Pharming Receives Accelerated Assessment in Europe for Leniolisib for the Treatment of APDS

The European Medicines Agency’s Committee for Medicinal Products for Human Use has granted an accelerated assessment to Pharming Group for the Marketing Authorization Application for leniolisib for the treatment of activated PI3K delta syndrome (APDS), a rare primary immunodeficiency, in adults and adolescents ages 12 or older in the European Economic Area.

Photo: Anurag Relan, chief medical officer of Pharming

Pharming is on track and plans to submit its marketing authorization application for leniolisib to the EMA in October 2022. Accelerated assessment reduces the timeframe for the CHMP to review an MAA from 210 days to 150 days. The EMA will grant, upon request, accelerated assessment of an MAA if they decide the product is of major interest for public health and therapeutic innovation.

APDS is a rare primary immunodeficiency that affects approximately one to two people per million. Also known as PASLI, 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 inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA PI3K with immunomodulating and potentially anti-neoplastic activities. Unlike PI3Kα and PI3Kβ, which are ubiquitously expressed, PI3Kẟ and PI3Kγ are expressed primarily in cells of hematopoietic origin. The central role of PI3Kẟ in regulating numerous cellular functions of the adaptive immune system (B-cells and, to a lesser extent, T cells) as well as the innate immune system (neutrophils, mast cells, and macrophages) strongly indicates that PI3Kẟ is a valid and potentially effective therapeutic target for several immune diseases.

The clinical development for leniolisib includes positive data from a phase 2/3 study, which met both its co-primary endpoints in the target patient population of evaluated reduction in lymph node size and correction of immunodeficiency. The primary efficacy results demonstrated clinical efficacy of leniolisib over placebo with a statistically significant reduction from baseline in the index lymphadenopathy lesions and normalization of immune dysfunction, as evidenced by increased proportion of naïve B cells from baseline. The shrinking of lymphadenopathy lesions and increased proportion of naïve B cells are important in patients as they indicate a reduction in APDS disease markers.

In the study, leniolisib was generally well-tolerated, with the majority of reported adverse events in both treatment groups classified as mild. There were no adverse events that led to discontinuation of study treatment, there were no deaths, and the incidence of serious adverse events (SAEs) was lower in the leniolisib group than the placebo group. None of the SAEs were suspected to be related to study treatment.

“The acceptance of an accelerated regulatory review for leniolisib underlines the high unmet need for patients with APDS, with the product potentially being the first approved treatment for this rare disease,” said Anurag Relan, chief medical officer of Pharming.

Author: Rare Daily Staff