On June 30, 2021 Tweardy reported that it has been studying the signal transducer and activator of transcription 3 (STAT3) gene for 30 years (Press release, Tvardi Therapeutics, JUN 30, 2021, View Source [SID1234584512]). DePinho, who conceived andlaunched MD Anderson’s Cancer Moon Shots Program, successfully founded and raised capital for companies including Aveo Pharmaceuticals Inc. and KaryopharmTherapeutics Inc. Together, they raised $25 million in grants to move molecules targeting STAT3 toward the clinic, followed by $9 million in series A financing at thecompany’s launch in September 2018 to fund early clinical work.
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CEO Imran Alibhai, a long-time biotech investor and University of Texas- and Duke University-educated scientist, was hired to lead the company at the end of 2018. Hewas previously a senior vice president and managing director of Houston-based Dnatrix Inc.
STAT3 is important not only in the tumor itself, but also in the environment around the tumor, Alibhai said. Its activation is observed in about 70% of all cancers and up to95% of hepatocellular carcinomas (the most common type of primary liver cancer), according to research the company presented during a poster session at the 2021American Society of Clinical Oncology meeting.
As an orally bioavailable small molecule, TTI-101 "binds STAT3 and prevents phosphorylation, homodimerization, nuclear translocation, and ultimately, STAT3-mediatedtranscriptional activity," researchers explained.
To date, the drug has been "incredibly well tolerated," Alibhai told BioWorld, distinguishing it from other STAT3 inhibitor programs, such as Otsuka Pharmaceutical Co.Ltd.’s tablet-formulated OPB-31121, which the company quit developing following phase I results that reflected grade 3 adverse events (AEs) including lactic acidosis,diarrhea and vomiting. Another STAT3 gene inhibitor co-developed by Ionis Pharmaceuticals Inc. and Astrazeneca plc, danvatirsen, has also run into drug-related AEs insome patients, though the current status of the I.V.-administered candidate was unclear.
Selective targeting is the "secret sauce" of TTI-101, Alibhai said. "If you perturb STAT3 in general, you could potentially cause issues in all cells. So you have to be veryspecific about how you’re targeting it and only potentially disrupt the nuclear function," he said.
In Tvardi’s ongoing phase I study so far, TTI-101 has not only side-stepped dose-limiting toxicities, but also shown early signs of clinical benefit, Alibhai said. Multipleparticipants in the study also saw durable partial responses. The trial enrolled patients with both unresectable hepatocellular carcinoma and locally advanced, inoperable,metastatic and/or treatment-refractory solid tumors without other therapeutic options.
With dose escalation wrapped up in multiple arms of the study, it’s now moving on to dose-expansion cohorts which pave the way for phase II testing in liver cancer next.While the specific design of the phase II trial hasn’t been disclosed yet, Alibhai said investigators will enroll several cohorts of liver cancer patients which could generatesignals that could transition very quickly into confirmatory trials.
An expedited trial of TTI-101 in fibrosis could follow. So far, Tvardi has preclinical data demonstrating efficacy in liver fibrosis, idiopathic pulmonary fibrosis and sclerosis,Alibhai said. By the end of next year, the company could also move a second-generation STAT3 inhibitor it is developing, TTI-102, to the clinic. The ‘101 and ‘102 programsshare a similar scaffold, but the latter has shown early-on potency three to eight times greater than what has been seen with ‘101.
New investors Slate Path Capital, Palkon Capital, Arrowmark Partners and 683 Capital, led Tvardi’s series B round, with continued funding from existing investors,including Sporos Bioventures. In conjunction with the financing, Jamie McNab, partner at Slate Path Capital, will join Tvardi’s board. The company was Sporos’ firstinvestment. Along the way, it has attracted a number of high-profile scientific advisors, including MD Anderson Department of Immunology Chairman Jim Allison andKeith Flaherty, a professor of medicine at Harvard Medical School who co-founded Loxo Oncology and Scorpion Therapeutics Inc.
"As a physician, I am eager to see the potential of Tvardi’s molecules in diseases of high unmet medical need where STAT3 is a key driver," Flaherty said.