Evolving efficiency

LONDON—Now that Engitix Ltd. has closed a £5-million Series A financing, it will accelerate its efforts to develop both tissue-specific and disease-specific human extracellular matrix (ECM) for accelerating and improving the drug discovery process. The company has validated its ECM platform in determining drug efficacy in liver fibrosis through collaborations with numerous biotech and big pharma companies. It is evolving its business model to in-house drug discovery for developing a pipeline of candidate drugs targeting liver fibrosis and liver and pancreatic cancers.

“The ECM is the non-cellular component present within all tissues and organs and provides not only essential physical scaffolding for the cellular constituents, but also initiates crucial biochemical and biomechanical cues that are required for tissue morphogenesis, differentiation and homeostasis,” explained Dr. Giuseppe Mazza, Engitix co-founder and CEO. “However, dysregulated ECM remodeling is associated with pathological conditions and can exacerbate disease progression such as fibrosis and cancer.”

He added that the loss of tissue ECM homeostasis and integrity is seen as one of the hallmarks of cancer and typically defines transitional events in cancer progression and metastasis. Consequently, ECM molecules and/or mechanisms associated with ECM remodeling are important targets for pharmacotherapy.

“Unfortunately, until recently, ECM has been largely ignored in drug discovery,” Mazza said. “The rapidly increasing knowledge in the biology of the ECM will likely lead to compounds able to directly target the ECM, with significant advantages in the treatment of chronic fibrogenic human and oncology diseases.”

Mazza considers the current process of drug discovery “highly inefficient,” with the majority of compounds failing in late stage clinical trials because of lack of efficacy.

He explained that previous drug discovery platforms relied on artificial substrates and/or animal models. Considering clinical trials results, he thinks that it is “rather evident that targets discovered and tested employing those models did not always meet the expectations.” New approaches—such as lab-on-a-chip, bio-printing and organoids—represent “an incredible advancement towards better models” that can reproduce more human-like physiological conditions in a three-dimensional in-vitro model. However, those new techniques still lack the possibility to include tissue-specific and disease-specific human ECM microenvironment in the experimental setting for drug discovery, Mazza said.

Engitix’s mission is to reverse this “inherent constraint” by establishing more advanced platforms for target identification in which cells are provided with their physiological or pathological three-dimensional biochemical and biomechanical microenvironment, according to Mazza. To this end, Engitix acquired an exclusive license in 2017 from UCLB, University College London’s commercialization company, to use ECM patents and other intellectual property to develop human tissue-specific and disease-specific ECM scaffolds.

“Engitix 3D tissue- and disease-specific ECM scaffolds represent the enabling tool for a better understanding of the ECM remodeling process in cancer and fibrotic diseases, with the consequent selection of more realistic targets for biomarkers and drug identification, development and validation within the same unique, all-human 3D model,” Mazza said.

Deconstructing the complexity of the tumor ECM landscape and identifying the interactions between the many cell types, soluble factors and extracellular-matrix proteins has proved to be extremely challenging. Mazza believes that it is “crucial to develop and rigorously study” preclinical models of ECM targeting in different cancer types to overcome this translational hurdle and move from bench to bedside.

He said that Engitix is the first company in the world employing this set of unique tools for drug discovery. The commercial potential in cancer therapy can be “tremendous if successfully applied for the identification of novel targets to develop small molecules, immune oncology products as well as novel cell based therapies including CAR-T.” For the latter, he believes that a key problem is the limited efficacy in killing solid tumors. Engitix 3D ECM models enable the study of tumor infiltration cells and unlocking new mechanism of action by which immune cells are inhibited by the surrounding stroma, according to Mazza.

He concluded, “Overall, the cancer markets Engitix is targeting (liver and pancreatic cancer, respectively) are projected to have sales of up to $15 billion by the mid-2020s. Our hope is to contribute to this race against cancer and provide patients and their family with more effective treatments.”