Natural History Study Informs Potent Lifesaving Update to Standard of Care for PMM2-CDG Patients

Rare disease biotech Glycomine reported a key finding from a natural history study of the rare pediatric disease phosphomannomutase 2-congenital disorder of glycosylation that indicates these patients may be at risk for adrenal insufficiency, a previously unknown feature of PMM2-CDG.

Photo: Horacio Plotkin, chief medical officer of Glycomine

PMM2-CDG, previously known as CDG Type Ia, is the most prevalent of the more than 100 different congenital disorders of glycosylation (CDG). CDGs result in defective formation of the glycan chains essential for the structure and function of glycosylated proteins that represent as many as 50 percent of all proteins in the body. PMM2-CDG is caused by a deficiency of the enzyme phosphomannomutase 2 that is encoded by the PMM2 gene. The disease is a severe multisystem disorder with symptoms such as coagulopathies, endocrinopathies, hypotonia, stroke-like episodes, as well as immune and nervous system disfunctions, and resulting mortality of 20 percent in the early years of life.

In the study, published in Molecular Genetic and Metabolism, levels of morning cortisol and adrenocorticotropic hormone (ACTH) were measured in a cohort of patients and found to be significantly below normal, indicating PMM2-CDG patients are at risk for secondary adrenal insufficiency. These data provide key insights to improve standard of care, as early recognition of adrenal insufficiency and initiation of glucocorticoid replacement therapy and stress dosing could be lifesaving.

The authors conclude that morning cortisol and ACTH levels should be evaluated at least annually for all patients with PMM2-CDG. If abnormal, a low dose ACTH stimulation test should follow to evaluate the hypothalamus, pituitary, adrenal (HPA) axis.

“Endocrinopathies in PMM2-CDG have not received the attention they deserve, especially considering that glycoproteins are involved in virtually every endocrine axis,” said Kyriakie Sarafoglou, associate professor in the Department of Pediatrics at University of Minnesota and lead author of the paper. “Through an international collaboration, this study was the first to identify that patients with PMM2-CDG are at risk for secondary adrenal insufficiency and to suggest that morning cortisol and ACTH monitoring should become part of standard care in these patients.”

The natural history study completed enrollment with 139 PMM2-CDG patients at 11 sites around the world. Morning serum cortisol and ACTH levels were simultaneously measured in a cohort of 43 patients. In this cohort, 11 patients (25.6 percent) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Secondary adrenal insufficiency has a prevalence of 1.5 to 2.8 in 10,000 in the general population. Since this finding, two of the 11 patients have been confirmed to have central adrenal insufficiency after low dose ACTH stimulation test results and are on hydrocortisone replacement and/or stress dosing during illness.

“We initiated this natural history study, which is the largest longitudinal study ever undertaken for this disease, to learn more about how PMM2-CDG affects patients and inform the design of our clinical trials for GLM101,” said Horacio Plotkin, chief medical officer of Glycomine. “Through thoughtfully and scientifically studying the clinical presentation and biochemistry of PMM2-CDG, our investigators have uncovered a significant risk factor that is often masked by other co-morbidities of the disease. We thank the investigators and the patients and families who participated in this study for their time and support as we advance into clinical trials GLM101. Good things happen when patients and families, investigators, and companies work together.”

GLM101 is an experimental replacement therapy designed to deliver mannose-1-phosphate directly into cells and thereby bypass the PMM2 enzyme deficiency and address all disease-causing PMM2 mutations to restore pathway function. GLM101 has received Orphan Drug designation in the United States and Europe and Rare Pediatric Disease designation in the United States.

Glycomine plans to initiate by the end of the year the first interventional clinical trial of GLM101, a mannose-1-phosphate replacement therapy designed to address the underlying deficiency in PMM2-CDG.

Author: Rare Daily Staff