FDA Grants Priority Review to Pharming’ Leniolisib for APDS

The U.S. Food and Drug Administration has accepted for priority review Pharming Group’s New Drug Application for leniolisib to treat the rare primary immunodeficiency activated phosphoinositide 3-kinase delta syndrome (APDS) in adults and adolescents 12 years of age and older.

Photo: Anurag Relan, chief medical officer of Pharming.

The FDA is expected to act on the application by March 29, 2023.

“With FDA’s review, leniolisib moves further along the regulatory pathway as a potential disease-modifying targeted treatment for APDS patients who currently rely on supportive therapies such as antibiotics and immunoglobulin replacement therapy,” said Anurag Relan, chief medical officer of Pharming.

APDS is a rare primary immunodeficiency that affects approximately 1 to 2 people per million. It is caused by variants in either of two genes, PIK3CD or PIK3R1, that regulate maturation of white blood cells. Variants of these genes lead to hyperactivity of the PI3Kδ (phosphoinositide 3-kinase delta) pathway. Balanced signaling in the PI3Kδ pathway is essential for physiological immune function. When this pathway is hyperactive, immune cells fail to mature and function properly, leading to immunodeficiency and dysregulation. APDS is characterized by severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy. Because these symptoms can be associated with a variety of conditions, including other primary immunodeficiencies, people with APDS are frequently misdiagnosed and suffer a median seven-year diagnostic delay. As APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma. The only way to definitively diagnose this condition is through genetic testing.

Leniolisib is a small-molecule that inhibits the production of phosphatidylinositol-3-4-5-trisphosphate (PIP3). PIP3 serves as an important cellular messenger activating AKT (via PDK1) and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism.

To date, leniolisib has been well tolerated during both the phase 1 first-in-human trial in healthy subjects and the phase 2/3 registration-enabling study.

Pharming’s NDA was supported by positive data from a phase 2/3 study of leniolisib, which met its co-primary endpoints of reduction in index lymph node size and correction of immunodeficiency in the target population. Those results demonstrated the efficacy of leniolisib over placebo with a statistically significant reduction from the baseline size of participants’ index lymphadenopathy lesions and normalization of their immune function, as evidenced by an increased proportion of naïve B cells from the baseline. Those findings indicate a reduction in disease markers associated with APDS, whose clinical hallmarks include significant lymphoproliferation and immune dysfunction, as well as increased risk of lymphoma.

Author: Rare Daily Staff