LONDON – Heparegenix GmbH has raised €9 million (US$9.4 million) in a series A to advance a new approach to treating liver diseases into the clinic, with non-alcoholic steatohepatitis (NASH) as the first indication to be targeted.

Closing of the round coincided with fellow German company Phenex Pharmaceutical AG receiving a $100 million milestone payment under a deal with Gilead Sciences Inc., for GS-9674, an early phase II compound, also targeting NASH. That announcement underlines the huge commercial potential of treatments for NASH and its precursor, non-alcoholic fatty liver disease (NAFLD), both of which are increasing in incidence.

Products in development for treating NASH feature multiple mechanisms of action and Heparegenix is throwing another into the mix, in the form of mitogen-activated protein kinase 4 (MKK4) inhibitors, which are said to promote liver regeneration.

That builds on the discovery by Lars Zender, scientific founder of Heparegenix, that silencing of MKK4, a tumor suppressor, leads to the proliferation of hepatocytes after injury. While the liver is able to regenerate, its capacity to do so is tightly controlled by a balance of pro- and anti-growth factors and, during acute or chronic injury, demand for new liver cells cannot always keep up with supply.

Zender and colleagues at University Hospital Turbingen used an RNAi screen to silence about 300 tumor suppressor genes one at a time, in animals with either acute or chronic liver injury. They found that silencing MKK4 increased the proliferation of hepatocytes in both cases. Publishing the paper in Cell in April 2013, the researchers proposed small-molecule inhibitors of MKK4 could represent a new approach to treating liver diseases. (See BioWorld Today, April 11, 2013.)

Wolfgang Albrecht, CEO of Heparegenix, said the therapeutic concept is distinct from other NASH products in development, which have largely been repurposed from other indications. "Our target was identified by unbiased screening – no one had any idea MKK4 was related to liver disease at all," he told BioWorld Today.

Heparegenix has worldwide and exclusive rights to the intellectual property and in collaboration with Zender and the medicinal chemistry group of Eberhard-Karls University of Tubingen has discovered a number of small-molecule inhibitors of MKK4.

The series A funding will be invested over the next 18 to 24 months to advance the lead into the clinic in 2019. The work will continue to involve Zender, who has developed a number of preclinical models. "The target is for oral delivery; the first chemical [candidate] is orally bioavailable, at least in animal models," said Albrecht.

The technology has attracted two high-profile corporate venture funds, Boehringer Ingelheim Venture Fund (BIVF) and Novo Seeds as lead investors. The public fund High-Tech Grunderfonds also contributed.

For Detlev Mennerich, investment director of BIVF, the concept of applying MKK4 inhibitors to promote hepatocyte regeneration parallels the use of erythropoietin (EPO) in red blood cell production. "In a nutshell, Heparegenix is developing an EPO for the liver," he said.

AMBITIOUS ASPIRATIONS

Meanwhile, the $100 million payment from Foster City, Calif.-based Gilead to Phenex is a handsome return as GS-9674, a farnesoid X receptor (FXR) agonist, enters phase II development. The milestone is in addition to an undisclosed payment Ludwigshafen-based Phenex received when the product entered phase I trials last year.

Gilead acquired the program for up to $470 million in December 2014. (See BioWorld Today, Jan. 7, 2015.)

An "ambitious aspiration" has now become a reality, said Claus Kremoser, CEO of Phenex. "When we signed this FXR deal at the end of 2014, we could only hope that one day a molecule from our labs would be elected by Gilead as a clinical development candidate," he said.

Phenex will use the milestone payment to build up a pipeline of new drugs in liver, gastrointestinal tract and cancer indications. "Our next big goal is to take a drug all the way from research to approval and marketing. We are now in an excellent position to reach this goal with some certainty," Kremoser said.

NASH is characterized by inflammation and excessive fat accumulation in the liver that can lead to progressive fibrosis, cirrhosis and liver failure. Its precursor, NAFLD, is estimated to affect 10 percent to 20 percent of people in the U.S., with an estimated 2 percent to 5 percent having progressed to NASH.

That both are becoming more common is possibly related to increasing obesity rates, according to the National Institute of Diabetes and Digestive and Kidney Diseases. As yet, there are no approved treatments.

FXR is a nuclear hormone receptor that regulates bile acid, lipid and glucose homeostasis. Its activation can help reduce liver steatosis and inflammation and may help prevent liver fibrosis. In animal models of metabolic syndrome and NASH, FXR activation has been shown to lower liver lipids and improve hepatic insulin sensitivity, and to have liver-specific antifibrotic and anti-inflammatory effects.

In addition to Gilead, Intercept Pharmaceuticals Inc, with INT-747, and other companies, are developing FXR agonists. Intercept's product, obeticholic acid, currently in phase III development in NASH, was granted accelerated approval by the FDA in May 2016 for the treatment of another liver disease, primary biliary cholangitis. (See BioWorld Today, June 1, 2016.)