Dosing begins in Phase 1 trial of QRL-201 in promoting neuronal repair

Study in ALS patients testing safety of therapy to raise stathmin-2 protein levels

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by Andrea Lobo |

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A first patient has been dosed in a Phase 1 clinical trial evaluating QRL-201, an experimental antisense oligonucleotide (ASO) molecule in treating amyotrophic lateral sclerosis (ALS), the therapy’s developer, QurAlis, announced.

Dubbed ANQUR (NCT05633459), the study is reported to be the first into a potential therapy that works to increase production of stathmin-2 (STMN2), a protein needed for neuronal growth and repair. In nearly all ALS patients, STMN2 levels are low.

ANQUR is expected to enroll up to 64 adults with ALS, ages 18 to 80, and no SOD1 or FUS gene mutations at sites in Canada, Europe, and the U.S. It is testing the safety and tolerability of multiple ascending doses of QRL-201 against a placebo in groups of patients.

The trial currently is ongoing in Canada, and the first dose was given at the University of Montréal Hospital Centre.

“QRL-201 recently entered the clinic in Canada and we are pleased to dose our first patient. We look forward to advancing the ANQUR clinical trial of QRL-201 for the treatment of ALS so that we can make a meaningful difference in patients’ lives,” Angela Genge, MD, chief medical officer at QurAlis, said in a company press release.

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Raising stathmin-2 levels may protect neurons, slow ALS progression

ALS is a progressive condition that affects motor neurons, the nerve cells that control voluntary movements. The loss of these neurons weakens a person’s muscles. While a handful of ALS therapies are approved, their ability to slow the disease’s advance is limited.

“There is great need for therapies that could slow disease progression and improve outcomes,” said Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital and a member of QurAlis’ clinical advisory board.

Most ALS cases are characterized by abnormalities in the TDP-43 protein, which forms toxic clumps that damage cells. This protein is normally needed to process messenger RNA, an intermediate molecule that results from genes, which provides the instructions to make proteins.

When TDP-43 is faulty, the mRNA molecule carrying instructions for stathmin-2 production has an abnormal sequence, resulting in low levels of the STMN2 protein, previous research reported.

Raising stathmin-2 levels also has shown a potential to reduce the defects caused by TDP-43 clumping and restore a cell’s ability to repair neurons. These findings indicate QRL-201 could help to slow disease progression in ALS patients.

“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,” Genge said. “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.”

The ongoing trial is testing QRL-201’s safety, tolerability, and pharmacokinetics — how a drug moves into, through, and out of the body — in ALS patients. Participants, in groups of eight people each, will be randomly assigned to one of eight increasing doses of the therapy or to a placebo, both given by intrathecal injection (an injection into the spinal canal).

“This study has the potential to show QRL-201 … could potentially benefit ALS patients who have a loss of STMN2 due to TDP-43 pathology,” said Cudkowicz, who is also the director and a professor of neurology at Harvard Medical School.