FDA grants priority review to leniolisib sNDA for lower-weight children with APDS

Children with activated phosphoinositide 3-kinase δ syndrome (APDS) who are too small to qualify for the only approved targeted therapy may soon have access to it. The FDA has accepted a supplemental new drug application (sNDA) for lower doses of leniolisib (Joenja; Pharming) in patients aged 4 years and older who weigh 13 kg to less than 27 kg, granting it priority review with a Prescription Drug User Fee Act (PDUFA) target action date of January 30, 2027.¹

The acceptance comes 2 weeks after FDA approval extended leniolisib to children aged 4 to 11 years weighing at least 27 kg.² Anurag Relan, chief medical officer of Pharming, said the review "brings us closer to the possibility of reaching smaller children" who are currently ineligible for treatment.¹

Leniolisib pediatric phase 3 data supporting the APDS sNDA

The application draws on an open-label, multinational, single-arm phase 3 study in children aged 4 to 11 years with APDS.¹ Over 12 weeks, treatment was associated with reduced lymphadenopathy and increased naive B cells, 2 disease hallmarks the company describes as indicating correction of the underlying immune defect.¹ The submission also includes clinical pharmacology assessments intended to support dosing in lower-weight children.¹ Quantitative efficacy results from the pediatric study were not disclosed in the announcement.

The same study supported the September 2026 approval of 40-mg and 50-mg twice-daily doses for children weighing at least 27 kg.² In that population, all treatment-emergent adverse events were mild to moderate, with no drug-related serious adverse events.² The most common adverse reactions (incidence >10%) in children aged 4 to younger than 12 years were abdominal pain, cough, and respiratory tract infection.² Five of 8 patients (63%) in that group developed an absolute neutrophil count (ANC) between 500 and 1500 cells/μL; none had an ANC below 500 cells/μL or infection associated with neutropenia.²

APDS disease burden and diagnostic delay in children

APDS is an inborn error of immunity caused by variants in PIK3CD or PIK3R1 that drive hyperactive PI3Kδ signaling, preventing immune cells from maturing and functioning normally.¹ Patients typically present with severe recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy; the condition affects an estimated 1 to 2 people per million worldwide.¹

Because these features overlap with other primary immunodeficiencies, a median diagnostic delay of 7 years has been reported, during which progressive damage, including permanent lung injury and lymphoma, can accumulate.¹ Diagnosis is confirmed by genetic testing.¹ Symptoms usually emerge in early childhood, and before the September approval, care for children aged 4 to 11 years centered on symptom management rather than the underlying pathway.²

Leniolisib mechanism and pivotal phase 3 trial in APDS

Leniolisib is an oral, selective PI3Kδ inhibitor that blocks production of phosphatidylinositol-3,4,5-trisphosphate, a messenger regulating lymphocyte proliferation, differentiation, and survival.¹ The FDA first approved it in March 2023 for patients aged 12 years and older.¹

That approval rested on a triple-blinded phase 3 trial in which 31 patients were randomized 2:1 to leniolisib 70 mg or placebo twice daily for 12 weeks.³ Both coprimary end points were met: the adjusted mean difference vs placebo was −0.25 (95% CI, −0.38 to −0.12; P = .0006) for log-transformed index lymph node size and 37.30 percentage points (95% CI, 24.06-50.54; P = .0002) for naive B cells.³ Adverse events were mostly grade 1, with no treatment-related serious adverse events.³ An interim analysis of the open-label extension reported reductions in annualized infection rates with continued treatment.⁴

Limitations of pediatric leniolisib data and what the PDUFA decision could change

Evidence in younger children remains limited. The pediatric study was single-arm, open-label, and 12 weeks long, and it relied on immunologic and lymphoproliferative surrogate end points rather than infection rates or long-term outcomes.¹ Cohorts are small, reflecting disease rarity: the pivotal trial enrolled 31 patients, and labeled pediatric safety data for children weighing at least 27 kg come from 8 patients.²,³ Whether earlier PI3Kδ inhibition prevents irreversible lung damage or malignancy has not been established.

Labeling considerations particularly relevant to young children include neutropenia monitoring, avoidance of strong CYP3A4 inhibitors and strong or moderate inducers, and potentially reduced effectiveness of live attenuated vaccines.² If approved, eligibility would extend to children aged 4 years and older weighing at least 13 kg; no dosing has been established for children younger than 4 years.¹,²

References

1. Pharming announces U.S. FDA acceptance and priority review of sNDA for lower doses of Joenja to treat children with APDS. News release. Pharming Group N.V. September 25, 2026. Accessed September 28, 2026. https://www.globenewswire.com/news-release/2026/09/25/3369191/0/en/pharming-announces-u-s-fda-acceptance-and-priority-review-of-snda-for-lower-doses-of-joenja-to-treat-children-with-apds.html

2. FDA approves Pharming's Joenja as first treatment for children with APDS in the U.S. News release. Pharming Group N.V. September 11, 2026. Accessed September 28, 2026. https://www.globenewswire.com/news-release/2026/09/11/3360484/0/en/fda-approves-pharming-s-joenja-as-first-treatment-for-children-with-apds-in-the-u-s.html

3. Rao VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971-983. doi:10.1182/blood.2022018546

4. Rao VK, et al. Interim analysis: open-label extension study of leniolisib for patients with APDS. J Allergy Clin Immunol. 2024;153(1):265-274. https://pmc.ncbi.nlm.nih.gov/articles/PMC10841669/