinical program for QRL-101 in ALS.”
Why reducing motor-neuron overactivity may matter in ALS
In ALS, motor neurons — the nerve cells that send movement signals from the brain and spinal cord to muscles — gradually become damaged and die. This leads to muscle weakness and other movement-related symptoms.
In about half of people with ALS, researchers believe that some of this motor-neuron damage is caused by the cells becoming “over-excitable,” meaning they fire signals too frequently or too strongly. Because of this, reducing overactivity has become an important treatment target.
QRL-101 is designed to open Kv7.2/7.3 ion channels, tiny “gates” that control the flow of potassium in nerve cells. These channels help regulate how easily nerve cells fire. By opening them, QRL-101 is expected to reduce hyperexcitability, which may help protect motor neurons from damage.
A recent study found that abnormalities in the TDP-43 protein, seen in nearly all ALS cases, can cause errors in how Kv7.2/7.3 channels are produced. This leads to faulty channels that make nerve cells overactive and more vulnerable to damage, “further validating this disease mechanism,” Roet said.
As seen previously in a Phase 1 study in healthy adults, the QRL-101-04 trial also showed that QRL-101 reduced motor-neuron hyperexcitability compared with placebo. The effect was stronger at higher doses, and results were consistent across several different measures of excitability.
The pharmacokinetics and pharmacodynamics of QRL-101 were also consistent with earlier results. No serious side effects or discontinuations due to side effects were reported, supporting plans to move QRL-101 into a Phase 2 proof-of-concept study.
“Quralis’ co-founders and collaborators had previously demonstrated that loss of Kv7.2/7.3 leads to motor neuron death and we are excited by these data which confirm that QRL-101 has the potential to provide a therapeutic effect for ALS patients,” Roet said.
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