Chordia Therapeutics is on a mission to deliver first-in-class cancer drugs to patients. This Japan-based clinical-stage biotech company, launched in 2017 as a spin-out from Takeda Pharmaceutical, is developing next-generation, small-molecule inhibitors for the treatment of cancers with high unmet medical needs. It is focused on R&D of anticancer drugs from target discovery to proof of concept in clinical trials.
Chordia’s pipeline is built on expertise in RNA deregulation; a newly proposed cancer hallmark whose therapeutic potential is relatively unexplored (Fig. 1). Recent research has shown that RNA processing is systematically altered in cancer by the mutation of RNA splicing factors or the aberrant expression of RNA regulatory molecules1,2. RNA deregulation, which is caused by the accumulation of abnormal RNA, plays a pivotal role in tumor growth and progression. The company’s goal is to develop life-changing cancer treatments by creating medicines that modify RNA deregulation.
“The key to the sustainable growth of biotech companies is the successful development of new drugs, and we aspire to deliver first-in-class anticancer drugs from Japan to patients around the world as soon as possible by leveraging our strengths,” said Chordia’s CEO, Hiroshi Miyake. “We are advancing drug development quickly and steadily by making the best use of the flexibility of our lean organization, a broad network of experienced professionals, and accumulated R&D wisdom.”
Fig. 1 | Chordia’s pipeline candidates target RNA deregulation stress to treat cancer.
Next-generation cancer hallmark, RNA deregulation stress, takes center stage
The concept of cancer hallmarks provides a useful framework to develop novel therapies. Drug discovery efforts to target these hallmarks, including stress phenotypes, have successfully generated many effective cancer treatments. Cancer cells are exposed to an unusually large amount of stress; drug treatments can generate stress overload, resulting in unbalanced conditions that induce the death of cancer cells while sparing normal cells.
All the drug candidates in Chordia’s pipeline target RNA maturation processes and generate aberrant RNA, leading to additional stress in cancer cells. The processes targeted include transcription, splicing, degradation and tRNA recruitment. Currently, there are no drugs approved by the US Food and Drug Administration (FDA) that inhibit any of these steps.
The company’s lead asset, CTX-712, is in phase 1 clinical trials for advanced, relapsed or refractory malignant cancers. It is an orally available, selective, small-molecule inhibitor of CDC-like kinase (CLK). CTX-712 inhibits RNA splicing to generate RNA deregulation stress, which causes cancer cell death and tumor growth inhibition in multiple preclinical models3. It kills mutated cancer cells that have a splicing vulnerability, predisposing them to additional RNA deregulation stress4.
The phase 1 studies in Japan for the treatment of acute myeloid leukemia, myelodysplastic syndromes and solid cancers are expected to end soon; a phase 2 study is expected to begin in 2022. In addition, the company is preparing for a phase 1 study in the United States.
“CTX-712 is a first-in-class pan-CLK inhibitor and one of the first therapies to explore targeting RNA deregulation stress for use in cancer treatment,” said Chordia’s CSO Daisuke Morishita. “Generating stress overload is a proven method that has great potential to treat a broad range of cancers.”
Expanding Chordia’s research innovation
The company’s preclinical pipeline features CTX-177, a selective small-molecule inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). CTX-177 has a long story behind its development: after Morishita returned from a stint in the United States, he initiated the MALT1 project through an academia–industry collaboration with Seishi Ogawa of Kyoto university, based on his training at Harvard Medical School in Boston. After his team completed all the preclinical studies5, CTX-177’s manufacture and commercial rights were granted to Ono Pharmaceutical in 2020. Funding from this will be used to advance Chordia’s pipeline of transformative therapies for cancer patients.
Additional compounds in preclinical development include CTX-439—a first-in-class inhibitor of cyclin-dependent kinase 12 (CDK12)6—and CRD-1968099, which inhibits general control nonderepressible 2 (GCN2). These orally available compounds increase RNA deregulation stress by interfering with RNA transcription and tRNA recruitment, respectively, and have shown anticancer effects in preclinical models as a single reagent, as well as in a combination therapy with other medications. Chordia is proceeding with these preclinical pipelines and will soon begin clinical trials.
Currently, Chordia is pursuing collaborations to explore next-generation drug-design platforms, including in silico estimation, and is seeking additional partnerships to advance the clinical development of its drug candidates. The company’s growth model leverages licensing agreements to generate sustainable funding to progress R&D, expand into new indications, and develop additional pipeline assets to drive its long-term value.
“We also collaborate with academic researchers on cutting-edge, next-generation sequencing and gene-editing systems to thoroughly understand neoplastic disease states involving RNA deregulation, drive the discovery of novel therapeutic targets, and define patient selection strategies. To approach these targets or strategies, continued discussions with new and emerging platform companies are ongoing,” Morishita said. “Combining these strategies increases the probability that our pipeline will successfully produce beneficial therapeutics for patients with cancer.”