QurAlis’ Phase 2 data bolster case for genetic approach to sporadic ALS

QurAlis' QRL-201 Shows 50% Slowing of ALS Progression in Phase 2

QurAlis presented interim Phase 2 data for its antisense oligonucleotide (ASO), QRL-201, in 69 patients with amyotrophic lateral sclerosis (ALS) at Target ALS’s annual meeting. The study demonstrated up to a 50% decrease in disease progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R) at day 253 with the 10-mg dose. Additionally, the biotech reported significant reductions in cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL), both markers of axonal damage. The FDA considers CSF pNfH a predictor of ALS disease progression. QRL-201 aims to restore stathmin-2 expression, a protein crucial for neural repair and axonal stability, which is downregulated in most ALS patients. These positive results support QurAlis' genetic approach to treating ALS, with a Phase 3 study planned for Q1 2027.

• The Phase 2 Anqur trial of QRL-201 in 69 ALS patients showed a significant slowing of disease progression, with the 10-mg dose leading to a 50% decrease at day 253 on the Revised ALS Functional Rating Scale (ALSFRS-R). This outcome is particularly notable as ALSFRS-R remains the gold standard and a registrational endpoint for prospective ALS therapies, despite some recognized limitations. The effect was more pronounced during the six-month washout phase, consistent with the long half-life and delayed functional effects observed with ASOs.
• QRL-201 demonstrated clear evidence of target engagement, with STMN2 levels at least doubling. The study also reported reductions in cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL). These are critical biomarkers of axonal damage in ALS, and the FDA has recognized CSF pNfH as a predictor of disease progression. This biomarker data provides strong support for the drug's mechanism of action and its potential to impact the underlying pathology of ALS.
• QurAlis' lead asset, QRL-201, is a first-in-class antisense drug designed to restore stathmin-2 expression, a protein downregulated in nearly all ALS patients and directly tied to pNfH loss. The positive interim Phase 2 results validate the company's genetic precision medicine strategy, which CEO Kasper Roet believes is crucial for success in ALS. Building on this data, QurAlis is preparing to initiate a larger Phase 3 study for QRL-201 in the first quarter of 2027, expected to enroll approximately 270 patients, aiming for full regulatory approval.

QRL-201: Targeting Stathmin-2 for Sporadic ALS

CDK4/6 signaling pathway has emerged as a promising therapeutic target in C9orf72 ALS/FTD, with the FDA-approved CDK4/6 inhibitor palbociclib demonstrating therapeutic efficacy in preclinical models. Cell-cycle dysregulation has been established as a central pathogenic mechanism in C9orf72 ALS/FTD, where post-mitotic neurons exhibit age-dependent cell-cycle reentry, increased S-phase entry, and elevated cyclin and CDK expression. Mechanistically, arginine-containing dipeptide repeat proteins (poly-GR and poly-PR) translated from G4C2 repeats drive aberrant CDK4/6 pathway activation, whereas poly-GP and C9orf72 loss-of-function show no effect on this pathway.

Palbociclib treatment normalizes cell-cycle progression, reduces S-phase entry, decreases motor neuron death, and restores synaptic proteins PSD95 and synapsin-1 in C9orf72 ALS models. Supporting evidence from single-nucleus RNA sequencing of C9orf72 patient cortex reveals cell-cycle activation within excitatory neuron subclusters and alterations in DNA repair and cell-cycle regulation pathways. iPSC-derived post-mitotic neurons from C9orf72 carriers further validate these findings by demonstrating the age-dependent nature of cell-cycle reentry in this genetic form of ALS.

miR-206 represents another novel therapeutic target, showing disease-specific protective effects in ALS that contrast with its harmful effects in Alzheimer's disease, stroke, and depression. This microRNA has dual functionality, promoting muscle regeneration while potentially affecting the central nervous system, making it both a potential biomarker and therapeutic target that requires careful tissue-specific regulation approaches. Additionally, dysphagia has been recognized as an independent therapeutic target within disease-specific neurological treatment for ALS patients, with 19.5% of patients with initially unexplained dysphagia receiving ALS diagnosis at specialized neurogenic dysphagia outpatient clinics.

Navigating ALS Endpoints: ALSFRS-R and Biomarkers in QRL-201 Trial

ALS clinical trials utilize a diverse range of endpoints to capture disease progression, functional decline, and survival outcomes. The ALSFRS-R has emerged as the predominant functional assessment tool, though limitations have prompted exploration of alternative measures and biomarkers.

• ALSFRS-R serves as the primary functional endpoint in most ALS trials, measuring disease progression and functional disability with 99.5% data completeness and strong within-subject correlation (0.91), though it exhibits non-linearity, multidimensionality, and floor/ceiling effects

• Survival and tracheostomy-free survival remain critical primary endpoints, particularly in pivotal trials like those for riluzole, with pooled hazard ratio analyses demonstrating 9% improvement in one-year survival probability

• Forced vital capacity (FVC) and slow vital capacity serve as key respiratory function measures, with FVC showing weak correlation with ALSFRS-R (r = 0.31) but providing complementary prognostic value when combined

• Combined functional and survival endpoints using joint modeling frameworks demonstrate superior statistical power, requiring only 464 patients for 80% power compared to 524 for Cox models analyzing survival alone

• Neurofilament light chain levels have emerged as important biomarker endpoints for tracking neurodegeneration and treatment response in clinical trials

• Alternative functional scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS are being evaluated to address ALSFRS-R limitations

• Accurate Test of Limb Isometric Strength (ATLIS) shows greater sensitivity to change than ALSFRS-R, potentially reducing sample size requirements by approximately one-third while detecting prefunctional decline

• Circulating microRNAs (miR-206, miR-143-3p, miR-374b-5p) and COL19A1 protein levels serve as emerging biomarker endpoints for disease progression monitoring and mortality risk stratification

ALS Treatment Landscape: A Renaissance After Recent Setbacks

The ALS treatment landscape has undergone significant transformation over the past five years, marked by the introduction of novel therapeutic modalities and refinement of existing treatments. The most notable advancement has been the FDA approval of the first antisense oligonucleotide (ASO) therapy for ALS, representing a paradigm shift toward precision medicine approaches. Tofersen, targeting SOD1-associated familial ALS, demonstrated remarkable efficacy in clinical studies, with four patients showing either stabilization or improvement of motor function after 15-26 months of intrathecal treatment. These patients achieved a previously undocumented chronic nonprogressive ALS phenotype, with cerebrospinal fluid neurofilament light chain concentrations normalizing regardless of baseline ALSFRS-R scores. While initial ASO successes have focused primarily on rarer familial forms, first-in-class trials targeting mis-splicing events in sporadic ALS and genetic modifiers are now underway, potentially expanding treatment options for the broader ALS population.

Established therapies have also seen substantial clinical validation through real-world evidence and extended follow-up studies. Post hoc analyses of the pivotal edaravone phase 3 trial (Study MCI186-19) have reinforced its long-term clinical benefit, demonstrating efficacy across a broader spectrum of disease trajectories than originally defined in the approval criteria. The PARADIGM phase 2b trial introduced PrimeC, a fixed-dose combination of celecoxib and ciprofloxacin, which showed promising results with a 7.92-point ALSFRS-R difference at 18 months in continuously treated patients and a 64% reduction in risk of ALS complications including hospitalization, respiratory failure, or death. Additionally, novel cell-based approaches have emerged, with autologous stromal vascular fraction therapy demonstrating safety and potential efficacy signals in a 26-patient phase I trial, including significant reductions in key CSF biomarkers and self-reported symptomatic improvement in 57.7% of participants.

The therapeutic development pipeline has expanded to include innovative approaches targeting neuroinflammation, neuroprotection, and immune modulation. GLP-1 receptor agonists, originally developed for metabolic disorders, are being repurposed for ALS based on their neuroprotective properties, with newer agents like NLY01 and tirzepatide designed for enhanced CNS penetration. Regulatory T-lymphocyte therapy combined with IL-2 showed safety and tolerability in phase 1 studies, with 6 of 8 participants demonstrating slow to no disease progression during dose-escalation phases. Despite these advances, some promising preclinical candidates have faced clinical challenges, as evidenced by ceftriaxone's failure to demonstrate survival benefit in large-scale trials despite extensive preclinical validation, underscoring the continued complexity of translating ALS therapeutics from bench to bedside.

QRL-201: A Broad Approach to ALS Pathology

Amyotrophic lateral sclerosis (ALS) remains a devastating neurodegenerative disease with a profound unmet medical need. Despite decades of research, effective treatments that significantly halt or reverse disease progression are scarce, with existing therapies offering only modest benefits. The landscape has seen some progress with targeted gene therapies, particularly for specific genetic forms of ALS, but the vast majority of patients still lack tailored options.

The recent interim Phase 2 data for QurAlis' QRL-201, an antisense oligonucleotide (ASO), marks a potentially pivotal moment. Unlike therapies designed for rare genetic subtypes, QRL-201 targets a more pervasive pathological mechanism: the restoration of stathmin-2 expression. Stathmin-2 is critical for neural repair and axonal stability, and its downregulation is a direct consequence of TDP-43 mislocalization, a hallmark found in most ALS cases, both sporadic and familial. This broad applicability could position QRL-201 as a significant therapeutic option for a much wider patient population.

The reported reductions in disease progression, as measured by the ALSFRS-R, coupled with significant decreases in CSF levels of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL), are particularly encouraging. These neurofilament markers are recognized indicators of axonal damage, and the FDA considers CSF pNfH a predictor of ALS disease progression. This strong biomarker signal, alongside functional improvements, provides a robust foundation for the planned Phase 3 study.

However, the path forward is not without its challenges. The history of ALS drug development is replete with promising early-stage candidates that ultimately failed in larger trials, underscoring the complexity of translating biomarker changes into meaningful, sustained clinical benefit. Furthermore, the ASO therapeutic class, while innovative, has been associated with serious neurologic adverse events in other neurodegenerative conditions, including myelitis and aseptic meningitis, which will require careful monitoring in QRL-201's ongoing development. Demonstrating long-term efficacy and safety beyond the interim 253-day period will be crucial for QRL-201 to fulfill its potential and offer a new, broadly impactful treatment strategy for ALS patients.