Regulatory T (Treg) cells play a significant role in preventing autoimmune diseases and controlling inflammation, but cancer co-opts this protective feature of Treg cells by using them to dampen antitumor immune responses. Human Treg cells express C-C chemokine receptor 4 (CCR4), a receptor protein that plays a key role in the recruitment and accumulation of Treg cells in the tumor microenvironment. CCR4 provides an ideal target to selectively block Treg cell recruitment into the tumor microenvironment, allowing the immune system to elicit a more robust antitumor response.

Best-in-Class Oral, Small Molecule CCR4 Antagonists

We have developed a series of best-in-class oral, small molecule antagonists of CCR4, including our lead compound FLX475, currently entering Phase 1 clinical studies in healthy volunteers and patients with cancer. In preclinical efficacy studies, FLX475 demonstrated single-agent efficacy similar to a potent immune agonist. In addition, FLX475 significantly enhanced the antitumor effects of various checkpoint inhibitors including anti-PD-L1 and anti-CTLA4 antibodies as well as immune agonists such as anti-CD137. Both single agent and combination therapies inhibited tumor growth and increased tumor regression. We believe FLX475 has the potential to deepen responses in checkpoint inhibitor-sensitive patient populations (T-cell inflamed tumors) and broaden responses in checkpoint inhibitor-unresponsive populations (non-T-cell inflamed tumors). We also expect that FLX475 may be efficacious in combination with CAR-T and cancer vaccine approaches.

Precision Medicine Strategy

We employ a precision medicine strategy for prospective patient selection in our clinical studies, applying our robust computational and translational biology capabilities to identify key biomarkers that should maximize clinical response and increase the probability of clinical success. For FLX475, we are using a novel development strategy to accelerate early clinical development in cancer patients by first rapidly obtaining pharmacokinetic, pharmacodynamic, and preliminary safety data in healthy volunteers. Findings from the healthy volunteer study will enable a more focused and efficient Phase 1 study in cancer patients, which should result in faster achievement of clinical proof of concept.

In 2018, we expect to initiate a single agent and combination study of FLX475 in cancer patients. This study will enroll patients with multiple types of cancer, in particular concentrating on tumor types in which Treg biology plays a significant role, for example non-small cell lung, triple-negative breast, and head and neck cancers. In addition, we plan to explore tumors that are associated with the Epstein-Barr Virus (EBV). EBV-associated tumors have increased numbers of Treg in the tumor microenvironment, which has been linked specifically to the biology of EBV and CCR4. We believe that by selecting EBV+ tumors including gastric and nasopharyngeal carcinomas as well as classical Hodgkin’s lymphoma, we have the opportunity to demonstrate meaningful clinical activity leading to an accelerated clinical development path.