Experimental therapy ABX1100 shows early promise in LOPD trial
Drug exhibited strong and sustained biological activity, signs of clinical benefit
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ABX1100, an experimental substrate reduction therapy being developed by Aro Biotherapeutics, showed strong and sustained biological activity and early signs of clinical benefit in people with late-onset Pompe disease (LOPD), according to preliminary trial results.
The therapy was also well tolerated.
The preliminary results are based on the first four patients enrolled in the Phase 1b portion of an ongoing Phase 1 clinical trial (NCT06109948). The study is evaluating the safety, tolerability, and pharmacological profile of ABX1100 in nine adults with LOPD who are receiving ABX1100 as an add-on to enzyme replacement therapy (ERT), given as two infusions four weeks apart. The data were presented in both an oral session and a poster at the 22nd WORLD Symposium, held last week in San Diego.
The investigational therapy is designed to reduce the production of glycogen — a complex sugar that accumulates to toxic levels, mainly in muscle cells, in Pompe disease — by reducing the levels and activity of glycogen synthase 1 (GYS1), the enzyme muscle cells use to make glycogen.
“We look forward to additional analyses from this ongoing trial as we continue our efforts to measure the clinical potential of GYS1 inhibition as an option for patients in need of new therapeutic approaches to Pompe disease,” Purnanand Sarma, PhD, Aro’s CEO, said in a company press release.
ABX1100 takes different approach than enzyme replacement therapy
Pompe disease is caused by mutations in the GAA gene, which impair the production of the acid alpha-glucosidase (GAA) enzyme that breaks down glycogen. ERT, which provides the body with a functional form of the GAA enzyme, is the mainstay Pompe treatment. However, many patients continue to experience disease progression despite receiving therapy.
“Many patients with Pompe disease endure a significant loss of strength and independence, a burden compounded by the limited muscle-specific uptake of enzyme replacement therapy,” said Ozlem Goker-Alpan, MD, president of the Lysosomal and Rare Disorders Research and Treatment Center and an investigator on the study who presented the data at the WORLD Symposium.
ABX1100 takes a different approach by reducing glycogen production rather than replacing the missing or dysfunctional enzyme. The therapy uses a small interfering RNA (siRNA) that binds to the GYS1 messenger RNA (mRNA), the molecule that carries instructions for making GYS1. By binding to GYS1 mRNA, the siRNA triggers its breakdown — a process known as knockdown — reducing production of the enzyme. ABX1100 also includes an engineered protein, centyrin, to enhance the delivery of the siRNA into muscle cells.
Therapy persisted in muscle tissue
In the first part of the Phase 1 trial, which tested ABX1100 in healthy adults, two infusions given four weeks apart reduced GYS1 mRNA and protein levels in muscle samples by about 70% over 10 weeks. While ABX1100 cleared rapidly from participants’ blood, it persisted in muscle tissue. No serious adverse events were reported up to 85 days after treatment.
Newly shared interim results from the Phase 1b portion continue to show strong and sustained reductions in GYS1 mRNA in thigh muscle samples as early as six weeks after treatment, with effects lasting at least through 10 weeks. According to Aro, the therapy achieved the targeted level of GYS1 mRNA knockdown, indicating it reduced enzyme production as intended. Such data suggest the potential for dosing every three months or less frequently.
“The sustained knockdown of GYS1 mRNA in muscle, as demonstrated in this phase 1b trial in patients, and in the earlier Phase 1 trial in healthy volunteers, provides proof of principle that GYS1 inhibition may be a viable therapeutic approach in patients with late-onset Pompe disease, and a source for hope for the Pompe community,” Sarma said.
Evaluation of the remaining five patients is ongoing, with additional data expected at later time points — including 10 and 16 weeks after treatment — to better understand how long the GYS1 mRNA knockdown persists, the company said.
Our study is the first to demonstrate the effect of a substrate reduction therapy in patients with late-onset Pompe disease.
Investigators also reported early signs of clinical benefit. Levels of creatine kinase, a marker of muscle damage that is often elevated in Pompe disease, declined within 10 weeks of treatment. In addition, three of the four patients showed reductions in blood levels of Hex4, a biomarker of glycogen buildup.
The therapy was generally well tolerated, with no serious adverse events, dose interruptions, discontinuations, or withdrawals.
“Our study is the first to demonstrate the effect of a substrate reduction therapy in patients with late-onset Pompe disease,” Goker-Alpan said. “The favorable safety profile, predictable pharmacokinetics, GYS1 mRNA knockdown, and biomarker reductions support further development of ABX1100 as an addition or alternative to ERT in patients with late-onset Pompe disease.”
ABX1100 has received orphan drug and rare pediatric disease designations from the U.S. Food and Drug Administration, statuses intended to help expedite the development of treatments for rare conditions.
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