Pharming Group N.V. announced positive topline results from its Phase 3 clinical trial evaluating leniolisib in children aged 4 to 11 years with activated phosphoinositide 3-kinase delta syndrome (APDS). The study (NCT05438407) demonstrated improvements in key indicators of the disease, with a safety profile consistent with previous trials. These findings pave the way for regulatory submissions to extend the use of leniolisib to younger APDS patients.
Study Design and Endpoints
The Phase 3 trial enrolled 21 children with APDS across sites in the United States, Europe, and Japan. This single-arm, open-label study assessed the safety, tolerability, and efficacy of leniolisib over a 12-week treatment period. The primary efficacy endpoints focused on the reduction in index lymph node size and an increase in the proportion of naïve B cells out of total B cells from baseline.
Secondary endpoints included evaluating the impact of leniolisib on health-related quality of life, using validated patient questionnaires to measure physical, social, emotional, and school functioning. These endpoints mirrored those used in previous leniolisib trials involving adolescent and adult APDS patients.
Key Findings
All 21 enrolled patients completed the 12-week treatment period. The study met its primary endpoints, demonstrating a mean reduction in index lesion size, indicative of improved lymphoproliferation. Additionally, an increase in the percentage of naïve B cells indicated immunophenotype correction. These improvements were observed across all four dose levels investigated, aligning with results from trials in older patients.
According to Pharming, all treatment-emergent adverse events were mild to moderate, and there were no drug-related serious adverse events reported.
Clinical Significance
APDS is a rare primary immunodeficiency caused by variants in the PIK3CD or PIK3R1 genes, leading to hyperactivity of the PI3Kδ pathway. This hyperactivity impairs the maturation and function of immune cells, resulting in immunodeficiency and dysregulation. APDS is characterized by recurrent infections, lymphoproliferation, autoimmunity, and enteropathy. It affects an estimated 1 to 2 people per million worldwide.
"This is the first data from a clinical trial for younger pediatric patients with APDS, who have a significant unmet need for a disease modifying treatment," said Anurag Relan, MD, MPH, Chief Medical Officer of Pharming. He noted that over a quarter of known APDS patients are below the age of 12, highlighting the importance of potential treatment options for this population.
Leniolisib: A Targeted Approach
Leniolisib, marketed as Joenja in the U.S., is an oral small molecule phosphoinositide 3-kinase delta (PI3Kδ) inhibitor. It is approved in the U.S. for APDS in patients 12 years and older. Leniolisib inhibits the production of phosphatidylinositol-3-4-5-trisphosphate, a crucial cellular messenger involved in cell proliferation, differentiation, cytokine production, and survival.
Future Directions
Pharming plans to include the data from this trial in regulatory filings worldwide, starting in 2025, to seek approval for leniolisib in pediatric APDS patients aged 4 to 11 years. Eligible patients from the study are continuing to receive leniolisib in an open-label extension trial to further assess long-term safety and efficacy. Additionally, a separate Phase 3 clinical trial is ongoing to evaluate a new pediatric formulation of leniolisib in children aged 1 to 6 years with APDS.
"The 12-week data from the first clinical study evaluating leniolisib in pediatric APDS patients is encouraging," commented Manish Butte, MD, PhD, from UCLA. "These results highlight the potential for leniolisib to help pediatric patients living with APDS and their families. The pediatric APDS community is in need of more treatment options, and we look forward to leniolisib being one of those options."
