We are an innovative biopharmaceutical company dedicated to developing best-in-class
medicines for patients with difficult-to-treat diseases. We combine proven scientific
expertise with a passion for developing novel small molecule drugs that target
disease pathways for potential applications in oncology.
We are focusing our efforts on our lead product candidate, IPI-549, an orally
administered, clinical-stage, immuno-oncology product candidate that selectively
inhibits the enzyme phosphoinositide-3-kinase-gamma, or PI3K-gamma.
Role of PI3K-gamma in Cancer Growth and Survival
The body’s immune system is responsible for fighting off infections and
disease, including cancer, and helping the body to heal. The immune system functions
by identifying and destroying foreign cells and substances within the body.
When confronted by pathogens or disease, an early response of the bodys immune
system comes in the form of macrophages, a type of white blood cell that produces
pro-inflammatory proteins called cytokines. These cytokines activate T cells,
another type of immune cell, to attack the health threat. The macrophages then
switch gears to produce other types of cytokines that dampen T cell activation,
which, in turn, stimulates repair of the affected tissue.
Cancer cells arise from normal cells that have changed in a way that allows
them to grow out of control. Cancer cells are not always recognized by the immune
system as foreign cells that should be destroyed. However, if cancer cells are
recognized by the immune system, mechanisms exist to dampen this immune response
and include upregulation of “checkpoint proteins” on T cells, such
as programmed death receptor 1, or PD-1. Additionally, in cancer there exists
a tumor microenvironment, or TME, which refers to the non-cancerous cells present
in the tumor. Cells within the TME, including macrophages, can suppress the
immune response and provide signals to cancer cells allowing the tumor to grow.
The presence of the supportive TME is thought to be one reason why some cancer
therapies, including checkpoint inhibitors, have not provided durable or effective
results to date. Targeting cells that suppress the immune system represents
an emerging approach within the field of cancer immunotherapy, and inhibition
of PI3K-gamma by IPI-549 represents a novel approach to targeting this immune-suppressive
microenvironment.
Preclinical research found that macrophage PI3K-gamma signaling promotes a
genetic program that results in a macrophage type that suppresses the activation
of anti-tumor T cells. Preclinical data demonstrated that blockade of PI3K-gamma
by treatment with IPI-549 leads to a shift in the type of macrophages present
in the TME from macrophages associated with suppression of the immune response,
known as the M2 phenotype, to macrophages that are supportive of a pro-inflammatory,
anti-tumor immune response, known as the M1 phenotype. Treatment with IPI-549
increased the M1/M2 macrophage ratio, the number of T cells that attack the
tumor, and the production of pro-inflammatory cytokines.
In recent years, checkpoint inhibitors have shown promising results as a treatment
for multiple types of cancer, but many patients eventually become resistant
to checkpoint inhibitors and require treatment with an additional therapy. Preclinical
studies in a number of tumor models showed that resistance to checkpoint inhibition
is associated with increased numbers of tumor-associated macrophages and is
directly mediated by the immune-suppressive activity of these macrophages on
T cells. Furthermore, the data showed that inhibition of PI3K-gamma by IPI-549
switched the activation of macrophages from an immune-suppressive M2 state to
a pro-inflammatory M1 state, leading to enhanced anti-tumor cytotoxic T cell
activity, particularly when combined with checkpoint inhibitors. These data
demonstrate that IPI-549 treatment is able to reverse the lack of response to
checkpoint inhibitors in models that are initially insensitive to checkpoint
inhibition as a single therapy
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1.75%