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How ECM factor could speed liver treatments

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Efforts to develop new drugs by focusing on the ‘scaffold’ of human tissue rather than just cells themselves have received a major commercial boost that could accelerate this area of biotech.

In recent years UCL-spinout Engitix, based in the Royal Free Hospital in London, has been working on a platform that could advance treatments for conditions, including advanced liver disease, by factoring in the role of the extracellular matrix (ECM).

Liver fibrosis, or scarring, and its life-threatening end stage of liver cirrhosis, is the common pathway of chronic liver diseases (CLDs), such as NASH, alcoholic liver disease, viral hepatitis and cholangiopathies such as primary biliary cirrhosis and primary sclerosing cholangitis.

It is estimated that 844 million people have CLDs worldwide, resulting in a mortality rate of 2 million deaths per year.

Despite the clear need for effective therapeutics, there are currently no approved medicines to treat CLDs.

A barrier to their development has been an inability to test potential therapeutic agents on healthy and diseased cells within their natural physiological and pathological microenvironment.

By incorporating tissue- and disease-specific human ECM into in vitro models, Engitix’s platform preserves the natural cell microenvironment.

This enables researchers to better understand the bioactive role of human ECM in modulating disease progression in fibrosis.

CEO and co-founder of Engitix, Dr Giuseppe Mazza, tells Health Tech World: “Human tissues are mainly characterised by two components: cells and extracellular matrix. The latter represents the scaffold of human tissues.

“Initially, researchers thought that the key orchestrator of healthy or diseased status was strictly dependent on the cellular component while the scaffold was an inert construct simply maintaining the structure of tissues.

“However, during the last decade the scaffold of human tissues has been better characterised, and it has been confirmed that this ECM directly influences cellular function and plays a key role for maintaining normal and diseased states.

“Indeed, the normal function of human tissues relies on the fine interaction between those two. During chronic damage arising from continuous exposure to “toxic” substances such us fat, alcohol, or viruses (e.g. for chronic liver diseases) the balance and interaction between the cells and the ECM are affected.

“We believe that, so far, drug discovery programmes for chronic liver diseases have been limited by a failure to capture the full complexity of the disease by focusing only on the cellular component while overlooking the ECM.

“Advanced liver diseases impact both cells and the ECM, and the cell-ECM interaction is bidirectional and therefore both should be taken into account in order to better understand disease progression, identify new and/or more relevant targets as well as for target validation.”

It is hoped that a new deal potentially worth up to US$500m could advance this work further, raising the prospect of new treatments born out of ECM-based research.

Japanese pharma giant Takeda has signed a licensing agreement with Engitix to develop new therapies for advanced fibrotic liver diseases, including non-alcoholic steatohepatitis (NASH).

The companies will work together on the confirmation and validation of targets and preclinical development of therapeutics in liver fibrosis using the ECM discovery platform.

Dr Mazza says: “After having validated a therapeutic target as playing a role in causing and driving disease progression, it usually takes [around] four to five years to get a drug that affects such a target into patient usage.

“Having said that, new technologies, including AI, are being developed which continue to accelerate the transition from “bench to bedside” and Engitix is embracing those as well.

“The partnership will allow us to expand our team in the UK and we will also move into larger facilities by end of the year. In view of our important connections with physicians, scientists and biobanks, we will maintain a presence at the Royal Free Hospital.”

Those new facilities are reportedy at White City Place, the 1.9 m sq ft business, innovation and creative district in West London. The location is also home to life sciences biotech companies Gama Delta, Autolus and Synthace – plus global pharmaceutical company Novartis.

Takeda is the first pharma company to be convinced of the importance of ECM in drug discovery and development, according to Dr Mazza.

Engitix will receive an upfront payment, with additional near-term payments based on the confirmation and functional validation of selected targets.

It also stands to receive US$500m for the achievement of preclinical, development, regulatory and commercial milestones, as well as further royalty payments upon sales of commercialised products.

Dr Mazza says: “Having Takeda, one of the world’s leading pharmaceutical companies with world-class drug development and commercialisation capabilities, as a major collaborator, will accelerate the translation of novel ECM-derived targets into potential therapeutics for humans.

“We are excited to continue working with Takeda as this is the only partnership in the field of liver fibrosis currently using a human disease-specific ECM platform, paving the way for potential first-in class anti-fibrotic therapeutics”.

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