Phase 1 Proof-of-Mechanism Study of ALS Therapy QRL-101 Begins Dosing

Kasper Roet, PhD

Dosing has begun in a new phase 1, proof-of-mechanism study (NCT06714396) testing the therapeutic effects of QurAlis’ QRL-101, a Kv7 ion channel opener, as a potential treatment for patients with amyotrophic lateral sclerosis (ALS). Topline results from this single-dose, placebo-controlled study are anticipated in the first half of 2025.¹

Kv7 channels, also known as KCNQ channels, are voltage-gated potassium channels that play a critical role in regulating neuronal excitability by contributing to the M-current, a non-inactivating potassium current that stabilizes membrane potential and prevents excessive neuronal firing. Dysregulation of Kv7 channels has been implicated in various neurological disorders, including ALS, due to their role in maintaining excitability in motor neurons.

Also known as QRL-101-04, this phase 1 study is expected to enroll approximately 12 patients with ALS, testing the effects of QRL-101 on certain excitability biomarkers such as strength-duration time constant (SDTC), a known predictor of survival in patients with ALS. The study also employs several other secondary outcomes, including safety and tolerability, plasma pharmacokinetics (PK), and maximum concentration observed. In the study, patients will receive single doses of either QRL-101 or placebo, with dose levels that may change based on available nonclinical, clinical, safety, and PK data.

"QRL-101 is the only Kv7 ion channel opener being actively studied for the treatment of hyperexcitability-induced disease progression in ALS. The dosing of the first patient with ALS in the clinical development program of QRL-101 is a significant milestone," Kasper Roet, PhD, chief executive officer and co-founder of QurAlis, said in a statement.¹ "Kv7 is implicated in ALS as well as epilepsy. We believe that the data from this study, along with the data from our Phase 1 study evaluating biomarkers of ALS and epilepsy in healthy volunteers, will be valuable as we advance the clinical program for QRL-101 in ALS so that we can bring a much-needed therapeutic option to patients rapidly.”

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In terms of eligibility, patients must be between 18 and 80 years of age, have diagnosis of ALS, by either Gold Coast Criteria or El Escorial Criteria, and have body mass index of 18 to 32 kg/m2. Participants are excluded if they are currently enrolled in another clinical trial involving a study drug, off-label drug or device use, or any medical research deemed incompatible with this study. Additional exclusions include a history of significant medical illnesses, off-label use of investigational ALS therapies, recent participation in another clinical study, or use of medications affecting cytochrome P450 3A4 within the specified timeframe.

"Preclinical models of QRL-101 show its strong potential to control motor neuron hyperexcitability-induced neurodegeneration with an attractive side effect profile,” Leonard H. van den Berg, MD, PhD, professor of neurology and chair of TRICALS, said in a statement.¹ "ALS is a devastating, fatal neurodegenerative disease and there are currently no therapies that can significantly extend patients' lives. We look forward to results from this Phase 1 study in patients with ALS."

QurAlis is also conducted in a phase 1 proof-of-mechanism biomarker trial (QRL-101-05; NCT06681441) to evaluate biomarkers of ALS and epilepsy of QRL-101 in healthy volunteers. In addition, multiple-ascending doses of the agent are also being tested in another study of healthy volunteers (NCT06532396), known as QRL-101-03. That phase 1 trial is expected to include 60 healthy participants, with topline results expected in the first half of 2025.²

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.

REFERENCES
1. QurAlis Doses First Patient With ALS in Phase 1 Clinical Trial Evaluating QRL-101, a First-in-Class Kv7 Precision Therapy for ALS. News release. December 4, 2024. Accessed December 16, 2024. https://www.prnewswire.com/news-releases/quralis-doses-first-patient-with-als-in-phase-1-clinical-trial-evaluating-qrl-101-a-first-in-class-kv7-precision-therapy-for-als-302321243.html
2. 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 December 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