Biomarker Improvement Did Not Translate to Clinical Efficacy

BioMarin Pharmaceutical (BMRN) has discontinued the development of BMN 401, a candidate therapy for ENPP1 deficiency. BMN 401, which does not have a brand name, was being developed as an INZ-701, a subcutaneous recombinant ENPP1-Fc fusion protein, an enzyme replacement therapy (ERT) designed to supplement deficient inorganic pyrophosphate (PPi) and adenosine. In the open-label Phase 3 ENERGY 3 trial, which enrolled 27 pediatric patients aged 1-12 years in a 2:1 randomization, a 52-week increase in plasma PPi was statistically significant, but the co-primary endpoint of radiographic skeletal improvement (RGI-C) was not met. While target binding and pharmacological activity were demonstrated, these did not translate into meaningful bone growth and improvement in rickets, weakening the basis for approval.

Key Secondary Endpoint Also Failed Consistently

Rickets severity score (RSS), height/length, and weight growth Z-scores also showed no positive trend in the BMN 401 treatment group. This is a stronger negative signal than the failure of a single endpoint, indicating that normalizing PPi levels for 52 weeks is not sufficient to reverse established skeletal lesions. BioMarin reviewed the overall data after releasing mixed topline results on May 18, 2026, and concluded with the decision to discontinue development in August. The ongoing infant and adolescent/adult expansion strategy has also lost its commercialization path.

The Rationale for the $270 Million Acquisition Has Been Undermined in Just 13 Months

In July 2025, BioMarin acquired Inozyme Pharma for $4 per share, totaling $270 million in cash, to secure INZ-701. This was a corporate acquisition with no conditional milestones or royalties, and BMN 401 accounted for the majority of the acquired asset's value, so this discontinuation essentially means the elimination of a key acquired asset. The original goal was to file for approval in the second half of 2026 and launch in 2027, but the strategy of acquiring late-stage assets to shorten the development period failed to avoid clinical endpoint risk. On the other hand, the decision not to invest additional clinical costs in a failed asset will limit future cash burn.

The Gap in the Market with No Approved Treatment Remains

There are no FDA, EMA, or PMDA-approved disease-modifying therapies for ENPP1 deficiency, and standard management includes symptomatic treatment with oral phosphate and active vitamin D. BioMarin estimates that the company's addressable patient population is 2,000-2,500 across all ages, a very rare market, but the pricing power of rare skeletal diseases has been demonstrated by the $926.9 million in revenue generated by the company's skeletal disease product, Voxzogo, in 2025. BMN 401 received Fast Track and Orphan Drug/Rare Pediatric Disease designations from the FDA in September 2020, and Orphan Drug designation in Europe on July 31, 2018, but did not reach the approval or advisory committee stage. There are also no direct competitors in late-stage clinical development for ENPP1 replacement therapy, so patients will continue to rely on existing symptomatic treatments.