QurAlis Corporation has announced positive topline data from its Phase 1 proof-of-mechanism clinical trial evaluating QRL-101 in healthy volunteers. The study assessed biomarkers related to amyotrophic lateral sclerosis (ALS) and epilepsy, showing promising results that support further development of the drug candidate for both conditions.
The Cambridge, Massachusetts-based clinical-stage biotechnology company reported that QRL-101, a selective Kv7.2/7.3 ion channel opener, demonstrated statistically significant effects on key biomarkers that predict ALS disease progression and severity.
Significant Impact on ALS Biomarkers
The trial's topline results revealed a dose-dependent, statistically significant decrease in motor nerve excitability threshold tracking (mNETT) strength-duration time constant (SDTC), which served as a co-primary endpoint related to ALS. SDTC is a well-established electrophysiological biomarker of peripheral motor excitability in ALS, where elevated levels have been clinically linked to faster disease progression and higher mortality rates.
Notably, the decrease in SDTC observed with QRL-101 was approximately 50% greater than previously reported for ezogabine, another Kv7 potassium channel opener, in a single-dose study involving ALS patients. The trial also demonstrated significant impacts on multiple secondary and exploratory endpoints related to motor nerve excitability.
"Loss of Kv7.2/7.3 function from the mis-splicing of the KCNQ2 gene leading to hyperexcitability-induced neurodegeneration was one of the first genetic breakthroughs from human ALS motor neuron stem cell models made by our founders at Harvard," said Kasper Roet, Ph.D., CEO and co-founder of QurAlis. "QurAlis was started to develop a best-in-class Kv7 ion channel opener for the treatment of hyperexcitability-induced disease progression in ALS, which occurs in about half of all people living with ALS."
Promising Results for Epilepsy Treatment
Beyond ALS, the clinical trial demonstrated a statistically significant impact on multiple secondary and exploratory endpoints related to epilepsy. These included transcranial magnetic stimulation electromyography (TMS-EMG) intracortical facilitation, which indicates effective inhibition of cortical excitability, as well as significant increases in electroencephalography (EEG) spectral power in beta and gamma spectral bands.
These findings further demonstrate cortical target engagement and brain penetration of QRL-101. Importantly, there was minimal to no impact on the slower delta and theta EEG bands, suggesting a low potential for GABA-A receptor activation and sedation—a common side effect of many anti-seizure medications.
The study did not reach statistical significance on the co-primary endpoint of TMS-EMG motor evoked potential (MEP) amplitude, another measure of corticospinal excitability.
Safety Profile and Mechanism of Action
Results demonstrated that QRL-101 maintained a favorable safety and tolerability profile consistent with previously reported study results. No serious adverse events or discontinuations due to adverse events were reported during the study.
QRL-101 targets Kv7.2/7.3, a voltage-gated potassium channel crucial for regulating neuronal excitability and membrane potential. The drug is designed as a selective Kv7.2/7.3 ion channel opener for treating hyperexcitability-induced disease progression in ALS, which occurs in both sporadic and genetic forms of the disease.
In vivo and in vitro studies have demonstrated that QRL-101 is more potent in threshold track studies and exhibits the potential for fewer clinical adverse events than ezogabine, a less selective, first-generation Kv7.2/7.3 channel opener.
Study Design and Future Development
The Phase 1 proof-of-mechanism study (QRL-101-05, NCT06681441) was a randomized, double-blind, placebo-controlled, three-way crossover trial conducted at the Centre for Human Drug Research in Leiden, The Netherlands. The study evaluated two dose levels of QRL-101 versus placebo in healthy volunteers.
Dr. Roet expressed optimism about the drug's potential: "QRL-101 has the potential to be a promising therapeutic, especially considering the encouraging results from a previous study with ezogabine in ALS patients showing positive effects on both SDTC and the disease progression biomarker compound muscle action potential (CMAP)."
He added, "Based on the strong clinical validation of Kv7.2/7.3 ion channel openers in seizure reduction, the TMS-EMG intracortical facilitation together with the EEG data from this study suggest QRL-101 may have the potential to reduce both frequency and severity of seizures in people living with epilepsy without causing sedation."
Broader Clinical Program
QurAlis is conducting several additional clinical trials to further evaluate QRL-101:
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QRL-101-01 (NCT05667779): A completed first-in-human, single-ascending dose clinical trial in 88 healthy participants that showed QRL-101 to be well tolerated.
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QRL-101-03 (NCT06532396): An ongoing randomized, double-blind, placebo-controlled, multiple-ascending dose clinical trial evaluating safety, tolerability, and pharmacokinetics in up to 60 healthy participants.
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QRL-101-04 (NCT06714396): A Phase 1 proof-of-mechanism single-dose, placebo-controlled clinical trial designed to evaluate safety and tolerability in people living with ALS, expected to enroll approximately 12 participants.
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QRL-101-06: A Phase 1 randomized, open-label, single-dose, cross-over study to evaluate the pharmacokinetics of three formulations of QRL-101 under different conditions.
Based on these promising results, QurAlis intends to advance QRL-101 into proof-of-concept studies as a potentially best-in-class treatment for both ALS and epilepsy, furthering the company's mission of bringing precision medicine options to patients with neurodegenerative and neurological diseases.
