Boehringer Ingelheim will expand its pipeline in nonalcoholic steatohepatitis (NASH) and related liver diseases by partnering with Yuhan to develop a first-in-class dual agonist, the companies said, through a collaboration that could generate more than $870 million for the South Korean pharma.

By combining Yuhan’s expertise in fibroblast growth factor 21 (FGF21), obesity, and NASH with Boehringer Ingelheim’s drug development and partial therapeutic focus on cardiometabolic diseases, the companies aim to create a single-molecule, combined Glucagon-like peptide 1 (GLP-1) and FGF21 agonist.

The companies cited preclinical evidence of high efficacy when both agonists are combined—such as reducing liver cell injury and hepatic inflammation by treating steatohepatitis, as well as showing direct effect against fibrosis.

The dual agonist is a fusion protein that uses long-acting (HyFc) technology developed by another South Korean biopharma, Genexine, but which has been developed in-house by Yuhan. Back in 2013, Genexine licensed out its hyFc technology to Yuhan and added four more target proteins to the portfolio in a partnership with Yuhan.

“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,” Yuhan CEO and president Lee Jung-hee said in a statement.

It is not, however, the first partnership between the companies. In South Korea, Yuhan markets three type 2 diabetes treatments co-developed by Boehringer Ingelheim and Eli Lilly under a partnership launched in 2011 and restructured as of 2015. They include Trajenta® (linagliptin), which is sold in the U.S. as Tradjenta®; Trajenta Duo® (linagliptin and metformin HCl), sold in the U.S. as Jentadueto®; and Jardiance® (empagliflozin).

“We are excited about this new opportunity which adds to our longstanding and successful partnership with Yuhan,” Michel Pairet, PhD, a member of Boehringer Ingelheim’s Board of Managing Directors with responsibility for the Innovation Unit, said in a statement. “This partnership brings us closer to next-generation treatments for patients with NASH.”

Second NASH collaboration

The Boehringer partnership is Yuhan’s second NASH-related collaboration with a Western biopharma giant inked this year. In January, Gilead Sciences agreed to pay Yuhan up to $785 million—$15 million upfront, the rest in milestones—in return for rights to commercialize novel small molecules against two undisclosed targets in all countries except South Korea.

Those molecules will be designed to treat advanced fibrosis due to NASH.

In the new NASH collaboration, Yuhan agreed to license rights for the dual agonist to Boehringer Ingelheim worldwide except South Korea. Boehringer Ingelheim agreed to pay Yuhan $40 million upfront, of which $10 million will come after a preclinical toxicity test; and up to $830 million in payments tied to achieving milestones, plus tiered royalties on future net sales.

In a separate statement, Yuhan said it agreed to pay 5% of what it receives to Geneixine in return for using its technology.

Boehringer Ingelheim says the GLP-1/FGF21 agonist planned by the companies would complement its existing NASH pipeline, which has focused on developing next-generation therapies that target three key drivers of the liver disease: steatosis, inflammation, and fibrosis.

Speaking with GEN last month during the Biotechnology Innovation Organization (BIO) 2019 International Convention, held in Philadelphia, Ioannis Sapountzis, PhD, corporate senior vice president, business development & licensing with Boehringer Ingelheim, cited the company’s progress with a couple of NASH candidates.

He said Boehringer Ingelheim expects to read out data in the second half of this year from a Phase IIa study assessing the oral amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335. The study (NCT03166735) was completed as of the most recent update, posted June 28 on ClinicalTrials.gov. Boehringer acquired the candidate in 2015 for up to €222.5 million (nearly $253 million) from Pharmaxis, which initially developed the drug as PXS-4728A.

In January, Boehringer Ingelheim exercised an option for exclusive rights to a second hepatic disease target from its collaboration with Dicerna Pharmaceuticals. The collaboration, established in October 2017, aims to discover and develop novel RNAi therapeutics for chronic liver diseases, initially focusing on using Dicerna’s GalXC technology platform.

”We look forward to working jointly with Boehringer Ingelheim, with its strong track record of bringing new treatments to patients with cardiometabolic disease,” Lee added. “Boehringer Ingelheim’s clinical expertise will now be applied to the development of this drug which has the potential to make a real difference for patients with NASH.”

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