The FDA has expanded approval for leniolisib as an oral treatment for activated phosphoinositide 3-kinase delta syndrome (APDS) to include children aged 4-11 years who weigh at least 27 kg, according to a news release from the Small Business and Industry Assistance program in the FDA’s Center for Drug Evaluation and Research.

“Leniolisib is especially promising because it directly targets the action of the proteins that dysfunction to cause APDS,” said Penelope Bonnen, PhD, associate professor of molecular and human genetics at Baylor College of Medicine in Houston.

“The hope is that by mitigating the underlying defect we can improve the health and quality of life, as well as lifespan, of the children who experience this terrible disease,” said Bonnen, who was not involved in the drug approval studies.

Leniolisib, marketed as Joenja, was approved in 2023 for APDS in patients aged 12 years or older, after receiving orphan drug designation, rare pediatric disease designation, and priority review. Adolescents and adults treated with leniolisib take 70 mg orally twice a day; children aged 4-11 years and weighing at least 27 kg take a weight-based dose of 40, 50, or 70 mg twice daily, with approximately 12 hours between doses.

In APDS, a rare genetic disorder, the immune system cells that prevent infection are impaired because of mutations in the PIK3CD or PIK3RI genes, and those affected are susceptible to a range of recurrent infections, especially in the respiratory tract, sinuses, and ears. 

The original approval for leniolisib was based on data from a 12-week randomized trial of 31 patients aged 12 years or older with confirmed APDS. The co‑primary endpoints were lymph node reduction and improvement in the immunophenotypes (defined as the percentage of naive B cells out of total B cells). Both primary endpoints improved significantly after 85 days compared with the placebo.

The extended approval to patients aged 4-11 years was based on a single-arm, open-label study in which eight patients received leniolisib based on body weight. No differences in pharmacokinetic data emerged in patients younger than 12 years and those older than 12 years. The most common side effects associated with leniolisib in children included stomach pain, respiratory tract infection, diarrhea, headache, cough, nausea, rhinitis, and alopecia. The drug is contraindicated for patients of any age with moderate-to-severe liver impairment. Full prescribing information is available here.

New Hope and Old Challenges

APDS symptoms typically appear at about 2 years of age, and damage to the body accumulates over time, which makes treatment of younger children particularly important, Bonnen said.

Before leniolisib, APDS management consisted of piecemeal treatments to manage the symptoms and consequences of the disease, Bonnen said. “Leniolisib is a game-changer because it is the only treatment for APDS that directly targets the causative pathology,” she said. “The pediatric approval moves APDS toward a model in which we identify the molecular diagnosis early and treat the causal signaling abnormality before accumulated immune dysregulation causes permanent damage,” she added.

With the availability of an effective targeted therapy that can begin in childhood, early recognition is much more consequential, said Bonnen. “Children with a clinical presentation that is in the differential for APDS should receive prompt genetic testing for PIK3CD and PIK3R1. The historically long diagnostic delay becomes increasingly unacceptable when a pathway-specific treatment is available,” she emphasized.

However, diagnosis remains a persistent barrier to effective treatment, given the rarity of the disease, and the average diagnostic delay is roughly a decade, Bonnen noted. “APDS has an estimated incidence of only 1 to 2 per million, and it is clinically heterogeneous, with presenting features that overlap with those of other primary immunodeficiencies,” she said. 

“The expanded approval of leniolisib changes what that delay means for APDS: 10 years without a diagnosis can now mean 10 years during which a child could have been receiving disease-targeted treatment but was not, and that is unacceptable,” said Bonnen. Lack of access to specialized care can also contribute to diagnostic delay, she said. “Wider access to genetic testing, greater awareness among clinicians, and cascade testing of relatives after an affected family member is identified could all help shorten the time to diagnosis,” she added. 

“The next challenge is demonstrating that early treatment actually changes long-term outcomes, such as malignancy risk, autoimmunity, or bronchiectasis; long-term studies are required to answer those questions definitively,” said Bonnen. Determining whether genotype or differences in baseline immune phenotype predict treatment response would be valuable as well, and identifying such predictors could ultimately guide more individualized treatment decisions, she said.

The studies were supported by Pharming Group. Bonnen reported having no financial conflicts to disclose.