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Concord, MA-- March 3, 2017-- Valerion Therapeutics announced today that it has developed a fusion protein, VAL-1221, which combines its proprietary antibody delivery technology with recombinant human acid alpha-glucosidase (rhGAA) to improve the delivery of rhGAA into affected tissues of patients with Pompe disease (Glycogen Storage Disease, Type II; GSDII). Pompe disease is caused by a deficiency of the lysosomal enzyme, GAA, that leads to accumulation of glycogen in multiple tissues, with cardiac and skeletal muscles being the most severely affected. Glycogen, a complex sugar, is known to accumulate in both the lysosomes and cytoplasm of late-onset Pompe disease patients. However, the currently approved enzyme-replacement therapy is limited to the lysosome for therapeutic activity.

In a study recently published by Sun et al, Duke University, Division of Medical Genetics (J Mol Med, 2 Feb, 2017), Valerion’s proprietary antibody-mediated enzyme replacement therapy [VAL-1221 (humanized 3E10Fab-GAA)] demonstrated efficacy in both cultured Pompe patient fibroblasts and in Pompe (GAA-deficient) mice. Importantly, not only did VAL-1221 reduce lysosomal glycogen accumulation as effectively as rhGAA (current enzyme replacement therapy or ERT) but it was also demonstrated to penetrate living cells independent of the mannose-6-phopsphate receptor (M6PR), the mechanism of cell entry associated with current ERT which directs enzyme to the lysosome. These results suggest that VAL-1221 has potential benefit over current ERT by clearing both lysosomal and cytoplasmic glycogen.

Valerion is initiating a clinical trial in both the US (Duke University Medical Center) and the UK (The National Hospital for Neurology and Neurosurgery, London) next month to evaluate this novel therapy in patients with late-onset Pompe disease.

“We believe our findings are a game-changer in the treatment of Pompe disease,” said Deborah Ramsdell, Valerion’s Chief Executive Officer. “We are excited about the potential to help patients who are looking for alternatives to the current approved therapy.” This randomized, parallel active control, single and repeat dose, dose-escalation study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of VAL-1221 in ambulatory and ventilator-free patients with late-onset Pompe Disease. Top line results are expected later this year. 100 Main Street, Suite 110, Concord, MA 01742

“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,” said Dr. Priya Kishnani, Principal Investigator at Duke University Medical Center. “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.” ...

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The attempt to clear glycogen from the cytoplasm (in addition to clearance from the lysosomes) is a new approach and may add a benefit to enzyme replacement therapy (ERT). It is known from literature that autophagy and other processes in the cell are not yet completely understood but may influence the efficacy of ERT. Here are some quotes from papers that address the glycogen clearance from the cytoplasm:

"FabGAA can be delivered to both the cytoplasm and lysosomes in cultured cells. FabGAA equally reduced lysosomal glycogen accumulation as rhGAA in GAA-KO mice. FabGAA has the beneficial potential over rhGAA to clear cytoplasmic glycogen. This study suggests a novel antibody-enzyme fusion protein therapy for Pompe disease." (Source: Yi et al: Antibody-mediated enzyme replacement therapy targeting both lysosomal and cytoplasmic glycogen in Pompe disease. - J Mol Med (Berl). 2017 Feb 2. doi:10.1007/s00109-017-1505-9,

"The stages and progression of skeletal muscle damage have been described for the classical infantile form: small glycogen-filled lysosomes in between intact myofibrils are typical for stage 1; an increase in cytoplasmic glycogen and the size and number of lysosomes combined with fragmentation of myofibrils constitute stage 2; after that, glycogen-filled lysosomes are tightly packed, some show membrane rupture, and only few myofibril fragments remain in stage 3; finally, in stages 4 and 5, most glycogen is cytoplasmic, the contractile elements of muscle cells are completely lost, and the cells bloat due to the influx of water (Thurberg et al., 2006)." (Source: Lim et al.: Pompe disease: from pathophysiology to therapy and back again. - Front Aging Neurosci. 2014; 6: 177. doi:10.3389/fnagi.2014.00177,

"The prevailing view of pathogenesis, which has not changed significantly since the 1980’s, is that the glycogen-filled enlarged lysosomes eventually rupture releasing toxic contents into the muscle cytoplasm.5 A recent study has identified several stages of disease progression in skeletal muscle. At the early stage, muscle cells contain small, glycogen-filled lysosomes. This is followed by enlargement of the lysosomes and leakage of glycogen into the cytoplasm in some areas. As the disease progresses, lysosomal rupturing continues until the majority of glycogen is cytoplasmic, replacing the cell’s contractile elements.6 However, this view of pathogenesis may be too simplistic in light of new data concerning additional pathological hallmarks of the disease." (Source: Schoser et al.: Therapeutic approaches in Glycogen Storage Disease type II (GSDII)/Pompe disease. - Neurotherapeutics. 2008 Oct; 5(4): 569–578. doi:10.1016/j.nurt.2008.08.009,


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