Phase 2 trial results of oral AL01211 in Fabry patients likely this year

Around 16 men with classic disease being treated daily at 30 or 60 mg doses

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration marking a clinical trial.

The investigational therapy AL01211 safely lowered levels of globotriaosylceramide (Gb3) — the molecule that toxically accumulates in Fabry disease — among healthy adults taking part in a Phase 1 trial, according to published results.

The oral treatment, being developed by AceLink Therapeutics, also is being tested in a Phase 2 clinical trial (NCT06114329) in about 16 men with classic Fabry disease, ages 18-60, who have never used a disease-related treatment. Recruitment may be continuing at six sites across China.

Top-line Phase 2 trial results are anticipated in the second half of this year.

“These data reinforce our commitment to provide more convenient and more effective therapeutic options to patients suffering from glycosphingolipid storage diseases such as Fabry disease,” Michael Babcock, PhD, vice president of research and early development at AceLink, said in a company press release.

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“The insights gained from this study have set us up nicely to test the therapeutic benefits of AL01211 in patients,” Babcock said.

The AceLink-supported study, “Phase 1 Healthy Volunteer Study of AL01211, an Oral, Non-brain Penetrant Glucosylceramide Synthase Inhibitor, to Treat Fabry Disease and Type 1 Gaucher Disease,” was published in Clinical Pharmacology In Drug Development.

Fabry disease is due to mutations in the GLA gene that lead to a lack of the alpha-galactosidase A (Gal A) enzyme, which is responsible for breaking down Gb3 inside lysosomes, the cells’ recycling centers. Consequently, Gb3 accumulates to toxic levels and disrupts organ function.

Standard treatment approaches involve enzyme replacement therapies, which provide the body with a working version of Gal A that can break down these molecules. Substrate reduction therapy (SRT) takes the opposite approach. Basically, it intends to reduce Gb3 production altogether, making the lack of Gal A less important.

Investigational SRTs for Fabry, like venglustat and lucerastat, aim to lower Gb3 production by inhibiting glucosylceramide synthase (GCS), an enzyme involved in the synthesis of a group of fatty molecules called glycosphingolipids. Gb3 belongs to this fatty molecule group.

AL01211 is a novel SRT that’s designed to avoid entering a patient’s central nervous system (the brain and spinal cord) as it works to block GCS. In this way, it aims to maximize its effects on targeted organs and minimize any side effects on the brain.

AceLink is developing AL01211 as an oral treatment for Fabry disease and Gaucher disease type 1, which is characterized by the accumulation of a different type of glycosphingolipid, one called glucosylceramide (GL1).

The Phase 1 trial (NCT04908462) was launched in 2021 to evaluate the safety, tolerability, and pharmacological properties of single and multiple doses of AL01211 against a placebo in 69 healthy adults, ages 18-55.

In the single ascending dose arm, participants were administered a single dose of AL012111 (2, 5, 15, 30, or 60 mg ) or a placebo under fasting conditions. A week later, people in the 15 mg dose and its matched placebo group received another single dose after a standard, high-fat and high-calorie breakfast.

In the multiple ascending dose arm, adults were given oral AL01211 (2, 5, 15, or 30 mg) or a placebo once daily on an empty stomach for two weeks.

Treatment safety and tolerability reported in Phase 1 study in healthy adults

As previously reported, AL01211 was well tolerated at all doses, with most side effects being mild or moderate in severity and seen at similar rates in the placebo and treated groups.

Over two weeks of treatment, AL01211 concentrations in the bloodstream increased, reaching steady levels after about 10 days.

Correspondingly, blood levels of GL1 fell in a dose dependent manner, indicating the medication had its intended biological effects. The 30 mg dose of AL01211 led to a 53.1% reduction in Gb3 after two weeks of daily treatment, and a 78% reduction in the GL1 levels of importance to Gaucher patients. These levels did not change in those given a placebo.

Pharmacological analyses indicated that eating a high-fat meal before taking a single dose of AL01211 lowered the medication’s exposure in the bloodstream. “Further food effect studies will be needed to clarify the impact of food on AL01211 exposure,” the researchers noted.

“These results highlight the transformative potential of AL01211 as a best-in-class GCS inhibitor,” said Jerry Shen, PhD, AceLink’s founder and CEO. “Our Phase 1 study provided the critical safety and biomarker data to support our ongoing Phase 2 clinical trial in patients with Fabry Disease.”

In this ongoing trial, which started dosing Fabry patients in October, all are being treated with AL01211 at a daily dose of 30 or 60 mg, on an empty stomach, for up to two years.

Its main goal is to evaluate the therapy’s safety. Secondary trial goals relate to Gb3 and GL1 levels, kidney and heart function, pain related to nerve damage, gastrointestinal issues, and life quality, as well as patient- and clinician-rated measures of overall disease severity.

While an extended trial, its primary part is considered to involve 26 weeks (about 6.5 months) of treatment.