VAL-1221 is a potential treatment for Pompe disease being developed by Valerion Therapeutics.

How VAL-1221 works

Pompe disease is an inherited disease caused by a genetic defect that leads to the deficiency or dysfunction of an enzyme called acid alpha-glucosidase (GAA). This allows glycogen, a complex sugar molecule that the GAA enzyme is responsible for breaking down, to accumulate in various cells of the body, primarily in muscle tissues. The buildup of glycogen disrupts cellular functions and leads to muscle weakness and a loss of respiratory function.

Age of disease onset and its severity depend on the extent to which the specific genetic mutation disrupts the workings of the GAA enzyme.

Enzyme replacement therapy, where the missing enzyme is supplied to the body from the outside is commonly used to treat the disease and can provide some relief from the symptoms. However, after a certain period of time, nearly all patients resume their decline in skeletal muscle and respiratory function. This lack of efficiency of enzyme replacement therapy is due to the accumulation of glycogen in multiple cell compartments, not all of which can be accessed by the treatment.

Excessive amounts of glycogen generated in the course of the disease are stored in cellular compartments called lysosomes, as well as in other parts of the cells (extra-lysosomal storage). Enzyme replacement therapy can reduce the amount of glycogen stored in lysosomes but cannot address the problem associated with extra-lysosomal storage.

VAL-1221 is a recombinant fusion protein of Valerion’s proprietary delivery antibody 3E10 with GAA. Due to the presence of the 3E10 antibody, the fusion protein can be delivered to both lysosomal and extra-lysosomal storages of glycogen within cells, where the GAA component of the fusion protein can break down glycogen to reduce its levels inside cells.

VAL-1221 in clinical trials

Valerion initiated a Phase 1/2 clinical trial (NCT02898753) of VAL-1221 in patients with late-onset Pompe disease in 2017. This is a randomized, single- and multiple ascending dose-escalation open-label study designed to evaluate the safety, tolerability, pharmacokinetics (movement in the body), pharmacodynamics (effect on the body), and preliminary efficacy of VAL-1221 in up to 12 patients. All participants are able to walk, do not require a ventilator to breathe, and are being treated with the enzyme replacement therapy Lumizyme.

The trial is currently recruiting participants at two sites in the U.S. and one in the U.K. It is due to end in December 2018.

