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
 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.
 www.clinicaltrials.gov, NCT02637531.