A small molecule with big potential for treating ALS

Amyotrophic lateral sclerosis, or ALS, gets its name from the very process that defines the disease. “Amyotrophic” comes from the Greek: “a” meaning no, “myo” for muscle, and “trophic” meaning nourishment — literally, “no muscle nourishment.” In ALS, motor neurons — the nerve cells that control voluntary muscle movements — gradually die. As these neurons are lost, the muscles weaken, shrink, and waste away, eventually leading to paralysis and death usually within two to five years of diagnosis (1). Despite decades of research, currently available ALS treatments offer only modest benefits, as they don’t address the underlying causes of neurodegeneration in the disease.

QurAlis, a biotech company co-founded by neuroscientist Kasper Roet, is working to change that. The company’s lead drug candidate, an oral small molecule called QRL-101, targets motor neuron hyperexcitability — a key hallmark of ALS wherein motor neurons become overly responsive to stimulation, firing too easily and too frequently.

“Hyperexcitability leads to neuronal death,” explained Roet. “And that is driven by a potassium imbalance.” QRL-101 helps correct this imbalance by activating specific potassium channels known as Kv7.2/3 channels, which generate a stabilizing current that acts like a brake, preventing neurons from firing excessively.

In a recent Phase 1 trial, QurAlis reported that QRL-101 significantly improved multiple biomarkers linked to ALS progression in healthy volunteers. The drug also showed promising effects on brain activity measures relevant to epilepsy. With future clinical trials planned for the drug in both diseases, Roet is optimistic that QRL-101 could offer a new approach in how to treat ALS, epilepsy, and other neurological diseases.

What motivated you to start QurAlis?

I did my PhD on spinal cord repair, and while my lab also did ALS research, the field didn’t understand the disease as well as it does now. For instance, researchers had identified mutations in SOD1 as a significant genetic cause of the disease, but we didn’t yet know if they were gain- or loss-of-function mutations. Because I wanted to make therapies and I didn’t see a clear path to doing that for ALS, I didn’t focus on it then. Later in my PhD, I went to Johnson & Johnson to learn how to develop therapies. While there, I also worked with the Netherlands Brain Bank, where I had a lot of exposure to ALS patients and their families. That reinforced my belief that I should work on developing treatments for neurodegenerative diseases.

Around that time, scientists started to identify many of the genetic causes of ALS, and key pathways that contribute to the disease like autophagy and endoplasmic reticulum stress began to emerge. I started looking for drug targets using large datasets and meta-analyses from postmortem tissues, but I couldn’t find any overlap between humans and animal models, which was frustrating. Then I discovered Kevin Eggan's work at Harvard University. He was using induced pluripotent stem cells (iPSCs) from ALS patients to make motor neurons. That approach made sense to me, and it seemed like a model that could translate clinically. I left Johnson & Johnson and joined Kevin Eggan and Clifford Woolf at Harvard University to learn stem cell technology with the goal of starting an ALS company. After three years, I was ready. I had worked on Kv7 channel openers with both Eggan and Woolf, and when I told them I wanted to start a company, they suggested we do it together. That’s how QurAlis was started — first based on developing a Kv7 channel opener which became QRL-101.

What is QRL-101, and how does it work?

QRL-101 is a Kv7.2/3 potassium channel opener. When we generated the first motor neurons from ALS patient iPSCs, we saw that they were hyperexcitable, and that hyperexcitability leads to neuronal death. That hyperexcitability was driven by a loss of potassium current, specifically the “M current” which normally puts a brake on excitability by preventing neurons from firing repeatedly. The dominant M current in motor neurons comes from the Kv7.2/3 channel. In ALS, the Kv7.2 gene is mis-spliced — an exon is skipped in the pre-mRNA, leading to a non-functional protein that gets degraded. This means there’s less of the channel available, which explains the decrease in M current. QRL-101 changes the activation state of the remaining Kv7.2/3 channels. Even though there are fewer total channels, the drug shifts more of the existing ones into an activated state by changing their sensitivity. That compensates for the loss of the potassium channel. I personally find that absolutely beautiful.

As Chief Executive Officer of QurAlis, Kasper Roet leads the company’s efforts to develop precision medicine solutions for ALS and other neurodegenerative diseases.

Credit: Johnny Ciotti

What was the development process for QRL-101 like?

It started when the Kv7.2/3 target was discovered. At the time, there was an approved drug for epilepsy, a Kv7.2/3 channel opener called ezogabine. GlaxoSmithKline (GSK) sponsored a trial in ALS patients to evaluate biomarkers that predict survival and disease progression. Ezogabine treatment normalized these biomarkers, but GSK eventually pulled the compound off the market due to tolerability issues. We started QurAlis to develop a better Kv7.2/3 channel opener. We believed ezogabine’s tolerability profile was due to off-target activity, so we began an internal program to create a more selective molecule. While we were doing that, we discovered Lilly had a stealth program also on Kv7.2/3 channels with a similar design hypothesis, so we partnered with them for two and a half years. Together, we tested molecules against the selectivity profile we had defined. This led to us discovering a range of very potent, ultra-selective Kv7.2/3 channel openers, eventually settling on QRL-101 and bringing it into development.

What are the key findings of your Phase 1 trial for QRL-101?

The main result for ALS was the strength-duration time constant (SDTC), which is a measure of peripheral motor neuron excitability. In ALS, SDTC is typically elevated, and that elevation has been shown to predict faster disease progression and mortality. In our trial, we saw that QRL-101 led to a statistically significant decrease in SDTC in healthy volunteers. When we did a cross-comparison with ezogabine, QRL-101 was more potent. It had about a 50 percent greater effect on SDTC than what’s been reported for ezogabine in ALS patients. That result also matched what we saw in our preclinical work in rats and in human motor neurons, so it translated really well from preclinical studies to the clinic. We were also interested in the effects of the compound in the brain because ALS is not just a spinal cord disease; it also affects the motor cortex. We looked at intracortical facilitation, which measures the inhibition of cortical excitability, and we showed that QRL-101 led to a statistically significant effect for this biomarker. That’s an important biomarker not just for ALS, but also for epilepsy, where reducing cortical excitability is key. Overall, we’re very confident in the SDTC results for ALS, and we saw clear signs of brain engagement for epilepsy without the off-target effects we might expect from less selective Kv7 channel openers.

What has been the most rewarding part of developing QRL-101 so far?

The most rewarding part was seeing our in vitro data on selectivity and potency recapitulated in vivo in a rat model. The potency and selectivity profile were very similar between the two models. That’s what led us to declare QRL-101 a development candidate — a big milestone for us. Another milestone was seeing that the tolerability profile translated in humans. We now have selectivity and tolerability in humans as well as clear biomarker engagement. I really believe that with QRL-101 we may have a best-in-class Kv7.2/3 opener with potential in ALS, epilepsy, and possibly even more indications. It’s been exciting to see it move through the development pipeline. Of course, there have been challenges — that’s drug development. But we have a great team at QurAlis, and this molecule also went through rigorous testing with Lilly, which really set it up for success.

What’s next for QurAlis?

I’m looking forward to starting proof-of-concept trials for QRL-101 in both ALS and epilepsy —that’s the next critical phase. I’m also excited about the upcoming readout from our QRL-201 trial, which targets STMN2, a gene that is dysregulated in most ALS patients. We’re dosing across six countries and looking for signs of efficacy. It’s a very important trial, and we’re working hard to see it succeed.