What started off as basic research 25 years ago has now lead to a successfully approved drug: The entry blocker bulevirtide (brand name Hepcludex, formerly known as Myrcludex B), jointly developed by researchers from Heidelberg University Hospital (UKHD) and the Medical Faculty of Heidelberg, the DZIF and other partners, has now been approved by the European Commission. Hepcludex is a first-in-class entry inhibitor for the treatment of hepatitis D and prevents hepatitis D and B viruses (HDV/HBV) from entering liver cells. The development of this new drug brings new hope to approximately 25 million people in the world suffering from hepatitis D infection, as no other approved drug has been available to treat this infectious disease up to now. Hepatitis D virus infections are a particularly severe form of viral hepatitis as they only occur as co-infections with HBV and lead to an accelerated progression of liver cirrhosis and liver cancer. To date, liver transplants have been the only chance of survival for many patients.

"We are very pleased about this success which is based on decades of virology research in Heidelberg," notes Prof. Hans-Georg Kräusslich, spokesman of the Center of Infectious Disease Research at the UKHD and Chairman of the German Center for Infection Research (DZIF). "This drug was developed in close collaboration between partners in science, public funders and a biotech company and is therefore an epitome of successful translation of laboratory results into clinical application."

How a "broken key" protects liver cells

Hepcludex's mechanism of action is based on a lock-and-key principle: Hepatitis B and D viruses exclusively replicate in the liver as they require the bile acid transporter NTCP to do so, which is only found on liver cells. They use this transporter like the 'lock' (virus receptor) through which they enter the cell. Hepcludex blocks this lock, acting like a broken key that is stuck in the lock. However, Hepcludex also works after an infection has occurred and the virus has already entered the cell, why is this so? "The virus continually needs to infect healthy liver cells in order to persist, as the infected ones either die or are eliminated by the immune system," says Prof. Stephan Urban. Over the course of 25 years of research, Urban and his team developed Hepcludex and, since his appointment as a DZIF professor in 2014, have focussed on developing the drug. "Liver cells evidently divide very rapidly when the liver is infected. The drug then protects the new, regenerated liver cells from infection whilst the infected cells are eliminated," explains Stephan Urban. Several phase I and II clinical trials showed that humans tolerate the agent well and that it efficiently prevents the replication of hepatitis B and D viruses. A phase III trial is currently being conducted, investigating Hepcludex's long-term effects, amongst other things.

The research was initially funded by the German Federal Ministry of Education and Research (BMBF), which provided 2.4 million euros for the preclinical development through the funding programme "Innovative Therapies". As of 2014, the German Center for Infection Research (DZIF), which was founded in 2012, joined in and has been financing Stephan Urban's professorship at the Medical Faculty of Heidelberg, amongst other projects.


https://www.eurekalert.org/pub_releases/2020-08/gcfi-fdf080520.php


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