Early trial of late-onset Pompe disease drug yields positive results
Data suggest ABX1100 may provide 'substantial benefit' for LOPD patients
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ABX1100, an experimental substrate reduction therapy for late-onset Pompe disease (LOPD), was well tolerated and seemed to work as designed in an early clinical trial involving nine adults with LOPD, new data show.
Developer Aro Biotherapeutics noted that, in addition to meeting the study’s primary endpoints, or goals, the top-line data “showed positive effects on lung function and exploratory biomarkers in LOPD, findings that suggest functional improvement.” The infusion treatment also demonstrated “excellent safety,” the company stated in a press release.
“The totality of these data show compelling clinical evidence that ABX1100 may offer a substantial benefit to people with late-onset Pompe disease,” said Purnanand Sarma, PhD, Aro’s CEO.
In Pompe disease, mutations in the GAA gene lead to the absence or dysfunction of the enzyme responsible for breaking down glycogen, a complex sugar molecule. As a result, glycogen builds up to toxic levels in cells, especially muscle cells that normally rely on glycogen as a way to store energy. The buildup of glycogen ultimately causes muscle damage that drives Pompe symptoms.
The mainstay of Pompe treatment is enzyme replacement therapy (ERT), in which a working version of the dysfunctional enzyme is infused into the body. ABX1100 works in a different way.
Developer calls ABX1100 ‘first-in-class therapy’ for LOPD
A substrate reduction therapy, ABX1100 aims to reduce levels of glycogen synthase 1 (GYS1), which is the enzyme mainly responsible for making glycogen in muscle. By reducing this enzyme’s levels and activity, ABX1100 aims to reduce the amount of glycogen that’s made in cells, thereby lessening the toxic buildup of this sugar molecule.
The Phase 1 clinical trial (NCT06109948) enrolled adults with LOPD who had been on stable long-term ERT for at least a year. All participants were treated with ABX1100, administered via two infusions four weeks apart. Participants were then followed for 20 weeks, or about five months, with muscle biopsies collected regularly over the course of follow-up.
The study’s main goal was to assess safety, and those results were positive overall: In line with previously-reported interim data, ABX1100 was generally tolerated well, with no serious side effects documented.
Analyses of muscle biopsy in the thigh indicated that ABX1100 was working as intended. Levels of messenger RNA (mRNA) encoding the GYS1 protein were decreased by an average of 62% at week 10, according to Aro. mRNA is an intermediary molecule that serves as a template to make proteins; a reduction in mRNA encoding GYS1 is indicative of a reduction in GYS1 enzyme levels, suggesting the therapy is working as intended. ABX1100 contains a small RNA molecule designed to bind and degrade the mRNA encoding GYS1.
According to Aro, the effect on mRNA indicates that subsequent infusions of ABX1100 would need to be given no more frequently than once every three months to maintain a consistent effect on GYS1 enzyme levels.
[These results] will guide our discussions with regulatory authorities as we explore how to rapidly move this first-in-class therapy into registrational development.
The researchers also explored percent predicted forced vital capacity (ppFVC), which is a standard measure of lung function that looks at how much air someone can blow out in a single forceful breath. According to Aro, ppFVC usually worsens over time in LOPD patients as the disease progresses, even among individuals taking ERT. But in the seven patients with evaluable data, ppFVC improved by a mean of 2.5% at five months after starting ABX1100 treatment.
Aro also reported that most patients experienced reductions in creatine kinase, a marker of muscle damage, and urinary Hex4, a marker of overall glycogen load, after starting treatment with ABX1100.
“The robust GYS1 mRNA knockdown is quite striking, as is the efficacy on lung function and LOPD biomarkers observed after the administration of just a two-dose loading regimen,” Sarma said. “In particular, the improvement in forced vital capacity – an approved endpoint in other LOPD registrational trials – will guide our discussions with regulatory authorities as we explore how to rapidly move this first-in-class therapy into registrational development.”
