AL01211 for Fabry disease

Last updated June 5, 2024, by Lindsey Shapiro, PhD
Fact-checked by Ana de Barros, PhD

What is AL01211 for Fabry disease?

AL01211 is an experimental substrate reduction therapy that’s being investigated for the treatment of Fabry disease.

Developed by AceLink Therapeutics, it’s intended to slow or prevent organ damage by reducing the levels of fatty molecules that accumulate to toxic levels inside cells.

Relative to other therapies in its class, AL01211 is designed to be more specific for the tissues affected in Fabry disease, such as the heart and kidneys, while avoiding the brain, where it could cause side effects.

AL01211 has been granted orphan drug status for Fabry disease in the U.S., a designation that’s intended to provide incentives to speed its clinical development. The therapy is also being developed for the treatment of type 1 Gaucher disease, another condition where fatty molecules toxically accumulate to cause organ damage.

Therapy snapshot

How does AL01211 work?

In Fabry disease, mutations in the GLA gene mean that not enough of a functional alpha-galactosidase A (alpha-Gal A) enzyme is produced. Alpha-Gal A is needed to break down fatty molecules, particularly globotriaosylceramide (Gb3), in cells. When it is lacking, Gb3 accumulates to toxic levels, driving progressive organ damage and other Fabry disease symptoms.

Substrate reduction therapies, or SRTs, broadly work to lower levels of a molecule that has accumulated because the enzyme that normally maintains its balance is impaired. A substrate is a molecule on which an enzyme acts.

AL01211 is an SRT that works to lower levels of Gb3 (the substrate) without the need for alpha-Gal A (the faulty enzyme). It does this by inhibiting glucosylceramide synthase (GCS), an enzyme that’s necessary for the production of Gb3 and related molecules, called complex glycosphingolipids. By inhibiting GCS, AL01211 should lower production of Gb3, thereby slowing the progression of organ damage and easing Fabry symptoms.

According to AceLink, relative to other SRTs, AL01211 is more potent and exhibits strong penetration into tissues affected in Fabry, such as the kidneys and heart, but has low penetration in the brain. This should help avoid side effects associated with SRT activity in the brain.

How is AL01211 administered?

In an ongoing Fabry disease clinical trial, AL01211 is being administered as once daily oral capsules at a dose of 30 or 60 mg. Oral doses ranging from 2 mg to 60 mg have been tested and found safe in healthy adults.

AL01211 in clinical trials

To date, the safety of AL01211 has been established in Phase 1 trials involving healthy adult volunteers.

Data from a Phase 1 trial (NCT04908462) showed that single (up to 60 mg) and multiple (up to 30 mg for two weeks) doses of AL01211 were well tolerated with no serious side effects. The treatment also dose-dependently reduced levels of Gb3 and related molecules.

At a 30 mg dose, blood levels of GCS and Gb3 were reduced by 78% and 52%, respectively, compared with the beginning of the study.

In another Phase 1 trial (ChiCTR2200061431), the treatment was similarly found to be safe and well tolerated with favorable pharmacological properties in healthy adults.

Ongoing Phase 2 trial

An ongoing open-label Phase 2 trial (NCT06114329) is testing AL01211 in about 16 men with classic Fabry disease, its most severe form, ages 18-60, who’ve never before received a Fabry disease-specific treatment.

Participants will receive AL01211 (30 mg) taken orally once per day for an initial period of 26 weeks, or about six months. Should preliminary data show good safety, a higher dose group (60 mg) will also be enrolled. The initial six-month period will be followed by an extension phase, where all will continue treatment for up to two years. While safety is the study’s primary outcome measure, disease biomarkers and other measures of Fabry disease symptoms and severity will also be evaluated.

Common side effects of AL01211

Clinical studies of AL01211 in Fabry disease patients are still new, so its side effect profile in that patient group isn’t yet known.

However, in clinical trials involving healthy adults, the treatment was well tolerated. Side effects were mostly mild to moderate in severity, with no serious adverse events, and included:

• headache
• nausea
• abdominal pain
• diarrhea
• tongue lesions
• eye discomfort and fatigue

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