Objective:

Evaluate the safety, tolerability, and pharmacokinetics of QRL-101 in healthy volunteers and people living with ALS. 

Background:

Amyotrophic lateral sclerosis (ALS) is a progressively fatal, neurodegenerative disease resulting in the loss of motor neurons in the motor cortex, brainstem, and spinal cord.  In ALS, evidence of increased cellular excitability in peripheral nerves and central motor neurons has been observed through advanced neurophysiological, imaging, pathological and biochemical techniques. Clinically, hyperexcitability has been correlated with decreased longevity in people living with ALS.  QRL-101 is an investigational product targeting motor neuron hyperexcitability. Preclinical studies in models of ALS have indicated QRL-101, a potent, selective KCNQ2/3 channel positive allosteric modulator, may be effective in reducing motor system hyperexcitability in people living with ALS. 

Design/Methods:

QRL-101 will be evaluated in two, consecutive, randomized, placebo-controlled, double-blind, phase 1 studies. QRL-101-01, is an ongoing first-in-human, single-ascending dose (SAD) study in approximately 40 healthy participants. The study design includes five dose escalation cohorts of 8 participants each, randomized in a 6:2 ratio of study drug to placebo. Information from QRL-101-01 will be used to determine a safe and tolerable dose range for the subsequent multicenter multiple-ascending dose (MAD) study, QRL-101-02, which will evaluate QRL-101 in approximately 24 adults living with ALS. Both studies will utilize a sentinel dosing strategy, as well as multiple safety reviews. 

Results:

In both studies, the primary and secondary endpoints will be incidence of adverse events and measurements of the PK of QRL-101. In QRL-101-02, additional exploratory endpoints will be evaluated to assess the impact of QRL-101 on clinical outcomes, and electrophysiological markers of motor nerve excitability in people living with ALS.  

Conclusions:

The findings from these studies will be used to advance the development of QRL-101, and other next-generation precision medicines for people living with ALS and other neurodegenerative diseases.