The U.S. Food and Drug Administration has accepted Pharming Group's supplemental New Drug Application for leniolisib in children aged 4 to 11 years with activated phosphoinositide 3-kinase delta syndrome (APDS), a rare primary immunodeficiency. The application has been granted Priority Review status with a Prescription Drug User Fee Act target action date of January 31, 2026.
If approved, leniolisib would represent the first and only treatment specifically indicated for children with APDS under 12 years of age globally. The oral, selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor is already approved in the U.S., U.K., Australia, and Israel for APDS treatment in adult and pediatric patients 12 years of age and older.
Phase III Trial Results Support Pediatric Application
The supplemental application is based on positive data from a multinational, single-arm Phase III study in children aged 4 to 11 years with APDS. The trial demonstrated improvements over 12 weeks in two clinically relevant hallmarks of the condition: reduced lymphadenopathy and increased naïve B cells. These changes together indicate a correction of the underlying immune defect characteristic of APDS.
The submission also included safety data from 8 months of treatment, providing additional support for the drug's tolerability profile in this younger patient population.
Addressing Critical Unmet Medical Need
APDS is a rare primary immunodeficiency that was first characterized in 2013. The condition is caused by variants in either PIK3CD or PIK3R1 genes, which are vital to the development and function of immune cells. These genetic variants lead to hyperactivity of the PI3Kδ pathway, causing immune cells to fail to mature and function properly, resulting in immunodeficiency and dysregulation.
The syndrome affects approximately 1 to 2 people per million worldwide and is characterized by severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy. Due to the variety of symptoms that can be associated with other conditions, patients with APDS are frequently misdiagnosed and suffer a median 7-year diagnostic delay.
"APDS is a rare, complex, and progressive primary immunodeficiency," said Fabrice Chouraqui, Chief Executive Officer of Pharming. "Typically, it begins in early childhood causing immune dysregulation, recurrent infections and potentially permanent lung damage and lymphoma. Early access to targeted therapies has the potential to change the trajectory of the disease for young patients."
Mechanism of Action and Clinical Impact
Leniolisib, marketed under the brand name Joenja® in the U.S., is an oral small molecule PI3Kδ inhibitor that works by inhibiting the production of phosphatidylinositol-3-4-5-trisphosphate. This cellular messenger regulates multiple cell functions including proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism.
Results from previous randomized, placebo-controlled Phase III clinical trials demonstrated statistically significant improvement in coprimary endpoints, reflecting a favorable impact on the immune dysregulation and deficiency seen in APDS patients. Interim open-label extension data has supported the safety and tolerability of long-term leniolisib administration.
Regulatory Status and Future Development
The FDA grants Priority Review to applications for medicines that, if approved, would offer significant improvements in effectiveness or safety of treatment, prevention, or diagnosis of serious conditions. This designation reflects the critical unmet medical need for effective treatments in pediatric APDS patients.
Leniolisib is currently under regulatory review in the European Economic Area, Japan, Canada, and several other countries for APDS treatment. The drug is also being evaluated in two additional Phase III clinical trials in children with APDS and in two Phase II clinical trials in primary immunodeficiencies with immune dysregulation.
As APDS is a progressive disease, diagnostic delays can lead to accumulation of damage over time, including permanent lung damage and lymphoma. The potential approval of leniolisib for younger children could provide earlier intervention opportunities that may help prevent or minimize these serious complications.
