First-Ever Study of STATHMIN-2 Therapy in ALS Commences

Article

The multicenter, multiple-ascending dose trial will feature 64 patients with ALS who will be assessed on safety and pharmacokinetic outcomes.

Angela Genge, MD, FRCPC, chief medical officer, QurAlis

Angela Genge, MD, FRCPC

According to a recent announcement, patient dosing has begun for the phase 1 ANQUR study (NCT05633459) assessing QRL-201 (QurAlis), an investigational agent designed to restore STATHMIN-2 (STMN2) expression in patients with amyotrophic lateral sclerosis (ALS). STATHMIN-2 has been shown to be highly expressed in human motor neurons, the cells that primarily degenerate in ALS.

ANQUR, a multi-center, randomized, double-blind, placebo-controlled multiple ascending dose study, is the first to assess a therapy that rescues STMN2 expression in patients with ALS. In total, 8 cohorts of 8 participants each, will be randomly assigned 6:2 to either QRL-201 or placebo. The primary outcome is safety, assessed by number of treatment-emergent adverse events, with secondary outcomes evaluating pharmacokinetics in plasma.

"STATHMIN-2 is a well-validated protein important for neural repair and axonal stability and is the most significantly regulated gene by TDP-43 exclusively in humans. Its expression is significantly decreased in nearly all ALS patients and it is the most consistently decreased gene over all sporadic ALS patient data sets," Angela Genge, MD, FRCPC, chief medical officer, QurAlis, said in a statement.1 "QRL-201 rescues STMN2 loss of function in QurAlis ALS patient-derived motor neuron disease models in the presence of TDP-43 pathology."

STATHMIN-2 is a well-known protein important for neural repair and axonal stability, the expression of which is significantly decreased in a majority of patients with ALS. Additionally, previous research has shown that patients with the disease almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial forms of ALS. In 2019, QurAlis co-founder Kevin Eggan, PhD, discovered that the expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cords.2

READ MORE: Enrollment Complete for Phase 2 Study of Imlifidase in Guillain-Barré Syndrome

Shortly after, in 2021, research published in Frontiers in Aging Neuroscience linked the novel STMN2 variant to ALS risk, with potential for disease-modifying effects. That analysis, a case-control study, featured 321 patients with ALS and a control group (n = 332) who had CA repeats systematically analyzed using PCR, Sanger sequencing, and high throughput capillary separation for genotyping. Findings showed that long/long CA genotypes were significantly associated with disease risk (P = .042), and most strongly when 1 allele was a 24 CA repeat (P = .0023).3

Additional findings from that study revealed that longer CA allele length was associated with earlier age-of-onset (P = .039) and shorter survival duration in bulbar-onset cases (P = .006). Furthermore, STATHMIN-2 mRNA expression was reduced in sporadic patient olfactory neurosphere-derived cells. Investigators concluded that STMN2 24 CA repeat, which was present in 11.5% of the ALS cases observed, could potentially uncover disease risk in a significantly larger proportion of sporadic patients than the few existing genetic markers currently known.

"ALS is a serious neurodegenerative disease with limited treatment options. There is great need for therapies that could slow disease progression and improve outcomes," Merit Cudkowicz, MD, MSc, director, Sean M. Healey & AMG Center for ALS, chief of neurology, Massachusetts General Hospital, and member of QurAlis’ Clinical Advisory Board, said in a statement.1 "This study has the potential to show QRL-201 could be such a therapy that could potentially benefit ALS patients who have a loss of STMN2 due to TDP-43 pathology."

REFERENCES
1. QurAlis announces first patient dosed with QRL-201, a first-in-class STATHMIN-2 precision therapy for ALS. News release. April 6, 2023. Accessed April 11, 2023. https://www.prnewswire.com/news-releases/quralis-announces-first-patient-dosed-with-qrl-201-a-first-in-class-stathmin-2-precision-therapy-for-als-301790444.html
2. Klim JR, Williams LA, Limone F, et al. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nature Neuroscience. 2019;22:167-179. doi:10.1038/s41593-018-0300-4
3. Theunissen F, Anderton RS, Mastaglia FL, et al. Novel STMN2 variant to amyotrophic lateral sclerosis risk and clinical phenotype. Front Aging Neurosci. 2021;13. doi:10.3389/fnagl.2021.658226.
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