AstraZeneca’s experimental enzyme replacement therapy efzimfotase alfa delivered mixed results across three late-stage trials targeting hypophosphatasia, a rare genetic condition that can lead to soft and weak bones. The setbacks add to pressure on rare-disease programs that rely on consistent pivotal endpoints. The company is already facing scrutiny from the pattern of trial uncertainty in rare metabolic disorders—where patient heterogeneity and long-term outcomes can complicate endpoint interpretation. While the underlying biology remains compelling, the data will determine whether development continues, is re-engineered, or pivots to different subpopulations. For clinicians and investors, the report reinforces how quickly expectations can shift when late-stage trials do not converge on a single clear efficacy signal.