Terns Pharmaceuticals Inc., a nonalcoholic steatohepatitis (NASH) specialist based in San Francisco and Shanghai, has out-licensed the greater China rights of its BCR-ABL inhibitor, TRN-000632, for treating chronic myeloid leukemia (CML) to Chinese pharma giant Hansoh Pharmaceutical Group Co. Ltd. to move the preclinical oncology asset to the clinic faster.

Brian Yang, Terns’ director of finance and business development, told BioWorld that both companies will jointly carry out the preclinical and IND-enabling studies for TRN-000632, which will lay the foundation for the candidate to be marketed in other regions. An up-front payment from Hansoh will also help Terns advance its NASH candidates.

“We haven't gotten a chance to do much of the IND-enabling work [for TRN-000632],” said Yang. “Hansoh will lead these activities, and we will in turn have access to these study results. When we want to develop the asset in ex-China territories, we can leverage those study results in China to fast track our development outside of China.”

The up-front payment amount is undisclosed, but Terns is set to get development, regulatory and commercial milestone payments of up to $68 million, plus royalties from future product sales. Hansoh will be developing and commercializing TRN-000632 in greater China, while Terns keeps the rights for other markets for now.

Terns has mainly focused on chronic liver diseases and liver cancer. Yang said that while the company will continue to focus on its NASH candidates, it will also find ways to advance other assets, such as TRN-000632 from its oncology portfolio.

“For the non-NASH assets, we are trying to think of a creative way to add value to them to move them forward. The TRN-000632 program is one of them,” Yang said.

Yang described the partnership with Hansoh as “a natural fit,” as Hansoh is a major CML company in China with a marketed second-generation BCR-ABL tyrosine kinase inhibitor (TKI) for the indication. In November 2019, its Hansoh Xinfu (flumatinib mesylate) won NPMA approval for Philadelphia chromosome-positive chronic adult patients with CML.

“They are investing heavily in this space. In terms of driving the commercial outlook for our CML drug, working with Hansoh is a good fit,” Yang added.

According to Frost & Sullivan, the sales revenue of CML drugs in China was ¥4.6 billion (US$655.2 million) in 2018 and is estimated to increase to ¥14.2 billion in 2023.

TRN-000632 is a small-molecule allosteric inhibitor of BCR-ABL. Terns believes TRN-000632 may work better than other BCR-ABL TKIs by binding an allosteric pocket unique to the mutant BCR-ABL. It may potentially resolve CML patients’ resistance and tolerance issues.

“Because of this, TRN-000632 is highly selective for a target that is distinct from that of currently available BCR-ABL TKIs, leading to an enhanced efficacy and overcoming difficult-to-treat acquired resistance,” Yang explained.

“TRN-000632 binds the myristate allosteric pocket and by doing so mimics myristate, the auto-inhibitory natural ligand for this pocket. This mechanism of inhibition is very different from TKIs that inhibit the active kinase pocket of BCR-ABL.”

“Because cell signalling kinases are ubiquitous in human biology, even the most selective BCR-ABL TKIs still inhibit other kinases, leading to tolerability issues. In contrast, myristate autoregulatory pockets are rare in human biology,” he said.

Terns sees the drug candidate’s greatest potential in combination therapies with TKIs, which bind to the active site of the BCR-ABL protein, while TRN-000632 binds to the myristal site.

“By targeting different pockets, the combination will raise the barrier to resistance development and increase therapeutic pressure to achieve an accelerated and improved major molecular response, hence improving long term outcomes for patients,” Yang said. Simply put, better potency leads to lower doses and a better safety profile.

TRN-000632 is a legacy program of the company, which was established in 2017 and later found its footing in NASH. Out-licensing the greater China rights of this oncology asset will help Terns better consolidate resources for its NASH programs.

Yang said the up-front payment from Hansoh will go to TERN-101, a well-differentiated, liver-targeted FXR agonist in the phase II stage, TERN-201, a highly specific phase II-ready SSAO inhibitor, and TERN-501, a preclinical THR-b selective agonist.

The company acquired global rights for two NASH assets when it was established, then brought in elafibranor, a phase III asset from French company Genfit SA, for NASH and primary biliary cholangitis (PBC) in June 2019 to reinforce its presence in this space.

For now, Terns has four candidates for NASH, elafibranor for PBC, and three assets for oncology and other targets.

Yang revealed to BioWorld that the company will file an IND for TERN-501 in the U.S. by the end of this year. “If everything goes well, it will be in the clinic next year,” he said.

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