Emerging Treatment

Apabetalone (RVX-208)

Apabetalone (RVX-208) is a new oral medication being developed by Resverlogix for the treatment of several conditions, including Fabry disease.

How apabetalone works

Apabetalone is a selective BET (bromodomain and extra-terminal) inhibitor. BET bromodomain inhibition is a new approach that can regulate disease-causing genes. This selective inhibition produces a specific set of biological effects with potentially important benefits for patients with conditions such as high-risk cardiovascular disease, diabetes mellitus, chronic kidney disease, dialysis, Alzheimer’s disease, and Fabry disease.

Apabetalone modulates the expression of a variety of genes. Due to its beneficial effects on several biochemical pathways regulating the accumulation of Gb3, apabetalone holds promise as a potential add-on therapy to accompany ERT in Fabry disease patients.

PRX-102 (Pegunigalsidase Alfa)


PRX-102 (pegunigalsidase alfa) is an investigational enzyme replacement therapy for Fabry disease that was developed by Protalix BioTherapeutics.

Pegunigalsidase alfa is designed to be a plant cell culture-expressed, and a chemically modified version of, the recombinant alpha-Galactosidase-A protein. Protein sub-units are covalently bound via chemical cross-linking using PEG chains, resulting in a more active and stable molecule compared to the current available versions of the molecule as seen in preclinical models. In clinical research, pegunigalsidase alfa appears to have a favorable circulatory half-life, with targeted enzyme activity in organs affected by Fabry disease.

How PRX-102 works

Fabry disease is a genetic condition where patients lack the enzyme called alpha-galactosidase A, which is responsible for breaking down a fat molecule called globotriaosylceramide (Gb3 or Gl-3). Patients with Fabry disease have widespread blood vessel damage due to accumulated Gb3. This can lead to kidney, heart, brain, and nerve problems, and increase the risk of stroke.

PRX-102 consists of recombinant alpha-galactosidase A enzyme administered as an infusion directly into the bloodstream. It aims to replenish levels of this enzyme in people with Fabry disease. PRX-102 is made with Protalix’s plant-based ProCellEx platform.

The treatment is currently being investigated as a therapy that may reduce the number of required enzyme infusions to once a month, compared to existing enzyme replacement therapies that need to be administered every two weeks.

AVR-RD-01 (Clinical Trials*)


AVR-RD-01 is an investigational lentiviral-based gene therapy developed by AVROBIO to treat Fabry disease.

About AVR-RD-01

AVR-RD-01 is an investigational, ex vivo lentiviral gene therapy being developed as a single-dose therapy with the potential to provide life-long therapeutic benefit for patients with Fabry disease. AVR-RD-01 employs a state-of-the-art lentiviral vector system that is designed to be an efficient gene transfer system with the goal of permanent integration of functional copies of the AGA transgene into an individual’s own stem cells. The safety and efficacy of AVR-RD-01 have not yet been established.

How AVR-RD-01 works

Fabry disease is a rare genetic condition caused by a mutation in the GLA gene, which results in the deficiency of an enzyme called alpha-galactosidase A. The lack or reduced activity of the enzyme causes a fatty substance called globotriaosylceramide (Gb3 or GL-3) to build inside cells, leading to irreversible organ damage.

AVR-RD-01 is a gene delivery system using a harmless virus that inserts the nonmutated form of the GLA gene containing information for making functional alpha-galactosidase A into the body.

For the treatment, adult stem cells in the blood (hematopoietic stem cells) are isolated from the patient and exposed to the lentiviral vector, or modified virus. The virus inserts the gene into the stem cells, which are then returned to the patient’s body. Because secreted alpha-galactosidase A by modified blood stem cells is taken up by other cells in the vicinity, this therapy potentially restores alpha-galactosidase A levels to normal ranges throughout the body.

Lucerastat (Clinical Trials*)

Lucerastat is an experimental treatment by Idorsia now in advanced clinical studies for Fabry disease. It functions as a substrate reduction therapy.

How does lucerastat work?

Fabry disease patients are unable to make the enzyme alpha-galactosidase A because of a mutation in the gene (GLA) that contains the information to make this enzyme. Alpha-galactosidase A is necessary to break down fat molecules called globotriaosylceramide (Gb3 or GL-3). Without the enzyme, Gb3 builds up inside cells and damages them, leading to disease symptoms.

Lucerastat is a small molecule called an “iminosugar,” and is almost identical to a sugar molecule except for the substitution of a nitrogen atom in place of an oxygen atom. It is designed to block production of another enzyme, glucosylceramide synthase, which plays a role in the production of Gb3. With less glucosylceramide synthase, less Gb3 is produced, and its build-up is lower even in the absence of alpha-galactosidase A.

Venglustat (Ibiglustat)

Venglustat (ibiglustat) is an investigational therapy being developed by Sanofi Genzyme for the treatment of conditions caused by lysosomal dysfunction such as Fabry, Gaucher, and Parkinson’s diseases.

Lysosomes are small cellular compartments that collect, digest, and dispose of the waste in the cell. In Fabry disease, the lack of the alpha-galactosidase A enzyme in the lysosomes causes incomplete digestion of some lipids (fatty substances) and leads to the accumulation of an intermediate molecule called globotriaosylceramide (Gb3 or Gl-3).

How venglustat works

Venglustat is an oral inhibitor of an enzyme called glucosylceramide synthase (GCS). Enzymes modify specific molecules called substrates. GCS turns its substrate, ceramide, into glucosylceramide (GL-1) during lipid metabolism, a series of biochemical reactions that degrade and generate lipids. GL-1 acts as a substrate to other enzymes and is turned into globosides, a subclass of lipids where Gb3 belongs.

When venglustat inhibits GCS, it prevents the synthesis of GL-1, thereby reducing the substrate of the following reactions that lead to the formation of Gb3 and its accumulation in the absence of α-galactosidase A. That’s why venglustat is called a substrate reduction therapy.