Dosing Begins for Phase 1 Study of Kv7.2/7.3 Ion Channel Opener QRL-101 in ALS

Author(s):

Known as QRL-101-03, the phase 1 study is expected to include 60 healthy participants, with topline results expected in the first half of 2025.

Doug Williamson, MD, chief medical officer at QurAlis

According to a recent announcement, dosing has commenced for a phase 1 multiple-ascending dose (MAD) clinical trial (NCT06532396) assessing QRL-101 (QurAlis), a first-in-class selective Kv7.2/7.3 ion channel opener for the treatment of hyperexcitability-induced disease progression in amyotrophic lateral sclerosis (ALS). Known as QRL-101-03, the phase 1 study is expected to include 60 healthy participants, with topline results expected in the first half of 2025.¹

QRL-101-03 is a follow-on study to QRL-101, an ongoing phase 1, single-ascending dose study (NCT05667779) to determine the safety, tolerability, and pharmacokinetic profile of QRL-101 after a single dose. The newly initiated phase 1 MAD portion includes up to 5 cohorts of 8 participants each, who are randomly assigned in a 9:3 ratio to either QRL-101 or placebo. In total, the approximate duration of study participation for each participant may be up to 39 days.

QRL-101 has a unique mechanism of action than other ALS agents, acting as a Kv7 opener that aims to reduce hyperexcitability-induced neurodegeneration. Kv7.2/7.3 is a voltage-gated potassium channel whose role is critical for the regulation of neuronal excitability and membrane potential. While deactivating this channel leads to abnormal electrical activity in the brain, activating the channel has shown potential to decrease spinal and cortical/motor neuron excitability, signifying the potential for therapeutic benefit.

"We are excited to complete dosing of our first participant cohort in our Phase 1 MAD clinical trial of QRL-101. In the SAD study, QRL-101 was shown to be well tolerated, with no significant safety concerns or serious adverse events," Doug Williamson, MD, chief medical officer at QurAlis, said in a statement.¹ "ALS is a devastating, fatal neurodegenerative disease and there are currently no therapies that can significantly extend patients' lives. QRL-101 has the potential to be a first-in-class effective therapy for ALS patients suffering from hyperexcitability-induced motor neuron degeneration. We look forward to advancing the clinical program for QRL-101 so QurAlis can bring much-needed therapies to people living with ALS."

The phase 1 MAD study will primarily look at safety, specifically the number of treatment-emergent adverse events (TEAEs) and serious AEs, as well as the pharmacokinetics and half-life of the therapy. Patients in the study are between the age of 18 and 70 years, had clinical chemistry laboratory values within acceptable range for the population, body mass index of 18 to 32, and are willing and able to practice effective contraception. The study excludes those with a history or presence of medical illness including, but not limited to, any hepatic, respiratory, hematological, endocrine, psychiatric, neurological disease, or convulsions.

"Motor system hyperexcitability occurs in approximately 50 percent of all ALS patients and is linked to potassium channel dysfunction," Leonard H. van den Berg, MD, PhD, a professor of neurology and chair of TRICALS, said in a statement.¹ "QRL-101, is a highly selective Kv7.2/7.3 ion channel opener, which in preclinical models shows a strong potential to control motor neuron hyperexcitability-induced neurodegeneration with an attractive side effect profile. We are encouraged by the findings from the SAD study of QRL-101 and look forward to results from the MAD study."

QurAlis has another notable agent in development, QRL-201, which is designed to restore STATHMIN-2 (STMN2) expression in patients with ALS. STATHMIN-2 is a well-known protein important for neural repair and axonal stability, the expression of which is significantly decreased in a majority of patients with ALS. QRL-201 is currently being tested in a phase 1 study dubbed ANQUR (NCT05633459), a multicenter, randomized, double-blind, placebo-controlled trial that primarily focuses on safety, by assessing number of TEAEs and pharmacokinetics in plasma.²

Angela Genge, MD, FRCPC, eMBA, clinical director, executive director, clinical research unit, Montreal Neurological Institute, and chief medical officer, QurAlis, presented on therapy at the recent 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas. In her talk, she spoke about gene directed therapies for patients with sporadic ALS and the potential of QRL-201 in ALS care. During the meeting, she sat down to discuss the advantage of QRL-201, how it may restore STMN2 and rescue the disease phenotype seen in ALS.

REFERENCES
1. QurAlis Doses First Participant Cohort in Phase 1 Multiple-Ascending Dose (MAD) Clinical Trial Evaluating QRL-101, a First-in-Class Kv7 Precision Therapy for ALS. News release. QurAlis. September 10, 2024. Accessed September 16, 2024. https://www.prnewswire.com/news-releases/quralis-doses-first-participant-cohort-in-phase-1-multiple-ascending-dose-mad-clinical-trial-evaluating-qrl-101-a-first-in-class-kv7-precision-therapy-for-als-302239922.html
2. QurAlis announces first patient dosed with QRL-201, a first-in-class STATHMIN-2 precision therapy for ALS. News release. April 6, 2023. Accessed September 16, 2024. https://www.prnewswire.com/news-releases/quralis-announces-first-patient-dosed-with-qrl-201-a-first-in-class-stathmin-2-precision-therapy-for-als-301790444.html