First patient enrolled in Pharming APSD trial  

genetic disease

Pharming Group N.V. says the first patient has been enrolled in its phase III clinical trial evaluating the investigational drug leniolisib, an oral, selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, in children with activated phosphoinositide 3-kinase delta syndrome (APDS). There is currently no approved treatment for this complex and progressive disease caused by genetic variants.

At sites in the U.S., Europe, and Japan, the single-arm, open-label, multinational clinical trial will evaluate the safety, tolerability, and efficacy of leniolisib in approximately 15 children aged four to 11 years who have a confirmed APDS diagnosis. 

The study’s primary efficacy endpoints are a reduction in index lymph node size and an increased proportion of naïve B cells out of total B cells from baseline at 12 weeks. Secondary endpoints include an assessment of the ability of leniolisib to modify health-related quality of life based on measures of physical, social, emotional, and school functioning using a validated patient questionnaire. 

Pharming Group N.V. plans to initiate a similar clinical trial in the third quarter of 2023 that will include children aged one to six years, with APDS, to evaluate a new pediatric formulation of leniolisib. Eligible patients enrolled in either of the pediatric trials will continue to receive leniolisib for a year after the initial 12-week treatment period through an open-label extension trial.

Manish Butte, E. Richard Stiehm Endowed Chair, Professor with tenure in the Department of Pediatrics, and division chief of immunology, allergy, and rheumatology at UCLA, said:  “In treating APDS, the current standard of care is to use an array of supportive therapies. While these therapies can treat some of the manifestations of APDS, they do not target the underlying cause of the disease. Pharming’s studies of leniolisib in children with APDS are important for evaluating the possibility of minimizing symptoms earlier in the disease progression.” 

Endpoints met for Pharming Group’s leniolisib

Pharming Group’s program for the clinical development of leniolisib in pediatric APDS is supported by positive data from a phase II/III clinical trial that investigated the drug as a treatment for patients with the disease aged 12 years and older. As announced in February, 2022, and recently detailed in Blood, the international medical journal of the American Society of Hematology, the trial met both its co-primary endpoints, with patients who took leniolisib versus placebo achieving significant reductions in lymphoproliferation as measured by index lymph node size and increases in immunophenotype corrections as measured by the percentage of naïve B cells in peripheral blood.  

During the first half of 2022, positive opinions were received from the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) on the Pediatric Investigation Plan (PIP) for leniolisib as a treatment for APDS in children. The PIP(s) included the plans for both pediatric clinical trials.

Anurag Relan, chief medical officer of Pharming Group, said: “I am pleased we have initiated the first trial in our Phase III pediatric clinical program evaluating leniolisib in children with APDS, and I look forward to our second pediatric trial getting underway. Building on the encouraging findings from our successful phase II/III study in patients aged 12 years and older with APDS, we are committed to bringing leniolisib to even younger patients with the goal of intervening before they develop immune-related symptoms likely to progress throughout their lives. 

“While continuing to focus on patients of all ages with APDS, we are dedicated to collaborating with regulatory authorities with the goal of generating regulatory filings to gain approval that could support the treatment of children under 12 years of age who are living with this disease.”

Based on the phase II/III trial results and long-term open-label extension data, the U.S. Food and Drug Administration (FDA) is conducting a priority review of Pharming’s New Drug Application for leniolisib as a treatment for adolescents and adults with APDS and has assigned a Prescription Drug User Fee Act (PDUFA) goal date of March 29, 2023. 

Also, Pharming Group’s Marketing Authorisation Application (MAA) for leniolisib in the same patient population is under evaluation  by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP). Pharming expects that the CHMP will issue its opinion on the leniolisib MAA in 2H 2023.

About activated phosphoinositide 3-kinase δ syndrome (APDS)

APDS is a rare primary immunodeficiency that affects approximately 1 to 2 people per million. APDS 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 7-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. A definitive diagnosis can be made through genetic testing.

About leniolisib

Leniolisib is a small-molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA PI3K. PI3Kδ is expressed predominately in hematopoietic cells and is essential to normal immune system function through conversion of phosphatidylinositol-4-5-trisphosphate (PIP2) to phosphatidylinositol-3-4-5-trisphosphate (PIP3). 

Leniolisib inhibits the production of PIP3 and 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. 

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 immune diseases such as APDS. 

To date, leniolisib has been well tolerated during both the phase 1 first-in-human trial in healthy subjects and the phase II/III registration-enabling study in patients with APDS.

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