We are developing IPI-549, an oral, selective inhibitor of phosphoinositide-3-kinase gamma (PI3K-gamma). Broadly, PI3Ks belong to a family of signal-transducing enzymes that mediate key cellular functions in cancer and immunity. In contrast to the other major PI3K isoforms, PI3K-gamma is highly expressed in tumor-associated macrophages and plays an important role in the pro-tumor function of these cells.1

Our preclinical research has demonstrated that blockade of PI3K-gamma signaling by treatment with IPI-549 results in the transcriptional reprogramming of tumor associated macrophages.1 This reprogramming shifts macrophages in the tumor microenvironment from the M2, or pro-tumor phenotype, to the M1, or anti-tumor phenotype.1 This was an important finding because reprogramming macrophages from a pro-tumor to anti-tumor type is emerging as a compelling approach to promoting an anti-tumor immune response.

In preclinical studies, IPI-549 administered alone resulted in delayed tumor growth.1 Additionally, in preclinical models, IPI-549 demonstrated the ability to enhance the activity of and to reverse tumor resistance to checkpoint inhibitors2, a class of medicines that has shown promise for the treatment of several types of cancer.

As the only selective PI3K-gamma inhibitor in clinical development, IPI-549 has the potential to offer a unique approach within the emerging field of immuno-oncology. A Phase 1/1b study evaluating IPI-549 as a monotherapy and in combination with nivolumab, a PD-1 immune checkpoint inhibitor, is ongoing in patients with advanced solid tumors.3



[1] Kaneda, M., Messer, K., Ralainirina, N., Li, H., et al. PI3Kγ is a molecular switch that controls immune suppression. Nature, 2016 Nov;539:437–442.

[2] De Henau, O., Rausch, M., Winkler, D., Campesato, L., et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature, 2016 Nov;539:443-447.

[3] www.clinicaltrials.gov, NCT02637531.