FLX475: CCR4 Antagonist for Oncology
We are developing FLX475 for the treatment of a broad range of “charged” tumors, which represent cancer types we believe are most likely to respond to FLX475. In cancer, the secretion of certain chemokines from tumor cells and tumor-resident immune cells is responsible for recruitment of immunosuppressive regulatory T cells Treg cells to tumor sites. Treg represents a dominant pathway for downregulating the immune response. Therefore, blocking the migration of Treg represents a dominant pathway for downregulating the immune response, and thus may limit the effectiveness of currently available therapies such as checkpoint inhibitors. Therefore, blocking the migration of Treg has the potential to restore naturally-occurring antitumor immunity as well as to synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators and adoptive T cell therapy. We believe that the inhibition of CCR4 has the potential to bring therapeutic benefit to patients across a wide spectrum of tumors in a manner similar to other immuno-oncology therapies that have been shown to be broadly effective against multiple tumor types, while also potentially deepening or broadening clinical responses to these therapies.
FLX475 is a small molecule CCR4 antagonist that blocks the migration of Treg cells specifically into tumors, but not healthy tissues, without depleting Treg throughout the body. We believe this will avoid many of the adverse safety events observed with Treg-depleting antibodies, including mogamulizumab (marketed as Poteligeo), a depleting antibody targeting CCR4. Treg-depleting antibodies have also been shown to deplete some effector immune cells, which is thought to limit their effectiveness in patients. In contrast, inhibition of CCR4 with FLX475 does not negatively impact these effector immune cells. In fact, in preclinical tumor models, FLX475 was shown to selectively binds to CCR4 on Treg and inhibits the recruitment of Treg into tumors without affecting healthy tissue, increase the number of CD8+ effector T cells in the tumor, improve tumor control and, as a single agent or in combination with checkpoint inhibitors, lead to tumor reduction or eradication.
We have completed a placebo-controlled, double-blinded dose-escalating Phase 1 clinical trial of FLX475 in 104 healthy volunteers. FLX475 was well tolerated in both the single dose and multiple dose arms of this study and there were no serious adverse events or dose limiting toxicities reported. Daily dosing within the single dose arm ranged between 5mg and 1,000 mg and in the multiple dose arm between 25mg and 150mg a day for 14 days. At the 75 mg daily dose, FLX475 exceeded the targeted receptor occupancy which, in our preclinical studies, corresponded with a 90% inhibition of in vitro Treg recruitment and the highest level of antitumor activity. We are currently enrolling a Phase 1/2 study of FLX475 as a monotherapy, and in combination with pembrolizumab, in patients with charged tumors and expect proof of concept data in the first half of 2020.
* FLX475 is still in development and not yet approved for commercial sale