Experimental SMA gene therapy helps with head control, sitting up

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by Margarida Maia PhD |

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A half-full prescription medicine bottle bears a label reading 'Clinical Trials.'

EXG001-307, an investigational nerve cell-targeting gene therapy being developed by Exegenesis Bio, was well tolerated and helped a small group of young children with spinal muscular atrophy (SMA) type 1 to better control their heads and sit up on their own.

That’s according to new data from a Phase 1/2 clinical trial (NCT05614531) that’s testing how safe EXG001-307 is and how well it works when given as a single intravenous or into-the-vein injection to children who have a diagnosis of SMA and are no older than 180 days, or about 6 months of age.

“We are excited about the clinical efficacy and safety data emerging from our Phase 1/2 SMA clinical trial in China,” Zhenhua Wu, PhD, the founder and CEO of Exegenesis, said in a company press release.

“Our team is making rapid progress in our mission to bring this much-needed treatment option to SMA patients worldwide,” Wu said, noting the company plans to accelerate the therapy’s development and file for clinical testing of EXG001-307 in the U.S. in the last quarter of this year.

Wu will present the trial data in a poster at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting, taking place May 7-11 in Baltimore. The poster’s title is “Clinical Safety and Efficacy of EXG001-307 in SMA Type 1 Patients: A Next-Generation AAV-Based Gene Therapy.”

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Exegenesis now testing gene therapy in young children with SMA type 1

According to Wu, Exegenesis is looking into developing EXG001-307 as a treatment for children with other forms of SMA in addition to type 1.

“We are also exploring an accelerated development path in the slightly older SMA type 2/3 patient population,” Wu said.

Unlike in SMA type 1, where symptoms usually become apparent at birth or early in life, in SMA type 2 or 3 symptoms appear after 6 months of age, or later in childhood or adolescence.

SMA is caused by mutations in the SMN1 gene, which provides instructions for producing a protein called SMN. This protein is needed for the proper functioning of motor neurons, the nerve cells that control voluntary movement. When SMN is faulty or missing, motor neurons die, leading to muscle weakness.

Gene therapy in SMA is currently limited to Zolgensma (onasemnogene abeparvovec), which was approved in the U.S. in May 2019 and is now available in more than 40 countries, according to its developer Novartis Gene Therapies. It works by delivering a working copy of SMN1 to the body’s cells so that they can start producing enough SMN on their own.

However, because delivery isn’t restricted to motor neurons, it carries a risk for side effects, including liver and heart damage.

“While first-generation gene therapies like Zolgensma have shown substantial benefits for SMA patients, challenges persist in achieving sufficient SMN1 gene expression [activity] in the target organs and avoiding off-target toxicity,” the researchers wrote.

Like Zolgensma, EXG001-307 carries its genetic cargo aboard a modified and harmless adeno-associated virus (AAV). However, it’s designed to favor delivery into neurons, which is expected to reduce off-target effects in the liver, heart, and other body organs.

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EXG001-307 may be next-generation SMA treatment, per developer

The open-label Phase 1/2 clinical trial is testing a single administration of EXG001-307 in children with clinical features of SMA type 1 who have two copies of the SMN2 gene, a backup gene that leads to the production of a small amount of SMN protein.

Data are available for a small number of children who received EXG001-307 at either 1.1×1014 or 1.5×1014 vector genomes per kilogram of body weight (vg/kg). All of the children showed significant increases in CHOP-INTEND scores, a measure of motor development in which higher scores indicate better function.  

Children in the low-dose group achieved head control at 3-6 months after dosing, and could sit without support 11 months after being given the therapy. Those given the higher dose could sit without support at three months after dosing, according to the researchers.

“All patients achieved significant motor milestones, suggesting EXG001-307 as a next-generation SMA treatment for improved patient outcomes,” the team wrote.

EXG001-307 was well tolerated at both doses. The most common side effects were fever, a type of fast heartbeat known as transient sinus tachycardia, mild elevation of liver and heart enzymes, and a trend toward low blood cell counts. There were no serious side effects that were moderate in severity or worse.

Wu said the company’s mission is “to bring innovative and life-changing genetic medicines to patients globally,” and congratulated his team “for driving our ambitious clinical development timelines.”

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