Targeting regulatory T cells (Tregs) and myeloid cells to launch full-force strikes against tumors
CEO: Brian Wong
Based: South San Francisco, California
Clinical focus: Immuno-oncology
The scoop: Going into 2018, IDO modulators of the tumor microenvironment looked set to become key components of the near-term immuno-oncology landscape. Then the pipeline suffered the sort of humility-inducing setback that periodically sweeps through the industry and reminds everyone just how hard biology is. The IDO field will end the year in tatters.
FLX Bio, the descendant of IDO developer Flexus Biosciences, thinks it has discovered better ways to modulate the tumor environment. By targeting regulatory T cells (Tregs) and myeloid cells, FLX hopes to enable the immune system to launch full-force strikes against tumors.
What makes FLX fierce: Since spinning out of Flexus after its takeover by Bristol-Myers Squibb, FLX has generated proprietary data sets and combined them with public resources such as the Cancer Genome Atlas to inform its R&D programs.
The goal was to capture detailed gene expression and profiling within Tregs and myeloid cells, and thereby “identify the key nodes, the key convergence points” involved in changing the tumor microenvironment, FLX CEO Brian Wong, M.D., Ph.D., said. In doing so, FLX wants to unlock the therapeutic potential of targeting cells that are found in the tumor microenvironment and suppress adaptive T cell responses.
“There have not been selective ways to target these cells, and to do so in a way that fundamentally alters their function within the tumor. That's what we've been able to do,” Wong said.
FLX’s lead asset is an oral CCR4 antagonist designed to inhibit Tregs in the tumor microenvironment without affecting their function in healthy tissues. The role the chemokine receptor plays in tumors has attracted other research groups, notably Kyowa Kirin, which won FDA approval for an anti-CCR4 antibody in August. But FLX thinks FLX475 is less prone to depleting Tregs in healthy tissues and will leave natural killer and T effector cells unharmed.
Since raising $60 million late last year, FLX has tested FLX475 in almost 80 healthy volunteers, enabling it to gather data on the pharmacokinetics, pharmacodynamics and safety of the drug. FLX thinks starting in healthy people will accelerate data generation, ensure the results are free from the confounding effects of other medications and lead to better designed studies in patients.
FLX is now putting that idea to the test. The dose-escalation stage of an early-phase trial in cancer patients is due to wrap up early next year, setting FLX up to move into the open-label phase 2 portion of the study. FLX has penciled in data readouts for early 2020 and 2021. FLX’s trial is assessing the effect of FLX475 as a monotherapy and in combination with a checkpoint inhibitor.
The trial will serve as a proving ground for another of FLX’s differentiators. While digging through data in search of novel targets, FLX also hunted for biomarkers that identify patients most likely to respond to a drug. That hunt led FLX to Epstein-Barr virus (EBV).
Once EBV infects tumor cells, it increases transcription of the chemokines CCL17 and CCL22 to evade the immune system. CCR4 is the receptor for CCL17 and CCL22. Given evidence that EBV drives the CCR4 pathway, FLX thinks FLX475 may be effective in tumors associated with the virus, such as gastric cancer, nasopharyngeal carcinoma and classical Hodgkin’s lymphoma.
Wong sees targeting EBV-related cancers as both a safer bet than all-comer immuno-oncology trials and as a way to achieve accelerated approval. Using Merck’s Keytruda approval in MSI-H tumors as its lodestar, FLX aims to bring FLX475 to market in a bucket of indications defined by EBV infection.
Work toward that goal is advancing in parallel with FLX’s second program. That program, due to enter the clinic next year, is designed to selectively target myeloid cells by inhibiting GCN2, a protein kinase involved in modulating amino acid metabolism. Studies suggest the kinase acts downstream of multiple amino acid dysregulations, enabling it to capture IDO, arginase and other pathways involved in the tumor microenvironment.
“This is the key target that results in immune suppression. By targeting CGN2, we believe we'll create a much more profound effect, a much more beneficial effect against the tumor than either IDO or arginase alone,” Wong said.
Investors: The Column Group, Kleiner Perkins, Topspin Partners, GV and Celgene