Pharming Group N.V. announced today that the first patient has been dosed in a Phase II clinical trial evaluating leniolisib for the treatment of common variable immunodeficiency (CVID) patients with immune dysregulation. This proof-of-concept study marks a significant expansion of the company's work in primary immunodeficiency disorders beyond the drug's current approved indication.
The single-arm, open-label, dose range-finding study will be conducted across multiple centers in the United States, United Kingdom, and European Union. The trial aims to enroll approximately 20 patients aged 12 years and older who have been diagnosed with CVID and show evidence of lymphoproliferation along with at least one additional manifestation of immune dysregulation, such as interstitial lung disease, autoimmune cytopenias, or enteropathy.
Trial Design and Objectives
The Phase II study will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of leniolisib in this patient population. Additionally, researchers will explore the clinical efficacy of the drug in treating CVID with immune dysregulation. The trial has been specifically designed to inform a subsequent Phase III program.
Dr. Jocelyn Farmer, Director of the Clinical Immunodeficiency Program at Beth Israel Lahey Health in Burlington, Massachusetts, is leading the investigation. Dr. Farmer emphasized the significant disease burden faced by CVID patients with immune dysregulation.
"Due to the absence of effective therapies for these CVID patients, the disease manifestations can easily progress, leading to the well-documented early mortality in this patient group," Dr. Farmer stated. "PI3Kδ is a multi-faceted regulator of lymphocytes, functioning to control their proliferation, differentiation, antibody production and migration, and hence leniolisib has significant potential to treat the immune dysregulation seen in these CVID patients."
Significant Unmet Medical Need
CVID represents the largest group of symptomatic primary immunodeficiency patients. Approximately 50% of these patients display autoimmune, lymphoproliferative, and/or end-organ lympho-infiltrative clinical manifestations driven by immune dysregulation. Notably, CVID patients with immune dysregulation have an 11-fold higher mortality rate compared to CVID patients with infectious manifestations alone.
Many of these patients exhibit clinical manifestations similar to those seen in activated phosphoinositide 3-kinase delta syndrome (APDS), for which leniolisib is already approved in the U.S. and several other countries. Based on epidemiological data, the global prevalence of CVID with immune dysregulation is estimated at approximately 39 patients per million.
Dr. Anurag Relan, Chief Medical Officer of Pharming, highlighted the importance of this trial: "Unlike the initial APDS indication and our ongoing Phase II study in PIDs with immune dysregulation with specific genetic drivers, CVID patients are diagnosed based on standard clinical findings, independently of genetics. CVID patients with immune dysregulation have significant clinical unmet need, with no approved therapies, and represent a significantly larger patient population."
About Leniolisib
Leniolisib (marketed as Joenja® in the U.S.) is an oral small molecule phosphoinositide 3-kinase delta (PI3Kδ) inhibitor. It works by inhibiting the production of phosphatidylinositol-3-4-5-trisphosphate, an important cellular messenger that regulates various cell functions including proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism.
The drug has demonstrated statistically significant improvements in clinical trials for APDS, showing a favorable impact on immune dysregulation and deficiency. Long-term administration data has supported its safety and tolerability profile.
Beyond this new CVID trial, leniolisib is currently under regulatory review in the European Economic Area, Canada, and Australia for APDS. The company also plans to pursue regulatory approvals in Japan and South Korea. Additionally, leniolisib is being evaluated in two Phase III clinical trials in children with APDS and in another Phase II clinical trial for primary immunodeficiencies with immune dysregulation linked to altered PI3Kδ signaling in lymphocytes.
Expanding Treatment Options
This trial represents a significant step in addressing the unmet needs of CVID patients with immune dysregulation. If successful, leniolisib could provide a much-needed treatment option for this patient population that currently lacks effective therapies and faces significantly higher mortality rates.
The company expects to continue enrolling patients in the coming months, with results potentially informing a larger Phase III program that could eventually lead to regulatory approval for this additional indication.
