RARE Daily

Pharming Reports Positive Results of Pivotal Study of Leniolisib for the Treatment of Rare Immunodeficiency

February 2, 2022

Pharming Group reported positive results from the pivotal phase 2/3 blinded randomized, placebo-controlled registration-enabling study of leniolisib for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome, or APDS, also known as PASLI (p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency).

Photo: Virgil Dalm, principal investigator, Erasmus University Medical Center Rotterdam, the Netherlands

APDS is an ultra-rare primary immunodeficiency disease that is caused by variants in either of two genes, PIK3CD or PIK3R1. 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. Patients with APDS suffer a median 7-year diagnostic delay. Because APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.

APDS affects approximately one to two people per million. Current treatment is generally limited to supportive therapies, such as antibiotics and the use of immunoglobulin replacement therapy, and there is no approved therapy for the treatment of the disease.

Leniolisib is a small molecule PI3Kδ inhibitor that was discovered and developed by Novartis and was licensed to Pharming in 2019. The study, sponsored by Novartis, is a phase 2/3 registration enabling study composed of two sequential parts, the first part was an open-label dose escalation study with results previously reported in Blood in 2017.

Part 2 of the study was a randomized, subject, investigator, and sponsor-blinded, placebo-controlled study, that enrolled 31 patients with APDS who were 12 years or older. Patients were randomized 2:1 to receive either leniolisib 70mg twice daily or placebo for 12 weeks. Following this, patients were permitted to rollover to an open-label extension study to evaluate long-term safety, tolerability, and efficacy. The co-primary endpoints of the randomized study were designed to evaluate 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 log10 transformed sum of product of diameters (SPD) in the index lymphadenopathy lesions and normalization of immune dysfunction, as evidenced by increased proportion of naïve B cells from baseline.

In the study, leniolisib was generally well-tolerated. The majority of reported adverse events in both treatment groups were 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.

Full results will be presented at upcoming medical conferences and published in a peer-reviewed journal.

“These study results demonstrate the tremendous power of collaborative clinical research with scientists, clinicians, and patients working together with the pharmaceutical industry. Less than 10 years ago, researchers at the University of Cambridge and National Institutes of Health described a genetic variant in the PIK3CD gene in patients leading to immune dysfunction and dysregulation due to overactive PI3Kinase pathway, giving the name APDS/PASLI to the condition,” said Virgil Dalm, principal investigator, Erasmus University Medical Center Rotterdam, the Netherlands. “These patients have limited treatment options including symptomatic therapies, such as antibiotics, antivirals and immunoglobulin replacement therapy (IgRT). Unapproved empirical therapies such as mTOR inhibitors, can have serious side effects, and the only potentially curative treatment, stem cell transplant, is also associated with high morbidity and mortality. Novartis, working with doctors across the world, studied leniolisib in APDS patients, which showed these positive results today.”

Global regulatory filings for approval of leniolisib for APDS are targeted for submission beginning in the second quarter of this year.

Author: Rare Daily Staff

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