BMRN: Previewing ENERGY-3 Trial: Small Catalyst but Meaningful Enough for BMRN

Research evidence excerpt

BMRN: Previewing ENERGY-3 Trial: Small Catalyst but Meaningful Enough for BMRN

BioMarin Pharmaceutical, Inc. Equity Research

Pre-clinical evidence established a critical role of ENPP1 in regulation of

mineralization

ENPP1 plays a critical role in regulating PPi levels. Mechanistically, ENPP1 is the key enzyme

responsible for maintaining the inorganic pyrophosphate (PPi) level via hydrolysis of the extracellular

ATP into AMP and PPi (Exhibit 1). Although rare, some patients harbor Biallelic loss-of-function

mutations in ENPP1, resulting in markedly reduced PPi levels compared to healthy individuals.

Exhibit 2 - Mechanism of action for ENPP1 in PPi and mineralization regulation

Source: Inozyme Pharma Presentation at ASBMR 2021

Lower-than-normal PPi level can lead to pathological calcification and bone defects, leading to

GACI in infants and ARHR2 in pediatrics/adults. In healthy individuals, PPi plays an essential role in

regulating mineralization by inhibiting ectopic growth and hydroxyapatite formation. In patients with

ENPP1 deficiency, persistently low PPi levels disrupt this balance, promoting inappropriate calcification

in tissues or skeletal structures. Importantly, clinical manifestations could vary by different age

groups, where tissue calcification such as arterial calcification is more common in infants and skeletal

abnormalities is more common in pediatrics and adults. As a result, infants are typically diagnosed

as generalized arterial calcification of infancy (GACI), whereas pediatric/adult patients are usually

diagnosed as autosomal recessive hypophosphatemic rickets type 2 (ARHR2) (Exhibit 2).

Exhibit 3 - Clinical manifestation in ENPP1 patients by age

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