Isofagomine (afegostat or AT2101) is an experimental therapy that was developed by Amicus Therapeutics to treat Gaucher disease. The treatment failed a clinical trial and is no longer under development.

How isofagomine works

A serious disorder that can affect many organs and tissues, Gaucher disease is caused by mutations in a gene called GBA. That gene encodes for the beta-glucocerebrosidase enzyme that is responsible for digesting a cellular waste product called glucocerebroside. Mutations in GBA cause the protein to be made incorrectly or not at all. This leads glucocerobroside to build up to toxic levels inside cells.

Gaucher disease can be broadly separated into types based on when symptoms appear, and whether neurological symptoms are present. There are treatments for non-neurological Gaucher disease types, such as enzyme replacement therapy and substrate reduction therapy. However, these treatments are unable to cross the blood-brain barrier, which means that they are not effective in treating neurological symptoms of the disease.

Isofagomine is one of the best-studied “chaperone therapies” — small molecules that help proteins fold correctly. These therapies bind to folding proteins and prevent them from misfolding, which results in more functional protein being produced. It also can mean that toxic buildups of misfolded proteins do not occur.

The structure of isofagomine is similar to glucose. It binds to the active site of the beta-glucocerebrosidase enzyme as it is folding. This was thought to help beta-glucocerebrosidase fold correctly, overcoming problems caused by gene mutations. Isofagomine was believed to be able to cross the blood-brain barrier, which would have allowed it to treat neurological symptoms as well as non-neurological symptoms of the disease.

Isofagomine in research

Preclinical studies in cells isolated from Gaucher disease patients demonstrated that cells treated with isofagomine had increased amounts, and activity, of beta-glucocerebrosidase.

Multiple mouse models had showed similar improvement in beta-glucocerebrosidase activity. For example, one mouse study showed increased enzyme activity in the spleen, liver, lungs, and brain tissue following treatment with isofagomine, which had indicated that the treatment was able to cross the blood-brain barrier.

A Phase 2 clinical trial was carried out in 18 adults with type 1 Gaucher disease over six months. Patients received 225 mg of isofagomine for either three days on/four days off, or seven days on/seven days off. All patients experienced an increase in beta-glucocerebrosidase activity in blood cells, but only 1 patient demonstrated a meaningful reduction in disease symptoms.

Although the treatment was well-tolerated, Amicus Therapeutics ultimately decided that there was insufficient evidence to support further development of isofagomine as a treatment for Gaucher disease.