Authors :
Presenting Author: Taylor Gray, MS – QurAlis
Taylor Gray, MS – QurAlis
Giovanni Facciponte, PhD – QurAlis
Thomas Bowman, MD, MPH – QurAlis
Hannah Kaneb, PhD – QurAlis
Samantha Rubino, BA – QurAlis
Sharon Lu, PhD – QurAlis
Amit Jain, PhD – QurAlis
Sandy Hinckley, PhD – QurAlis
Daniel Elbaum, PhD – QurAlis
Rationale:
Kv7.2/7.3 is a neuronal voltage-gated potassium channel with a crucial role in the regulation of both neuronal excitability and membrane potential. Kv7 is a clinically validated target to reduce hyperexcitability and susceptibility to epileptic seizures. QRL-101 is a potential best-in-class Kv7 modulator small molecule designed to enhance selectivity for Kv7.2/7.3 and against activation of the GABA-A receptor, Kv7.4, and Kv7.3/7.5. In vivo studies show that QRL-101 penetrates the brain with a Kp, uu of 1 and is safe and well-tolerated when chronically dosed.Methods:
Study QRL-101-05 is a Phase 1 proof-of-mechanism study of QRL-101 in healthy volunteers to evaluate biomarkers related to ALS, pain and epilepsy. A 3-period, 3-way cross-over design in which participants received low- and high-dose QRL-101 and placebo. Participants were assessed by EEG, TMS-EEG, and TMS-EMG at pre-dose, then post dose at an early (starting at 30 minutes) and later (starting at 4 hours) timepoint.
Cortical excitability was assessed through the primary endpoint single pulse TMS-EMG MEP amplitude (uV), secondary single pulse TMS-EMG MEP parameters and pEEG power in alpha frequency bands (eyes open and closed), and exploratory paired pulse TMS-EMG MEP parameters, single and paired pulse TMS-EEG TEP parameters, and other pEEG power bands.
Peripheral motor nerve excitability was assessed through the primary mNETT SDTC endpoint and other exploratory mNETT measurements. Assessments of safety, tolerability, and PK were also conducted.
Results:
TMS-EMG intracortical facilitation was statistically significant at both the high and low dose increasing into significance with time, from the early time point to the later timepoint. There were significant increases in EEG spectral power in beta and gamma spectral bands. Treatment with QRL-101 resulted in significant changes in TEP parameters N100, P180, and 0-300ms from single and paired pulses.
The primary mNETT endpoint and other endpoints related to peripheral nerve excitability were met, establishing a dose-dependent response. The safety and tolerability profile of QRL-101 was consistent with previously reported study results to date. There were no SAEs or discontinuations due to AEs reported in the study.Conclusions:
Biomarkers assessed through TMS-EMG, TMS-EEG, and pEEG indicate evidence of QRL-101 brain penetration, target engagement, and potential anti-seizure effects. Little to no effects on delta/theta waves coupled with no related AEs for somnolence suggest that selectivity for Kv7.2/7.3 against the GABA-A receptor, Kv7.4 channel and Kv7.3/7.5 channel is an effective strategy to improve tolerability of a Kv7.2/7.3 opener without decreasing efficacy. Results of QRL-101-05 support continued development of QRL-101 to a Phase 2 study in epilepsy (NCT06681441).
Funding: NA