One of Korea's largest pharmaceutical companies, Yuhan Corp., and German giant Boehringer Ingelheim GmbH (BI) have signed a collaboration and license agreement to develop a first-in-class dual agonist to treat nonalcoholic steatohepatitis (NASH) and related liver diseases, following a similar path trod by other companies.

Many chasing NASH use the same long-acting glucagon-like peptide-1 (GLP-1) but with different triggers. In the case of BI and Yuhan, it's combining GLP-1 and fibroblast growth factor 21 (FGF-21) activity in one molecule. The companies expect the dual agonist, GLP-1-R/FGF-21-R, to reduce liver cell injury and hepatic inflammation by resolving steatohepatitis and by having antifibrotic effects.

Yuhan receives up-front and near term payments of $40 million and could receive up to $830 million in potential milestone payments plus tiered royalties on future net sales.

An upsurge in research on FGF-21 during the past decade or so – along with the advance of drug candidates targeting NASH through that mechanism and others – helped Akero Therapeutics Inc. nail down a handsome $65 million series A round a year ago. Cambridge, Mass.-based Akero in-licensed the phase II-bound NASH prospect, FGF-21 hormone analogue AKR-001, from Amgen Inc., of Thousand Oaks, Calif., which had been developing it in diabetes and "made a high-level strategic decision on a therapeutic-area basis" to let the candidate go, Akero CEO Jonathan Young told BioWorld Asia. (See BioWorld, June 26, 2018.)

South Korean company Alteogen Inc. is working with its U.S. partner, Lynkogen Inc., of New Jersey, to develop GLP-1 mimetic and alpha-1 antitrypsin fusion proteins for the treatment of NASH and metabolic diseases. Clinical trials could begin within the next 12 months. That collaboration has a similar idea to the BI-Yuhan collaboration: target the different disease drivers.

"Complex metabolic diseases like NASH and type 1 diabetes are caused by more than one trigger," Arun Swaminathan, CEO at Lynkogen, told BioWorld Asia at the time. "There is a need for therapies that can address more than one trigger." (See BioWorld, July 11, 2018.)

BI noted that in many cases approaches targeting one of the features of NASH will not be able to achieve the desired resolution of NASH in patients with advanced stages of the disease. Instead it is building a program to develop next-generation therapy approaches targeting all three key drivers of the disease – steatosis, inflammation and fibrosis.

Preclinical evidence suggests high efficacy when combining the gut-derived hormone GLP-1 with FGF21. The dual GLP1R/FGF21R agonist is expected to reduce liver cell injury and hepatic inflammation by resolution of steatohepatitis as well as having direct antifibrotic effects, and it complements Boehringer Ingelheim's R&D portfolio in NASH.

"This molecule, which is a fusion protein utilizing the long-acting (HyFc) technology of Genexine, has been developed in-house by Yuhan Corporation. Not only is our collaboration with Boehringer Ingelheim on this molecule Yuhan's first external partnership with biologics, it is also the very first out-licensing of biologics targeting NASH from Korea," said Jung Hee Lee, Yuhan's CEO and president.

In a study published in the March issue of Ebiomedicine, researchers found that GLP-1 mediates the effect of glucagon-like peptide-1 in attenuating hepatic glucose output, FGF-21. The researchers found FGF-21 production in hepatocytes was stimulated by exenatide or liraglutide. Blocking FGF-21 attenuated the inhibitory effects of the GLP-1 analogues on hepatic glucose output. The researchers identified GLP-1 function in inhibiting hepatic glucose output was mediated by FGF-21, providing a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis.

Yuhan's stock (KRX:000100) closed up 2.86% Monday on the Korea Stock Exchange. The company, created in 1926, is the largest of Korea's pharmaceutical companies and has annual turnover of more than $1 billion.

In January, Yuhan banked $15 million up front in a potential $785 million deal with U.S. biotech Gilead Sciences Inc. to develop therapeutic candidates that treat patients with advanced fibrosis due to NASH. Under the terms, Yuhan out-licensed to Gilead the rights to develop and commercialize small molecules against two undisclosed targets in all countries except South Korea, where it will retain certain commercialization rights. In addition to the potential milestone payments tied to certain development and commercial milestones, Yuhan is eligible for royalties on future net sales. (See BioWorld, Jan. 9, 2019.)

For the current financial year, BI expects slight growth in net sales and further investment activities. The biopharmaceuticals business maintained its lead position in the contract manufacturing segment in 2018 and provided 4% of overall net sales.