QRL-201

EU CTA marks second regulatory clearance for Phase 1 ANQUR clinical trial of QRL-201 in ALS ANQUR is first-ever clinical trial to evaluate a therapy that rescues STATHMIN-2 expression in ALS patients QurAlis recently announced first patient dosed in Canada; enrollment completed in Cohort 1 portion of ANQUR CAMBRIDGE, Mass., June 6, 2023 /PRNewswire/ -- QurAlis Corporation, a clinical-stage biotechnology company developing breakthrough precision medicines for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases with genetically validated targets, today announced that the European review has been completed for the Clinical Trial Regulation (CTR) and each participating country has issued a notice of acceptance for QRL-201 for the potential treatment of ALS. QurAlis expects to initiate the Phase 1 ANQUR clinical trial of QRL-201 in participating European Union (EU) countries by the fourth quarter of 2023. "This EU Clinical Trial Authorisation marks the second regulatory clearance for QRL-201 as we execute our global strategy focused on bringing breakthrough precision medicines to patients with ALS and other neurodegenerative diseases," said Kasper Roet, Ph.D., CEO and co-founder of QurAlis. "We believe QRL-201 has the potential to halt disease progression, which could transform the care and treatment of ALS. We are dedicated to ensuring efficient advancement of our ANQUR clinical trial so that we can fulfill our mission to make a meaningful difference in patients' lives." QRL-201 is a first-in-class precision therapeutic product candidate aiming to restore STATHMIN-2 (STMN2) expression in ALS patients. ANQUR is the first-ever study to evaluate a therapy that rescues STMN2 expression in ALS patients. STMN2 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. QRL-201 rescues STMN2 loss of function in QurAlis ALS patient-derived motor neuron disease models in the presence of TDP-43 pathology. The Clinical Trial Authorisation (CTA) in Europe is part of a global regulatory strategy established by QurAlis for the clinical development of QRL-201, which also includes a cleared CTA in Canada. QurAlis has completed enrolling patients in the Cohort 1 portion of the ANQUR clinical trial in Canada and recently announced the first patient has been dosed. Participating countries in the EU CTA include Germany, Belgium, the Netherlands, and Ireland. About the ANQUR Clinical Trial ANQUR (NCT05633459) is a first-in-human global, multi-center, randomized, double-blind, placebo-controlled multiple-ascending dose Phase 1 clinical trial designed to evaluate the safety, tolerability, and pharmacokinetics of QRL-201 versus placebo in patients with amyotrophic lateral sclerosis (ALS). The primary objective of the study is to determine the safety and tolerability of multiple doses of QRL-201 in people living with ALS. The ANQUR clinical trial is expected to include 64 study participants with ALS across sites in Canada, the European Union, U.S., and United Kingdom. Visit for more information about the ANQUR study. About STATHMIN-2 and TDP-43 STATHMIN-2 (STMN2) is a well-validated protein important for neural repair and axonal stability, the expression of which is significantly decreased in nearly all ALS patients. Also known as SCG-10, STMN2 is a protein essential for the stabilization of microtubules which form an important component of the cytoskeleton of cells and axons. STMN2 is highly expressed in human motor neurons, the cells that primarily degenerate in patients suffering from ALS. In animal models, STMN2 deletion was found to cause axonal degeneration and loss of muscle innervation, which is the primary functional deficit that leads to paralysis in ALS patients. Using human neuronal stem cell models from ALS patients, QurAlis co-founder and former Harvard professor Kevin Eggan, Ph.D., discovered in 2019 that the expression of STMN2 is regulated by TDP-43. The Eggan Lab showed that loss of normal TDP-43 function leads to a highly significant decrease in expression of STMN2 and an impairment in neuronal repair which could be rescued by restoring STMN2 levels. These results were published in Nature Neuroscience. In addition to nearly all ALS patients, TDP-43 pathology is also associated with approximately 50 percent of patients with frontotemporal degeneration (FTD), the second most common form of dementia; about a third of Alzheimer's Disease patients; and up to seven percent of Parkinson's disease patients. There are currently no cures for ALS or FTD. Limited therapeutic options are available for ALS and FTD patients who are in desperate need for effective therapies. About QurAlis Corporation QurAlis is trailblazing the path to conquering amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases with genetically validated targets with next-generation precision medicines. QurAlis' proprietary platforms and unique biomarkers enable the design and development of drugs that act directly on disease-causing genetic alterations. Founded by an internationally recognized team of neurodegenerative biologists from Harvard Medical School and Harvard University, QurAlis is advancing a deep pipeline of antisense oligonucleotides and small molecule programs including addressing sub-forms of ALS that account for the majority of ALS patients. For more information, please visit or follow us on Twitter @QurAlisCo. SOURCE QurAlis

Pictured: 3D illustration of degradation of motor neurons/iStock, Dr_Microbe Wave Life Sciences continues to have issues with its antisense oligonucleotides. In 2021, the company shelved its lead antisense candidates for Huntington’s disease, and on Tuesday, it said goodbye to another being developed for ALS and frontotemporal dementia. In a Phase Ib/IIa trial of 35 people with C9orf72 (C9)-associated ALS or frontotemporal dementia (FTD), WVE-004 failed to show any clinical benefit after 24 weeks, Wave reported. Based on these data and a lack of biomarkers likely to predict clinical benefit, the company is discontinuing asset development. Five to 10% of ALS cases in the U.S. are familial, according to the NIH. Of these, 25% to 40% are caused by a hexanucleotide repeat expansion in the C9orf72 gene. Mutations in this gene have also been identified as a common cause of FTD. WVE-004 was designed to lower levels of the C9orf72 protein. The therapy aims to rescue normal C9orf72 protein by selectively targeting transcriptional variants containing the hexanucleotide repeat expansion. Mutations in the C9orf72 gene cause the accumulation of G4C2 RNA, which produce poly(GP) proteins. While studies have shown poly(GP) to be an effective biomarker by which to test therapies targeting C9orf72, Wave reported that reductions in this marker did not correlate to clinical benefit. The company did report “potent and durable target engagement,” with poly(GP) falling by up to 50%, perhaps providing positive signals for other programs. “These data reinforce that our preclinical data on target engagement and pharmacology are translating in the clinic,” Paul Bolno, CEO of Wave, said in a prepared statement. Paul Bolno Bolno said he’d hoped for better after data from the Ib/IIa FOCUS-C9 study, announced in April 2022, showed target engagement across all treatment groups. “Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field,” he said in the same statement. ASO Hits and Misses Antisense drugs targeting C9-ALS have had a bad run recently. In March 2022, Biogen and Ionis discontinued their ASO, BIIB078, after it also failed to show clinical benefit in the Phase I trial. But ASOs have also succeeded in ALS—namely, Biogen’s Qalsody (tofersen), which won FDA approval in April for superoxide dismutase 1 (SOD1)-ALS. The SOD1 protein is highly expressed in motor neurons, and the underlying SOD1 gene is mutated in up to 20% of familial cases of ALS and 2% of all cases. Merit Cudkowicz “I think the genetic mutation that causes C9 ALS is much more complicated than SOD1,” said Merit Cudkowicz, chief of the neurology department at Massachusetts General Hospital and co-principal investigator of Biogen’s VALOR study, told BioSpace. “It is a hexanucleotide repeat, intronic—and that field is still learning the best way to approach therapies for C9 ALS.” Cudkowicz is also an institutional consultant for Wave. Cudkowicz said that she believes antisense therapies are still highly relevant for other genetic forms of ALS “and maybe still for C9 in other ways.” Antisense therapies also have the potential to treat sporadic forms of ALS, Cudkowicz said, pointing to Cambridge, Massachusetts–based QurAlis, whose splice switching ASO, QRL-201, protects neurons against neurodegeneration, the company’s founder and CEO, Kasper Roet, told BioSpace in a previous interview. In terms of what led to the lack of clinical effect for WVE-004, Bolno said that C9-ALS/FTD biology is complex, “and we can only conclude at this time that there may be other biological factors that impact outcomes beyond those addressed in the design of WVE-004.” Looking ahead, Wave’s focus “remains on diseases where biomarkers correlated with functional outcomes are available,” Bolno told BioSpace via email. This includes a key readout from the Phase Ib/IIa SELECT-HD study in Huntington’s disease, which he said remains on track for the second half of this year. Bolno said that Wave would not exclude ALS as a therapeutic area in the future “if there was a clinically validated biomarker correlated with functional outcomes available to guide to clinical development.” Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.