Phase 1b study of Pompe disease treatment seeks LOPD adults
1st patient in substrate reduction treatment trial to be dosed by year-end
Aro Biotherapeutics is seeking adults with late-onset Pompe disease (LOPD) to participate in a Phase 1b trial testing ABX1100, the company’s experimental substrate reduction treatment, at a site in Canada.
“We anticipate dosing the first patient with Pompe disease in the Phase 1b study before the end of 2024,” Susan Dillon, PhD, co-founder, president and CEO of Aro, said in a company press release.
Pompe is caused by deficiency or malfunction of the acid alpha-glucosidase enzyme, which is needed to break down a complex sugar molecule called glycogen. Without enough of a working version of this enzyme, glycogen builds up to toxic levels and causes damage to cells, particularly muscle cells.
The only approved treatments for Pompe involve enzyme replacement therapy (ERT), in which a working version of the defective enzyme is administered as medicine. The recently approved combination medication Pombiliti + Opfolda delivers the enzyme alongside a molecule that stabilizes it, but it still fundamentally aims to provide a version of the enzyme to the body’s cells.
Substrate reduction therapies like ABX1100 represent an alternative approach to treating Pompe disease. Rather than targeting the missing enzyme, this treatment strategy focuses on reducing the production of glycogen. It’s expected that stopping glycogen production would lessen the toxic buildup of this sugar molecule, ultimately slowing disease progression.
Pompe disease treatment beyond ERT
“The encouraging preclinical and clinical evidence generated to date provides a solid foundation for ongoing clinical studies of ABX1100, which has the potential to be the first new treatment for Pompe disease beyond ERT,” Dillon said.
ABX1100 aims to reduce levels of GYS1, an enzyme involved in glycogen production. The therapy specifically is designed to reduce levels of messenger RNA (mRNA) from the gene that encodes the GYS1 enzyme, also known as GYS1. mRNA is an intermediary molecule used as a template for protein production; by targeting GYS1 mRNA, ABX1100 should prevent the enzyme from being made, ultimately lowering GYS1 levels.
Aro is conducting a first-in-human Phase 1 trial (NCT06109948) to assess ABX1100. The first part of the trial tested the experimental therapy in healthy volunteers, with results demonstrating an acceptable safety profile and proof-of-concept data suggesting the treatment works as intended.
“ABX1100 was well tolerated in a recently completed Phase 1a trial conducted in normal healthy volunteers, and it showed durable GYS1 mRNA knockdown in muscle biopsies, with effects lasting through at least 10 weeks following a single dose,” Dillon said. “The study achieved the goal of identifying a safe and effective starting dose for studies in patients with LOPD. We plan to present the Phase 1a results at a future medical conference.”
The next part of the trial will test ABX1100 in adults with LOPD. Participants will receive infusions of the experimental therapy on days 1 and 29 of the study. The main goals are to evaluate the safety and pharmacological profile of the investigational drug, as well as whether it induces an immune reaction.
Recruitment is ongoing at a center in Calgary, Alberta. To be eligible, patients must be able to walk at least 50 meters (164 feet) without an assistive device. They must also be on a stable dose of ERT for at least six months, or be off of ERT for at least six months, among other criteria.
“The limitations of enzyme replacement therapy for Pompe disease underscore the need for new therapies with novel mechanisms of action,” said Aneal Khan, MD, principal investigator of the trial and medical geneticist at the Metabolics and Genetics in Calgary (MAGIC) Clinic. “ABX1100 is being evaluated as a new therapeutic approach for individuals with late-onset Pompe disease, and we are eager to begin this trial in the underserved Pompe disease population.”
The U.S. Food and Drug Administration has granted ABX1100 both orphan drug and rare pediatric disease designations, which are intended to incentivize the development of therapies for rare disorders.
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