ENPP1 Deficiency

Understanding the biology of ENPP1 is key to changing the treatment paradigm for patients.

ENPP1 Deficiency is caused by mutations in the ENPP1 gene resulting in low levels of pyrophosphate (PPi) and adenosine in the blood. Low levels of PPi lead to abnormal mineralization and pathologic calcification, and low levels of adenosine lead to intimal proliferation – which can drive systemic and progressive conditions.  

Individuals who present in utero or in infancy are typically diagnosed with generalized arterial calcification of infancy (GACI), which is characterized by extensive vascular calcification and intimal proliferation (overgrowth of smooth muscle cells inside blood vessels), resulting in myocardial infarction, stroke, or cardiac or multiorgan failure. Approximately 50% of infants with ENPP1 Deficiency die within six months of birth. Children with ENPP1 Deficiency typically experience rickets, a condition also known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2), while adults experience osteomalacia (softened bones), and they can exhibit a range of signs and symptoms that include hearing loss, arterial calcification, and cardiac and/or neurological involvement.  

There are no approved therapies for ENPP1 Deficiency.

DISRUPTION OF THE PATHWAY:

The spectrum of manifestations for ENPP1 Deficiency includes an infantile phase, a pediatric phase, and an adult phase.

0-1 years

GACI

Generalized arterial calcification of infancy

50% of babies diagnosed with GACI do not live past 6 months

The acute infantile phase, GACI, is characterized by narrowing of large and medium arteries. This narrowing is caused by severe and pathological vascular calcification and neointimal proliferation, resulting in dysfunction and potential failure of major organs, such as the heart, lungs and kidneys.

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1-13 years

ARHR2 (Rickets)

Autosomal Recessive Hypophosphatemic Rickets Type 2

70% of babies who survive past one year develop ARHR2

ARHR2 is characterized by skeletal deformities, short stature, severe bone pain, bone fractures, hearing loss, neurological problems (stroke, seizure)

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13+ years

ARHR2 (Osteomalacia)

A marked softening of the bones

85% experience issues related to bone or joint pain, fatigue, mobility issues and calcification of arteries, organs, or joints

Osteomalacia is characterized by severe bone and joint pain, fatigue, muscle weakness, bone fractures, leading to loss of mobility

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Genetic Incidence

Live Birth Incidence

1: 64,000

~ 37,000 in Addressable Markets

Complications Caused by ENPP1 Deficiency

Cardiovascular

Pathologic mineralization of heart valves and arteries occur. Disease manifestations include high blood pressure, heart attack, and stroke.

Joint

Calcification in the joints of the body causes pain and reduced mobility.

Skeletal

Complications include severe skeletal deformities, short stature, severe bone pain and increased risk of bone fractures.

Auditory

Hearing loss in childhood affects many patients

Dental

Disrupted tooth movement and exfoliation may occur.