QRL-101 reduces motor neuron excitability in healthy volunteers
Nerve cells firing too frequently, too strongly seen in about half of ALS patients
An experimental oral small molecule being developed by Quralis for amyotrophic lateral sclerosis (ALS) reduced motor neuron excitability as intended in healthy volunteers.
That’s according to top-line data from a Phase 1 clinical study (NCT06681441) that tested two doses of QRL-101 against a placebo in healthy adults. A main goal of the study, dubbed QRL-101-05, was to see if the medication could reduce motor neuron excitability, that is, how easily the nerve cells that control movement send signals to muscles.
In ALS, motor neurons often become overly excitable, meaning they fire signals too frequently or too strongly. This feature is observed in about half of ALS patients and over time may contribute to nerve cell degeneration, so reducing excitability is an important focus of ALS research and potential treatment.
QRL-101 also tends to reduce cortical excitability, which is abnormal in people with epilepsy, suggesting it may be able to reduce the frequency and severity of seizures in these patients.
“We are excited by these [top-line] data from our biomarker study in healthy participants which suggest that QRL-101 has the potential to provide a therapeutic effect for both ALS and epilepsy,” Kasper Roet, PhD, CEO and co-founder of Quralis, said in a company press release. “We are encouraged by these results and look forward to advancing the clinical program for QRL-101 in both ALS and epilepsy so that we can fulfill our mission of bringing much-needed precision medicine options to patients.”
The company is also sponsoring a proof-of-mechanism Phase 1 clinical study (NCT06714396), called QRL-101-04, that started dosing adults with ALS late last year. The study is enrolling about 12 patients at a single site in the Netherlands, where participants will be randomly assigned to a single dose of QRL-101 or a placebo.
How would QRL-101 work in ALS?
QRL-101 is designed to open Kv7.2/7.3 ion channels, which work as gates for potassium in nerve cells and help to control their firing ability. By opening the channels, QRL-101 should reduce hyperexcitability, slowing nerve damage and the progression of ALS.
The now-completed Phase 1 clinical study in healthy volunteers included 24 adults who were randomly assigned to either of two doses of QRL-101 or a placebo in a set order. Each patient received all three interventions during separate visits, with a seven-day break between each one to “wash out” the previous treatment.
Researchers focused on two main goals: measuring motor nerve excitability, a biomarker of ALS, using threshold tracking strength-duration time constant (SDTC), and monitoring cortical excitability, a biomarker for epilepsy, using motor evoked potential amplitude.
In ALS, a higher SDTC predicts faster disease progression and shorter survival. In the study, QRL-101 reduced SDTC by about 50% more than ezogabine, a first-generation Kv7.2/7.3 ion channel opener. Ezogabine was approved as an anti-seizure medication, but was discontinued due to its side effects.
“Elevated SDTC has been clinically linked to faster disease progression and mortality, underscoring the need for an effective treatment for this population,” Roet said. Other measures of motor neuron excitability also showed significant improvements with QRL-101.
QRL-101 was well tolerated, with no serious side effects or treatment discontinuations due to side effects. Its safety profile matched previous studies, making it a promising treatment for ALS and epilepsy.
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