FLEXING AGAINST SUPPRESSION by Karen Tkach Tuzman, Senior Writer FLX Bio Inc

REPRINT FROM AUGUST 10, 2017

EMERGING COMPANY PROFILE FLEXING AGAINST SUPPRESSION By Karen Tkach Tuzman, Senior Writer FLX Bio Inc. is creating small molecules to dim immunosuppressive actors in the tumor microenvironment FLX BIO INC., South San Francisco, Calif. without the baggage of the antibodies dominating the Technology: Small molecule immuno-oncology agents targeting Tregs and myeloid-derived suppressor cells immuno-oncology space. Armed with $79 million in Disease focus: Cancer series A and B funds, the Flexus Biosciences Inc. spinout Clinical status: Preclinical has preclinical candidates targeting Tregs and MDSCs, and Founded: 2015 by Flexus Biosciences Inc. hopes to enter the clinic this year. University collaborators: None SAB member Philip Greenberg told BioCentury Tregs Corporate partners: None and myeloid-derived suppressor cells (MDSCs) have been Number of employees: About 60 a common hurdle for multiple cancer immunotherapies, Funds raised: $79 million Investors: Kleiner Perkins Caufield & Byers, The Column Group, Celgene limiting effective immune responses “at different levels, Corp., Topspin Fund and at different times.” Greenberg is head of the program in CEO: Brian Wong immunology in Fred Hutchinson Cancer Research Center’s Patents: None clinical research division. The newco was founded after Bristol-Myers Squibb Co. acquired Flexus for its IDO and TDO2 programs, and Kyowa Hakko Kirin Co. Ltd. markets Poteligeo for T cell is focused on five new immuno-oncology preclinical lymphoma and has it in Phase I/II testing for solid tumors. programs, with a Treg-targeting CCR4 antagonist in the It is also in Phase III for HTLV-1 associated myelopathy lead. It retained Flexus’ investors Kleiner Perkins Caufield (HAM). The company did not return BioCentury’s request & Byers, The Column Group, Celgene Corp. and Topspin for comment in time for publication. Fund. Wong and Greenberg noted that small molecules also have FLX Bio CEO Brian Wong said previous attempts to stop the advantages of penetrating tumors better than mAbs, Tregs from suppressing antitumor immunity were hobbled and being able to be developed for both intracellular because well-established Treg targets like IL-2 were also and extracellular targets. AstraZeneca plc also has a critical for effector T cell function. In contrast, he said, work small molecule CCR4 inhibitor, AZD2098, in preclinical in the last five years has shown the chemokine receptor development for cancer. CCR4, which is key for Treg migration into tumors, is “one of the cleanest ways to selectively inhibit Tregs.” FLX Bio plans to test its antagonist in the clinic alone and in combination with checkpoint inhibitors to treat solid FLX Bio’s compound blocks the chemokine receptor’s tumors, and is investigating biomarker candidates, including interaction with its ligands CCL22 and CCL17, which are CCL22 and CCL17, to predict patient responses. upregulated in tumors compared with healthy tissues. The company is developing two strategies to decrease the Wong believes that mechanism will make the compound suppressive effects of MDSCs: targeting the cells’ signal safer than mAbs like Poteligeo mogamulizumab, which transduction pathways, and promoting their conversion to trigger depletion of CCR4-expressing cells. “Every Treg that antitumor myeloid cells. expresses CCR4 throughout the body gets reduced,” he said. “They’ve seen severe toxicity in multiple tissues, including COO Rekha Hemrajani said FLX Bio has almost 20 chemists the skin.” and strong computational biology expertise in-house, which it is using to mine public and private datasets for new FLX Bio has shown its compound decreased Tregs in a more immuno-oncology targets. tumor-selective manner than an anti-CCR4 mAb.

BIOCENTURY INNOVATIONS ©2016 BIOCENTURY PUBLICATIONS, INC. FLX Bio terminated development of the Flexus asset TARGETS FLX925, which it retained after the spinout, to focus on CCL17 - Chemokine CC motif ligand 17 immuno-oncology. The compound was in Phase I/II for CCL22 (MDC) - Chemokine CC motif ligand 22 acute myelogenous leukemia. CCR4 (CD194) - CC chemokine receptor 4 IL-2 - Interleukin-2 COMPANIES AND INSTITUTIONS MENTIONED IDO (INDO) - Indoleamine 2,3-dioxygenase American Association for Cancer Research (AACR), Philadelphia, Pa. TDO2 (TDO) - Tryptophan 2,3-dioxygenase AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K. REFERENCES Bristol-Myers Squibb Co. (NYSE: BMY), New York, N.Y. FLX Bio Inc., South San Francisco, Calif. Talay, O., et al. “Potent and selective C-C chemokine receptor (CCR4) antagonists poten- tiate anti-tumor immune responses by inhibiting regulatory T cells (Treg).” Presented at the Fred Hutchinson Cancer Research Center, Seattle, Wash. annual meeting of the American Association for Cancer Research (2017) Kyowa Hakko Kirin Co. Ltd. (Tokyo:4151), Tokyo, Japan

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