A Pilot Study of Pyridostigmine in Pompe Disease

Pompe is a rare disease, which occurs in approximately 1 per 40,000 births. It is a
progressive and often fatal neuromuscular disorder resulting from mutation in the gene for
acid alpha-glucosidase (GAA), an enzyme necessary to degrade glycogen. Accumulation of
glycogen in multiple tissues results in cardiac, respiratory and skeletal muscle dysfunction.
Enzyme replacement therapy (ERT) is currently the only treatment available, and although it
prolongs survival, adjuvant therapies are needed to help alleviate the dire symptoms of Pompe
disease.

Recent data has revealed that degradation of the neuromuscular junction (NMJ) occurs in Pompe
disease. Acetylcholinesterase inhibitors (AChEI) are substances that inhibit the AChE enzyme
from degrading acetylcholine at the NMJ, and thus increase the functional impact of this
neurotransmitter. AChEI are established as a beneficial therapy for individuals with primary
diseases of the NMJ, such as myasthenia gravis. Recently, administration of an AChEI was
demonstrated to improve NMJ pathology in both mice and individuals affected by other
congenital myopathies, including autosomal centronuclear myopathies (CNM), X-linked
myotubular myopathy (XLMTM) and mutation of tropomyosin 3 (TPM3). Specifically, both NMJ
transmission and motor function were improved. These studies demonstrate that AChEI can be
beneficial in myopathy associated with NMJ pathology.

In this study, we will study the acute effects of pyridostigmine on neuromuscular
transmission, as well as the prolonged effects on respiratory function, skeletal muscle
function and quality of life over a 90 day treatment period.

This project focuses on developing an adjuvant treatment to ERT that targets dysfunction at
the NMJ. Our ultimate goal is to reduce the deleterious consequences of Pompe disease and
improve the overall quality and duration of life in affected individuals.

Inclusion Criteria:

1. Males or females between 8 and 60 years of age;

2. Diagnosis of Pompe disease (protein assay, genotyping, and positive clinical signs)

3. No contraindication to pyridostigmine

Exclusion Criteria:

1. Already receive pyridostigmine as part of their normal clinical care at screening

2. Are pregnant - participants will receive a urine pregnancy test at screening

3. Have received acute administration of antibiotic, corticosteroid, or neuromuscular
blockade medications within 30 days prior to screening

4. Any other concurrent medical condition which, in the opinion of the study team, would
make the subject inappropriate to participate in the assessments