BMN 401 raises plasma PPi but misses skeletal end point in pediatric ENPP1 deficiency

BioMarin reported that BMN 401, an investigational subcutaneous enzyme replacement therapy for ENPP1 deficiency, met 1 of 2 co-primary end points in the pivotal phase 3 ENERGY 3 trial of children aged 1 to 12 years, raising questions about whether correction of the biochemical abnormality translates into measurable skeletal benefit over 52 weeks.¹

“We are disappointed that the significant increases in plasma PPi observed with BMN 401 did not translate into meaningful clinical improvements for children with ENPP1 deficiency,” Greg Friberg, MD, executive vice president and chief research and development officer at BioMarin, said in the company announcement.¹

The multicenter, randomized, open-label ENERGY 3 trial enrolled 27 pediatric participants with ENPP1 deficiency. Participants were assigned 2:1 to BMN 401 or conventional therapy. The study’s co-primary end points were change from baseline in plasma inorganic pyrophosphate (PPi) concentration through week 52 and Radiographic Global Impression of Change (RGI-C) global score at week 52.¹

According to BioMarin, BMN 401 produced statistically significant increases in plasma PPi vs conventional therapy, meeting the biochemical co-primary end point. However, the trial did not show improvement in RGI-C scores, which had been added following discussions with health authorities as a measure of clinically meaningful change in rickets severity.¹

The company also reported no positive trends across key secondary end points, including Rickets Severity Score and growth z scores for height or body length and weight. BMN 401 was described as generally well tolerated, with no new safety signals reported. Numeric efficacy data, adverse event rates, and subgroup analyses were not included in the announcement; BioMarin said detailed results will be presented at a future medical meeting.¹

ENPP1 deficiency is caused by biallelic pathogenic variants in ENPP1, which encodes ectonucleotide pyrophosphatase/phosphodiesterase 1, an enzyme involved in extracellular PPi generation. Reduced PPi contributes to pathologic mineralization, particularly vascular and soft tissue calcification, and can also affect bone mineralization.²,³ In infancy, the condition may present as generalized arterial calcification of infancy type 1, a life-threatening disorder associated with severe vascular calcification, cardiac complications, and high early mortality. In childhood, survivors may develop autosomal recessive hypophosphatemic rickets type 2, with bone pain, lower-extremity deformity, impaired mobility, and growth complications.¹,³

Current care remains largely supportive and phenotype-driven. Infants with vascular calcification may receive intensive cardiology and supportive management, and children with hypophosphatemic rickets may be treated with conventional approaches aimed at improving phosphate homeostasis and skeletal mineralization. Published natural history data have highlighted substantial variability in presentation and long-term morbidity among individuals with ENPP1 and related mineralization disorders, complicating trial design and endpoint selection in small pediatric populations.³

BMN 401, formerly INZ-701, is intended to replace deficient ENPP1 activity and increase circulating PPi levels. The phase 3 result is therefore clinically important because it separates biomarker correction from radiographic skeletal response in a rare disease setting where validated outcome measures are limited. A statistically significant PPi increase supports pharmacodynamic activity, but the absence of benefit on RGI-C and secondary skeletal or growth measures limits conclusions about patient-centered efficacy at this stage.

The open-label design, small sample size, and rarity of ENPP1 deficiency are important interpretive constraints. However, the missed radiographic co-primary end point is a substantive finding, particularly because RGI-C was selected to capture clinically meaningful change in rickets severity. Without published numerical data, clinicians cannot yet assess the magnitude of PPi change, baseline disease severity, adherence to conventional therapy, age-related differences in response, or whether longer follow-up might identify delayed skeletal effects.

BioMarin said it is evaluating the ENERGY 3 data to determine next steps for the BMN 401 program. No regulatory approval for BMN 401 in ENPP1 deficiency was announced in the company update.¹

References

1. BioMarin Pharmaceutical Inc. BioMarin provides update on phase 3 trial for BMN 401 in children aged 1-12 with ENPP1 deficiency. PR Newswire. Published May 18, 2026. Accessed May 18, 2026. https://www.prnewswire.com/news-releases/biomarin-provides-update-on-phase-3-trial-for-bmn-401-in-children-aged-1-12-with-enpp1-deficiency-302774207.html

2. Rutsch F, Ruf N, Vaingankar S, et al. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat Genet. 2003;34(4):379-381. doi:10.1038/ng1221

3. Ferreira CR, Kintzinger K, Hackbarth ME, et al. Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies. J Bone Miner Res. 2021;36(11):2193-2202. doi:10.1002/jbmr.4418