BioMarin reported that the Phase 3 ENERGY 3 trial of BMN 401 in children with ENPP1 deficiency met one co-primary endpoint by significantly increasing plasma PPi levels but did not demonstrate improvement in RGI-C scores, a key clinical measure of rickets severity.
Written By: Samiksha Jadhav, BPharm
Reviewed By: Pharmacally Editorial Team
BioMarin Pharmaceutical Inc. announced that its pivotal Phase 3 ENERGY 3 trial (NCT06046820) evaluating BMN 401 in children with ENPP1 deficiency met one of two co-primary endpoints, demonstrating statistically significant increases in plasma inorganic pyrophosphate (PPi) levels through week 52. However, the study did not demonstrate improvement in Radiographic Global Impression of Change (RGI-C) scores, a key clinical measure of rickets severity and treatment response.
BioMarin did not disclose detailed efficacy statistics or p-values, limiting independent assessment of the magnitude and robustness of the PPi findings.
BMN 401, formerly known as INZ-701, is an investigational subcutaneous enzyme replacement therapy designed to restore PPi levels in patients with ENPP1 deficiency, a rare genetic disorder associated with progressive damage to blood vessels, soft tissues, and bones. While restoration of PPi reflects the intended biological mechanism of BMN 401, clinical and regulatory evaluations in rickets-related disorders generally prioritize functional and radiographic improvements.
The study also showed no clinically meaningful improvements across secondary endpoints, including Rickets Severity Score (RSS) and growth Z-scores for height, body length, and weight. BMN 401 was generally well tolerated, with no new safety signals reported.
The multicenter, randomized, open-label ENERGY 3 trial enrolled 27 pediatric participants aged 1 to 12 years in a 2:1 treatment-to-control design. While small enrollment is common in ultra-rare disease studies, the limited sample size may reduce statistical power and complicate interpretation of efficacy outcomes.
The trial’s co-primary endpoints included change from baseline in plasma PPi through week 52 and RGI-C global score at week 52. BioMarin noted that RGI-C was added as a co-primary endpoint following discussions with health authorities to assess clinically meaningful functional improvement. Because the study did not demonstrate improvement on this endpoint, future regulatory pathways for BMN 401 may require additional supporting evidence.
Greg Friberg, Executive Vice President and Chief Research & Development Officer at BioMarin, said the company was disappointed that the increases in plasma PPi did not translate into meaningful clinical improvements and that BioMarin is evaluating the data to determine next steps.
BioMarin also highlighted the significant unmet need in infants with generalized arterial calcification of infancy (GACI) type 1, a severe form of ENPP1 deficiency associated with high mortality, underscoring the continued need for earlier therapeutic intervention.
ENPP1 deficiency is a rare lifelong genetic disease linked to severe rickets, osteomalacia, vascular calcification, hearing loss, and cardiovascular complications. Approximately half of infants with GACI type 1 do not survive beyond six months of age.
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About the Writer
Samiksha Vikram Jadhav (LinkedIn) is a B. Pharm graduate with a strong academic foundation in pharmaceutical sciences, pharmacology, and drug development. She specializes in pharma market research, with a focused interest in mergers and acquisitions, strategic partnerships, and global pharma and biotech deals. Her work centers on analyzing industry transactions, market positioning, and business strategies, translating complex developments into clear, accurate, and insightful scientific and commercial reporting.