Dosing Starts in First-in-human Phase 1 Trial of QRL-101 for ALS
QRL-101 was developed to selectively target Kv7.2/7.3 potassium channel
A Phase 1 clinical trial has begun dosing adult healthy volunteers to investigate QurAlis Corporation‘s QRL-101, an oral treatment candidate for amyotrophic lateral sclerosis (ALS), the company announced.
The first-in-human Phase 1 trial (NCT05667779) aims to assess the safety, tolerability, and pharmacokinetics — the movement of a drug into, through, and out of the body — of increasing doses of QRL-101 versus a placebo. Ongoing at a single center in The Netherlands, it’s enrolling up to 40 participants, ages 18 to 70.
“We are excited to initiate dosing in this clinical trial of QRL-101,” Kasper Roet, PhD, CEO and co-founder of QurAlis, said in a company press release.
ALS is a progressive neurological disease that causes dysfunction and death of motor neurons, the nerve cells that control voluntary muscle movement. In about half of patients, this degeneration happens because neurons fire electrical signals more readily than normal (hyperexcitability), which is linked to poor survival.
“Motor system hyperexcitability occurs in approximately 50 percent of all ALS patients and is linked to potassium channel dysfunction,” said Leonard H. van den Berg, MD, PhD, professor of neurology at the University Medical Center Utrecht and chair of the Treatment Research Initiative to Cure ALS (TRICALS).
Potassium and other ion channels are proteins in the cell membrane that regulate the entry and exit of charged ions, thereby controlling electrical currents. Researchers believe motor neuron overactivation is linked to the low activity of a potassium channel called Kv7.2/7.3.
In clinical trials, ezogabine, an anticonvulsant that activates Kv7.2/7.3, was able to reduce hyperexcitability in motor neurons of ALS patients. However, it can cause substantial side effects, possibly because it targets other proteins besides Kv7.2/7.3. This caused the medication to be discontinued as an epilepsy treatment.
QRL-101, also known as QRA-244, is an orally available molecule developed to more selectively target Kv7.2/7.3, which could results in fewer side effects compared with ezogabine.
Preclinical research in patient-derived motor neurons showed QRL-101 activated these ion channels, but needed a concentration 20 times lower than ezogabine to achieve the same effect.
Furthermore, a head-to-head comparison in rat models showed QRL-101 had a better safety profile, with fewer and less severe side effects than ezogabine. In particular, it didn’t induce dizziness or fatigue nor affect bladder tissue, known side effects of ezogabine.
“QRL-101 has been shown in preclinical studies to have strong potential to control motor neuron hyperexcitability induced excitotoxicity with significantly fewer side effects than other drug candidates,” Roet said. “QRL-101 has the potential to be a first-in-class effective therapy for ALS patients suffering from hyperexcitability-induced motor neuron degeneration.”
QurAlis is also developing several other treatment candidates for ALS and frontotempotal dementia, a related disorder. These include its lead candidate QRL-201, designed to increase the production of the stathmin-2 protein to counter the damaging effects of TDP43 toxic clumps.