Pharming announces positive results of Phase II/III for the treatment of activated PI3K delta syndrome

Leiden, The Netherlands,Business News: Pharming Group N.V. (“Pharming” or “the Company”) (Euronext Amsterdam: PHARM/NASDAQ: PHAR) announces positive results from the pivotal Phase II/III blinded randomized, placebo-controlled registration-enabling study of leniolisib for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) also known as PASLI (p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency).

APDS is an ultra-rare primary immunodeficiency disease caused by genetic mutations affecting approximately 1-2 people per million. Clinical hallmarks of the disease are significant lymphoproliferation and immune dysfunction, as well as increased risk of malignant lymphoma. 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.

Figure 1. PIK3CD mutant transfectants treated with leniolisib or an mTOR inhibitor. Rat-1 fibroblasts were transfected with human WT (wt PI3K) p110δ or p110δ carrying published APDS mutations N334K, E525K, E1021K, and C416R. The pAKT(S473) levels in the presence of titrated concentrations of leniolisib (A) and the mTOR inhibitor everolimus (B) are shown as individual data points with interpolated data for leniolisib and linear regression for everolimus. (C) Western blot for PI3K, pAKT, and β-actin as loading control. (D-E) Quantification of the western blot from panel C. Arbitrary units of scanning density for PI3K or pAKT were calibrated for loading control by division with the corresponding scanning density of β-actin. Average variation over 6 independent experiments is <5% pAKT arbitrary units (AU) for mutant and wt PI3K. (F) Fifty percent inhibitory concentration (IC50) values with SD derived from 6 independent experiments.

Figure 2. T-cell blast activation in presence or absence of leniolisib. Peripheral blood mononuclear cells (PBMCs) from healthy subjects (n = 4) or APDS patients (n = 3) with the indicated p110δ mutation were activated with anti-CD3 and anti-CD28 (1 μg/mL each) and maintained in culture media containing IL-2 to generate T-cell blasts. (A) After 30 minutes of preincubation with a dimethyl sulfoxide (DMSO) vehicle control or the indicated concentration of leniolisib, cells were stimulated for 10 minutes with anti-CD3 or were left unstimulated. Then, cells were fixed and stained for intracellular levels of AKT phosphorylated on S473 or S6 phosphorylated on S240/244. A representative healthy subject is shown in panel A. Quantification of cumulative data for median fluorescence intensity (MFI) of pAKT (B) and pS6 (C) stains is shown. The patient with E525K mutation corresponds to study patient 1.

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 II/III registration-enabling study composed of two sequential parts, the first part was an open-label dose escalation study

Figure 3. Leniolisib pharmacodynamics: time- and dose-dependent PI3K/AKT pathway activity in B cells. (A) Whole blood from leniolisib-treated patients was stimulated ex vivo at the indicated dose and day with anti-IgM and IL-4 for 20 minutes. Then intracellular levels of pAKT(S473) were quantified by flow cytometry. The dotted line and asterisk indicate that the 12-hour values are mean from pooled data at day 8 and day 15. Data are shown as mean values of the indicated number of patients with SD. (B) Individual observed leniolisib blood exposure and pAKT inhibition in ex vivo–stimulated blood from APDS patients (circles) and results of Emax concentration-response model (line). Data points represent cumulated measurements of all 6 patients at multiple doses and time points. pAKT inhibition is defined as (−1) × percentage change from baseline pAKT value. Vertical lines represent from left to right: half maximal effective concentration (EC50), 70% effective concentration (EC70), and 90% effective concentration (EC90) values.

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.

Figure 4. Changes in immune cell phenotypes in response to leniolisib. (A) Frequencies of transitional (left) and naive (right) B cells. (B) Frequencies of senescent CD57+CD4− (left) and PD-1+CD4+ T cells (right). Data are shown as mean values of indicated number of patients with SD. Vertical dotted lines indicate start of leniolisib dosing. The healthy volunteers’ median reference values for naive B cells, transitional B cells, CD57+CD4− cells, and PD1+CD4+ cells are: 74.7%,24 4.7%,24 17%35 and 13.2%,36 respectively. (C) Representative fluorescence-activated cell sorting (FACS) dot blots for patient 3 from panels A and B at baseline and end of treatment.

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 (p=0.0012) and normalization of immune dysfunction, as evidenced by increased proportion of naïve B cells from baseline (p<0.0001).

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.

Dr. Virgil Dalm, Principal Investigator, Erasmus University Medical Center Rotterdam, the Netherlands commented:

“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 (NIH) 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.

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.

I look forward to working with Pharming to bring leniolisib to APDS patients and studying it further in younger children, as well as other patient populations that may benefit from this precisely targeted therapy.”

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

(results previously reported in Blood 2017;130(21):2307-2316.

Activated phosphoinositide 3-kinase δ syndrome (APDS)

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.^1,2 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.^1,3 APDS is characterized by severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy.^4,5 Patients with APDS suffer a median 7-year diagnostic delay.⁶ Because APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.^4-7

leniolisib

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. Leniolisib inhibits the production of phosphatidylinositol-3-4-5-trisphosphate (PIP3). PIP3 serves as an important cellular messenger specifically 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 (neutrophil, mast cells, and macrophages) strongly indicates that PI3Kẟ is a valid and potentially effective therapeutic target for several immune diseases.