Use of Fabry disease treatment leads to ‘robust’ cuts in clinical trial
Developer to talk with FDA about potential accelerated approval for AL01211
The main part of a Phase 2 trial testing Acelink Therapeutics‘ AL01211 in men with Fabry disease is now complete, and its developer is reporting that the oral treatment candidate showed a favorable safety profile and led to “robust” reductions in disease biomarkers.
Given these positive data, Acelink said it’s now preparing for discussions with the U.S. Food and Drug Administration about a potential pathway to accelerated approval for AL01211 in the U.S.
In China, AL01211 has received breakthrough therapy designation, a status intended to expedite a treatment’s clinical development and review. Acelink is leveraging that designation to engage with Chinese regulators on potential approval pathways, the company said in a press release.
“The successful completion of the [six]-month main treatment period of this Phase 2 clinical trial is an important milestone,” said Wen Chen, Acelink’s acting CEO. “We are looking forward to obtaining more clinical data and eventually being able to bring a safe and effective therapy to patients in urgent need.”
In Fabry, GLA gene mutations lead to a deficiency in alpha-galactosidase A, known as alpha-Gal A — an enzyme that’s important for breaking down the fatty molecule globotriaosylceramide (Gb3) in cells. Consequently, Gb3, which belongs to a class of molecules called glycosphingolipids, accumulates and causes damage to various organs and tissues.
Currently approved Fabry therapies work to increase the amount of alpha-Gal A available to break down Gb3, thus lowering its levels in order to ease disease symptoms.
AL01211 aims to bypass need for alpha-Gal A enzyme
AL01211 belongs to a class of experimental Fabry treatments called substrate reduction therapies that aim to bypass the need for alpha-Gal A. These therapies seek to reduce the production of Gb3 in the first place. They do this by inhibiting an enzyme called glucosylceramide synthase (GCS) that’s key for the production of Gb3 and other glycosphingolipids.
Substrate reduction therapies are named as such because they lower levels of an enzyme’s substrate, or the substance on which the enzyme exerts its effects. In this case, that’s Gb3.
Relative to other experimental treatments in this class, AL01211 is designed to potently and specifically target GCS in the tissues that are most affected in Fabry, such as the heart and kidneys, while avoiding other tissues where it could cause side effects, such as in the brain.
Acelink is also developing the therapy to treat Gaucher disease type 1, a condition in which a different type of glycosphingolipid accumulates.
In a Phase 1 study in healthy adults, AL01211 was found to be safe and well tolerated. Following those results, Acelink launched this Phase 2 trial (NCT06114329), which started dosing at clinical sites in China in 2023.
Treatment with Fabry disease candidate seen to reduce disease biomarkers
The study enrolled 18 men with classic Fabry — a more severe form of the disease in which little to no functional alpha-Gal A is made — who had not received any Fabry-specific treatment. The participants were assigned to receive daily oral capsules of AL01211 at a dose of 30 or 60 mg for 26 weeks, or about six months.
The main goal was to evaluate safety, with the therapy’s pharmacological properties and disease biomarkers measured as secondary trial goals.
Interim results announced earlier this year showed that the therapy was safe and well tolerated. The 30 mg dose cut Gb3 levels in half, while the higher 60 mg dose led to even faster and stronger Gb3 reductions.
Data also suggested the therapy may protect kidney function, ease pain, and improve life quality, according to Acelink.
While the company didn’t present any new results in its announcement that the main part of the trial was finished, it did indicate that AL01211 was safe and led to biomarker reductions it deemed “robust.”
The magnitude of substrate reduction [seen in trial] reinforces our belief that AL01211 has the potential to provide a convenient and effective oral alternative to current therapies.
Michael Babcock, PhD, cofounder and vice president of research and early development at Acelink, noted that the company is “very encouraged” by the Phase 2 findings.
“The magnitude of substrate reduction reinforces our belief that AL01211 has the potential to provide a convenient and effective oral alternative to current therapies,” Babcock added. “It’s also encouraging that most patients are continuing into the long-term extension” of the trial.
In the study’s long-term extension, participants who finished its main part are continuing to receive AL01211 for as long as two years. Safety, pharmacological properties, and treatment efficacy will be evaluated.
Chen shared the company’s appreciation for all involved in the trial.
“We are grateful to Fabry patients, their families and all investigators for their important contributions to the clinical research of rare disease drugs,” Chen said.
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