What is PMM2-CDG?

Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation, a group of ultra-rare hereditary metabolic disorders. Glycosylation is a process by which sugars are chemically attached to proteins to form glycoproteins, or a group of complex proteins. Since protein glycosylation is ubiquitously required in the human body, loss of PMM2 function has multi-organ systemic effects. PMM2-CDG is a serious disease, with up to 20% mortality in the first 4 years of life. There are ~1,000 patients identified worldwide, primarily in US and EU, and no approved drugs.

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Approximately 1,000 patients are affected globally

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Patients have a mortality rate of up to 20% in the early years

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Patients who survive infancy face lifelong chronic challenges

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PMM2-CDG is caused by mutations in the PMM2 gene. This gene provides instructions for making an enzyme called phosphomannomutase 2 (PMM2). Mutations in the PMM2 gene lead to the production of a malfunctioning or non-functioning PMM2 enzyme. The PMM2 enzyme is involved in a process called glycosylation, which attaches groups of sugar molecules (oligosaccharides) to proteins. Without a properly functioning PMM2 enzyme, glycosylation cannot proceed normally in the body.

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Infancy:

  • Physical abnormalities
  • Abnormal feeding/failure to thrive
  • Developmental delays
  • Organ system failures including hepatic, renal and cardiac failure

Childhood:

  • Cognitive and intellectual deficiency
  • Speech delay
  • Psychomotor delay
  • Coagulation deficiencies; stroke
  • Seizures
  • Peripheral Neuropathy
  • Muscle weakness
  • Ophthalmic issues

Adulthood:

  • Worsening of Peripheral Neuropathy
  • Increased muscle weakness; mobility impairment
  • Skeletal malformations apparent (short stature, fixed joints, etc.)
  • Infertility; hormonal insufficiency
  • Cerebellar ataxia
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  • A simple blood test to analyze the glycosylation status of transferrin can diagnose PMM2-CDG
  • Abnormal transferrin patterns can be detected through a test known as isoelectric focusing (IEF).
  • Molecular genetic testing can confirm a diagnosis of PMM2-CDG
  • Advanced imaging techniques, such as MRI, CT scans, can be used to confirm symptoms or features associated with PMM2-CDG
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The prognosis for PMM2-CDG patients is poor and there are currently no FDA-approved drugs. Current treatments are primarily supportive care to manage symptoms. Such care can include:

  • Maintain caloric intake and nutrition in infancy
  • Monitor for hepatic dysfunction, pericardial and/or pleural effusion
  • Non-medical interventions including occupational, physical and speech therapy, remedial education
  • Ophthalmic exams and corrective surgery as needed
  • Orthopedic or surgical intervention for skeletal and/or neuromuscular abnormalities
  • HRT for endocrine disorders e.g. hypothyroidism, ovarian insufficiency
  • Anticonvulsants for seizure control

Given the severity of symptoms across all stages of PMM2-CDG, significant unmet medical need exists.

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PMM2-CDG can lead to death in 20% of patients in the first 4 years of life, due to both neurological issues and multi-organ failure. While some individuals who survive to childhood have a good life expectancy, they also experience disability and typically need lifelong assistance.

Given the severity of symptoms across all stages of PMM2-CDG, significant unmet medical need exists.

Our Commitment to PMM2-CDG

Applied Therapeutics is committed to advancing research into the causes of, and treatment for, PMM2-CDG.

Patients with PMM2-CDG have imbalances in sugar metabolism pathways, including due to abnormal Aldose Reductase and PMM2 enzyme activity. Initial data in fibroblast cell lines derived from patients with PMM2-CDG demonstrates that AT-007, an investigational, novel Aldose Reductase Inhibitor, results in increased PMM2 activity and may provide therapeutic benefit in PMM2-CDG patients.

AT-007 has the potential to be the first FDA-approved therapy for PMM2-CDG.

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1.       Chang IJ, et al: https://pubmed.ncbi.nlm.nih.gov/30740408/

2.       PMM2-CDG, NORD Rare Disease Database: https://rarediseases.org/rare-diseases/pmm2-cdg/

3.       Chang IJ, et al: https://pubmed.ncbi.nlm.nih.gov/30740408/

4.       Iyer S, et al: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899038/

5.       Monin M-L, et al: https://ojrd.biomedcentral.com/track/pdf/10.1186/s13023-014-0207-4

6.       NIH, Genetics Home Reference: https://medlineplus.gov/genetics/condition/pmm2-congenital-disorder-of-glycosylation/

7.       Matthijs G, et al: https://www.nature.com/articles/ng0597-88