CONCORD, Mass. – (April, 2017) – Valerion Therapeutics, part of the Alopexx Enterprises portfolio of companies, has announced the development of VAL-1221, a fusion protein that combines its technology with recombinant human acid alpha-glucosidase (rhGAA) to improve delivery of rhGAA to affected tissues in patients with Pompe disease. Valerion specializes in the development of therapies for orphan genetic diseases through the use of its proprietary antibody-mediated delivery platform, which enables enhanced intracellular delivery of a range of active therapeutic molecules by way of a transport mechanism present in muscles and neurons.

Pompe disease, according to the National Organization for Rare Disorders (NORD), is a rare genetic disease consisting of low levels or a lack of the lysosomal enzyme GAA, which is needed to metabolize glycogen and convert it into glucose. As explained on NORD’s website, “Glycogen is a thick, sticky substance and failure to properly break it down results in massive accumulation of lysosomal glycogen in cells, particularly in cardiac, smooth and skeletal muscle cells … Pompe disease belongs to a group of diseases known as the lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units of cells. Enzymes within the lysosomes break down or digest particular nutrients, such as complex molecules composed of a sugar attached to a protein (glycoproteins).”

In the case of Pompe disease, glycogen can accumulate in the lysosomes and cytoplasm in patients with late-onset disease, but the therapeutic activity of existing enzyme-replacement therapies (ERT) is limited to just the lysosome. VAL-1221, by contrast, was found in preclinical experiments to work in the lysosome and through another mechanism to lower glycogen accumulation.

Valerion studied VAL-1221 in cultured Pompe disease fibroblasts and in Pompe (GAA-deficient) mice, and found that the compound both reduced lysosomal glycogen accumulation as effectively as current ERT, and penetrated living cells independent of the mannose-6-phosphate receptor (M6PR), the mechanism of cell entry seen with the current treatments that direct the ERT enzyme to the lysosome.

Deborah Ramsdell, CEO of Valerion, notes that based on this capability, “VAL-1221 has the potential to clear cytoplasmic glycogen outside of lysosomes, which is not currently being addressed by other Pompe disease treatments.”

“There are some other therapies in the clinic, but they are all geared toward increasing delivery directly to the lysosome via the MPR (M6P receptor), which is the same mechanism that the approved therapies (Myozyme and Lumizyme) use. Unfortunately, it is known that patients who are not responding to Myozyme have lower MPRs in their skeletal muscle, so less chance of uptake using this mechanism no matter how efficient the delivery or the product,” she adds.

“The approach is different from other ERT approaches as this has the ability to act on glycogen in the cytoplasm. This remains a challenge in the field of Pompe disease,” Dr. Priya Kishnani, principal investigator at Duke University Medical Center, said in a press release. “Glycogen that is leached out (either due to shearing effect or rupture of lysosomes) into cytoplasm needs to be cleared. The collaboration with Valerion is an important one, as it allows us to look at whether VAL-1221 has this additional benefit.”

This work will be moving to the clinical stage soon, as Valerion plans to initiate a clinical trial of this therapy in patients with late-onset Pompe disease in April. The trial will take place in the United States and the United Kingdom, at Duke University Medical Center and The National Hospital for Neurology and Neurosurgery of London, respectively.

The trial will be a randomized, parallel active control, single- and repeat-dose, dose-escalation study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of VAL-1221 in ambulatory and ventilator-free patients with late-onset Pompe disease. Valerion expects to see top-line results later this year.

“Patients who are not responding to Myozyme are accumulating glycogen in the lysosome, and once it becomes overloaded because there is no enzyme to clear it, the lysosome leaks or sometimes bursts, which causes glycogen to spill out into the cytoplasm,” Ramsdell explains. “The cell then starts to gather it into autophagic vacuoles. The vacuolar and cytoplasmic glycogen is very toxic to the muscle cell. Myozyme only works on lysosomal glycogen. Our hypothesis is that using the high expression of ENT-2 in human skeletal muscle, the antibody portion of the VAL-1221 fusion will drive both greater overall delivery of rhGAA enzyme to muscle as well as uniquely target both lysosomal and extra-lysosomal glycogen in the cytoplasm.”

Tagged: clinical trials, ERT, preclinical