Background/Purpose: Phosphoinositide-3-kinases (PI3K) play pivotal roles in cell signaling and regulate a variety of cellular functions.  PI3K-δ and PI3K-γ isoforms are necessary for adaptive and innate immunity and are important mediators in inflammatory and autoimmune diseases. IPI-145 is a potent PI3K-δ,γ inhibitor in clinical development for patients with advanced hematologic malignancies and inflammatory/autoimmune disorders. The isoform selectivity and activity of IPI-145 were evaluated using in vitro and in vivo models, and a Phase 1 study was conducted in healthy adult subjects.

Methods: In vitro isoform selectivity and activity of IPI-145 was determined by measuring direct binding to PI3K isoforms, and via isoform-specific cell-based assays. Cell proliferation assays were performed by stimulating human peripheral blood CD19⁺ B cells or CD3⁺ T cells in the presence or absence of IPI-145. The PI3K-δ inhibitory activity of IPI-145 in human whole blood was measured in a basophil activation assay. The in vivo anti-inflammatory activity of IPI-145 was assessed in a rat collagen-induced arthritis model. Female Lewis rats with established type II collagen-induced arthritis were treated with IPI‑145 (0.1 to 10 mg/kg) or vehicle once daily via oral gavage and paw swelling was assessed by plethysmometry.

The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses of IPI-145 was evaluated in a Phase 1 double-blind, placebo controlled, randomized clinical trial in healthy adult subjects. The ex vivo effect of IPI-145 on basophil activation in whole blood was assessed in both the single and multiple ascending dose portions of the study.

Results: IPI-145 potently inhibits PI3K-δ and PI3K-γ, with K_i values of 23 pM and 243 pM, respectively. IPI-145 is significantly less active against the PI3K-α isoform, with a K_i value of 25.9 nM, and inhibits PI3K-β with a K_i value of 1.6 nM. The IC₅₀ of IPI-145 in a PI3K-δ-selective assay is 1 nM, and the IC₅₀ in a PI3K-γ-selective assay is 32 nM. The IC₅₀ values of IPI-145 in human B-cell and T-cell proliferation assays are 0.5 nM and 9.5 nM, respectively. In human whole blood, IPI-145 potently inhibits PI3K-δ specific basophil activation with an IC₅₀of 78 nM. In the rat collagen-induced arthritis model, the area under the ankle diameter versus time curve was reduced 25% to 89% relative to vehicle controls across the 0.1 to 10 mg/kg dose range evaluated.

In the Phase 1 clinical study there was a proportional increase in IPI-145 exposure following single ascending and repeat dose administration. A rapid onset and durable effect of IPI-145 in the ex vivo basophil assay was observed at all dose levels. In addition, IPI-145 is clinically well tolerated following single and repeat daily doses of IPI-145.

Conclusion: IPI-145 is a potent inhibitor of PI3K-δ,γ in biochemical and cellular assays and is active in B-cell and T-cell proliferation assays and the rat  collagen-induced arthritis model.  The preclinical activity and the favorable tolerability, PK, and PD profiles of IPI-145 in healthy human subjects support ongoing Phase 2 clinical trial plans in subjects with autoimmune and inflammatory disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-potent-phosphoinositide-3-kinase-%ce%b4%ce%b3-inhibitor-ipi-145-is-active-in-preclinical-models-of-arthritis-and-well-tolerated-in-healthy-adult-subjects/