Therapeutics

QRL-101

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Overview

Name: QRL-101
Synonyms: QRA-244
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 1)
Company: QurAlis Corporation

Background

This small molecule is an opener of Kv7.2/7.3 voltage-gated potassium channels, which function to stabilize membrane potential and control neuronal excitability. QRL-101 is being developed to treat amyotrophic lateral sclerosis, with the aim to reduce hyperexcitability-induced motor neuron degeneration. It is taken by mouth.

Kv7 potassium channels were identified as a drug target for ALS using motor neurons derived from patient fibroblasts. In those cells, the channel opener retigabine reversed the cells’ intrinsic hyperexcitability (Wainger et al, 2014). A subsequent high-throughput unbiased screen using patient-derived cells identified the Kv7.2/7.3 subtypes as suppressors of hyperexcitability (Huang et al., 2021). In clinical studies, retigabine, also known as ezogabine, decreased cortical and spinal motor neuron hyperexcitability in ALS patients (Kovalchuk et al., 2018; Wainger et al., 2021).

Retigabine was approved to treat epilepsy in 2011, but was taken off the market a few years later due to safety issues. Among other effects, the drug caused blue skin discoloration and eye abnormalities (Clark et al., 2015). In meeting presentations, QurAlis claims QRL-101 to be more potent and selective for Kv7.2/7.3, and to elicit fewer side effects than retigabine in animal preclinical models (2020 press release). No preclinical data has been published for this compound.

Findings

In December 2022, Phase 1 began with a single ascending dose safety and pharmacokinetic study in The Netherlands. It will enroll up to 72 healthy adults ages 18 to 70 into five dose cohorts, each with placebo control. Completion is anticipated in September 2023.

For details on QRL-101 trials, see clinicaltrials.gov.

Last Updated: 15 May 2023

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References

Paper Citations

  1. Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014 Apr 10;7(1):1-11. Epub 2014 Apr 3 PubMed.
  2. Huang X, Roet KC, Zhang L, Brault A, Berg AP, Jefferson AB, Klug-McLeod J, Leach KL, Vincent F, Yang H, Coyle AJ, Jones LH, Frost D, Wiskow O, Chen K, Maeda R, Grantham A, Dornon MK, Klim JR, Siekmann MT, Zhao D, Lee S, Eggan K, Woolf CJ. Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation. Cell Rep. 2021 Jun 8;35(10):109224. PubMed.
  3. Kovalchuk MO, Heuberger JA, Sleutjes BT, Ziagkos D, van den Berg LH, Ferguson TA, Franssen H, Groeneveld GJ. Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial. Clin Pharmacol Ther. 2018 Apr 19; PubMed.
  4. Wainger BJ, Macklin EA, Vucic S, McIlduff CE, Paganoni S, Maragakis NJ, Bedlack R, Goyal NA, Rutkove SB, Lange DJ, Rivner MH, Goutman SA, Ladha SS, Mauricio EA, Baloh RH, Simmons Z, Pothier L, Kassis SB, La T, Hall M, Evora A, Klements D, Hurtado A, Pereira JD, Koh J, Celnik PA, Chaudhry V, Gable K, Juel VC, Phielipp N, Marei A, Rosenquist P, Meehan S, Oskarsson B, Lewis RA, Kaur D, Kiskinis E, Woolf CJ, Eggan K, Weiss MD, Berry JD, David WS, Davila-Perez P, Camprodon JA, Pascual-Leone A, Kiernan MC, Shefner JM, Atassi N, Cudkowicz ME. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2021 Feb 1;78(2):186-196. PubMed.
  5. Clark S, Antell A, Kaufman K. New antiepileptic medication linked to blue discoloration of the skin and eyes. Ther Adv Drug Saf. 2015 Feb;6(1):15-9. PubMed.

External Citations

  1. clinicaltrials.gov
  2. 2020 press release

Further Reading

No Available Further Reading