Biomarker Improvement Was Not Enough: BioMarin Ends BMN 401 Rare Disease Drug Program

Replacing a molecule that is missing in a disease does not necessarily reverse tissue damage that has already occurred. In its second-quarter earnings report, BioMarin announced that it was discontinuing development of the enzyme replacement therapy BMN 401 across all indications. The decision brings a mixed-outcome Phase 3 trial to a close and highlights the potential gap between biomarker improvement and actual patient benefit in rare disease drug development.

BMN 401, formerly known as INZ-701, is administered by subcutaneous injection and was intended to treat ENPP1 deficiency. Because patients have insufficient ENPP1 function, their plasma inorganic pyrophosphate (PPi) levels decline, causing abnormal calcium deposition in blood vessels, soft tissues, and bones. Infants may develop severe arterial calcification, while children who survive often develop hypophosphatemic rickets accompanied by pain, skeletal deformities, and difficulty with movement.

The pivotal ENERGY 3 trial enrolled 27 children aged 1 to 12 and randomly assigned them in a 2:1 ratio to receive BMN 401 or conventional treatment. After 52 weeks of treatment, BMN 401 significantly increased plasma PPi, meeting one of the two co-primary endpoints. However, there was no improvement in the radiographic global impression of change, which reflects changes in rickets, resulting in failure of the other primary endpoint.

The problem was not limited to a single scale. When BioMarin announced the preliminary results in May this year, it said that secondary endpoints—including rickets severity scores and Z-scores for height or length and weight—also showed no positive trends. The drug was generally well tolerated, with no new safety signals, indicating that the program was discontinued primarily because of insufficient efficacy rather than newly identified toxicity.

The radiographic clinical endpoint was added following discussions with regulators specifically to determine whether increased PPi could translate into meaningful improvement in pediatric bone disease. Its failure was therefore particularly consequential: although the drug was shown to act on the intended biological pathway, evidence of the clinical benefit required to support approval remained lacking. Multiple secondary measures also failed to provide a consistent signal, further weakening the possibility of seeking marketing authorization based on a surrogate endpoint.

The discontinuation also represents an acquisition setback. BioMarin acquired Inozyme Pharma in 2025 for approximately $270 million, with BMN 401 serving as the core development asset obtained through the transaction. Accounting disclosures also showed that it accounted for most of the fair value of the acquired assets. Less than a year elapsed between completion of the acquisition and disclosure of the Phase 3 results, after which BioMarin moved from evaluating next steps to terminating the program entirely. This shows that even late-stage assets can rapidly lose value because of risks related to clinical endpoint design and the translation of efficacy.

ENERGY 3 enrolled only 27 participants, and the information currently available to the public remains focused on topline results, making it insufficient to determine whether differences might emerge in particular age groups, disease stages, or with longer treatment. However, with one of the co-primary endpoints failing and secondary endpoints providing no support, BioMarin has chosen not to commit further resources. The high unmet medical need among patients with ENPP1 deficiency has not disappeared. The question that remains is whether increasing PPi requires earlier intervention, combination with other treatments, or a different mechanism to translate into observable skeletal and vascular benefits.