BioMarin’s investigational therapy failed to elicit clinical improvements in patients with ENPP1 deficiency, while also missing key secondary endpoints of rickets severity and growth.
BioMarin’s investigational enzyme replacement therapy significantly improved biomarker outcomes in a Phase 3 study of ENPP1 deficiency, a rare genetic disease—but failed to show clinical benefit.
The mixed readout “suggests that there’s significant risk to approval here, as well as clinical risk to the ongoing adolescent/adult and infant trials,” Stifel told investors on Monday, referring to BioMarin’s asset BMN 401. “The failure here removes an upside-driver” for BioMarin, the analysts continued, “even if this asset wasn’t core to the bull-case on the stock.”
In the Phase 3 ENERGY 3 study, BioMarin dosed BMN 401 in almost 30 patients aged 1 to 12 years with ENPP1 deficiency, a rare disorder that progressively damages blood vessels, bones and other soft tissues. Results presented Monday showed a significant reduction in plasma inorganic pyrophosphate (PPi) concentrations, a key disease marker.
The biomarker benefit, however, did not translate into clinical improvements. Patients on BMN 401 did not experience significantly better scores on the Radiographic Global Impression of Change (RGI-C) scale, a validated tool to assess the impact of treatment in children with rickets, according to the company.
BMN 401 also missed key secondary endpoints, showing “no positive trends” on the severity or growth of rickets, BioMarin said. Rickets is a condition that affects bone development.
“It’s unsurprising that BMRN observed increases in PPi levels in the study,” Stifel wrote, pointing to BMN 401’s mechanism of action: The therapy restores ENPP1 levels and cascades in patients in whom the enzyme is deficient. PPi is produced in these pathways.
“Unfortunately, this was not corroborated by the RGI-C, which failed to reach the already loosened stat [significance] criteria of p<0.2,” the firm continued, adding that the FDA had previously suggested that biomarker data should be backed by clinical findings. With the RGI-C miss, along with similarly failed secondary outcomes, “it’s hard to determine if BMRN still has a path towards filing.”
BioMarin is “disappointed that the significant increases in plasma PPi observed with BMN 401 did not translate into meaningful clinical improvements,” Greg Friberg, chief R&D officer, said in a statement.
The BMN 401 miss adds to the growing pressure on BioMarin. In October 2025, the company cut loose the hemophilia A gene therapy Roctavian “as we focus on the business units aligned with our strategic priorities,” CEO Alexander Hardy told investors on a call at the time.
Roctavian’s market performance had been underwhelming, making only $26 million in 2024.
Meanwhile, the achondroplasia drug Voxzogo, which analysts have called the main driver of the BioMarin story, gained a formidable challenger in March with the approval of Ascendis’ Yuviwel. Just days later, BioMarin suspended trials of Voxzogo in Turner syndrome, SHOX-deficiency and aggrecan (ACAN) deficiency, a move prompted by several slipped capital femoral epiphysis events detected in some studies of the drug.
