A new oral PI3K delta inhibitor for a rare primary immunodeficiency has moved a step closer to EU approval. The European Medicines Agency's (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for Joenja (leniolisib, Pharming Technologies B.V.). The recommendation covers adults and adolescents aged 12 years or older who weigh at least 45 kg and have activated phosphoinositide 3-kinase delta syndrome (APDS).

The opinion was adopted under “exceptional circumstances,” reflecting the rarity of APDS and the limits of the available data package. If cleared by the European Commission, Joenja would be authorized as a first-in-class oral treatment for this rare, complex primary immunodeficiency. 

Precision Pathway Inhibition 

APDS is a complex condition affecting approximately 0.01 in 10,000 people in the EU, characterized by a genetic overactivation of the PI3K delta protein. This overactivity interferes with the normal development of B and T cells, leaving people unable to fight infections effectively.

Leniolisib functions by targeting the catalytic p110δ subunit of PI3K delta. This mechanism helps normalize the deficiencies and dysregulation of immune cell populations, addressing the root cause of the system’s dysfunction rather than just managing secondary infections.

Restoring Immune Homeostasis 

The EMA’s decision was supported by a phase 3 trial involving 31 patients who received either 70 mg leniolisib or placebo twice daily for 12 weeks in this triple-blinded study.

Leniolisib significantly reduced lymphadenopathy compared with placebo, with an adjusted mean difference of -0.25 in log-transformed lymph node size. The treatment also increased the percentage of naive B cells, showing an adjusted mean difference of 37.30 percentage points compared with placebo. Additional benefits included reduced spleen volume, with an adjusted mean difference of -186 cm³ in three-dimensional volume compared with placebo.

Safety and Tolerability 

The therapy demonstrated favorable tolerability, with 23.8% of patients experiencing treatment-related adverse events compared to 30.0% in the placebo group. 

Most events were grade 1 or 2, and no treatment-related serious adverse events were reported. Common side effects to monitor include headache, vomiting, alopecia, weight increase, and decreased neutrophil count.

Prescribing and Availability 

Joenja will be available as 70-mg film-coated tablets for twice-daily administration. Due to the specialized nature of the condition, initiation of treatment is restricted to physicians experienced in managing primary immune deficiencies. 

This medicine was designated as an orphan medicine during its development. Following the European Commission’s final grant of marketing authorization, a full Summary of Product Characteristics will be published on the EMA website in all official EU languages.

As with other CHMP positive opinions, the Commission decision is normally issued within 67 days of adoption of the opinion.