FIB-NIT™ (Fibrosis Non-Invasive Tests) is an innovative panel that utilizes biomarkers of fibrotic processes. These biomarkers have been proven to associate with superior pharmacodynamic and supportive prognostic performance to investigate dynamics within fibrotic diseases, including understanding drug efficacy in such indications —demonstrated in over 100 publications in relevant and peer-reviewed scientific journals. The FIB-NIT™ panel consists of the fibrogenesis NordicPRO-C3™, the fibrolysis NordicCTX-III™, and the outcome risk NordicPRO-C6™ biomarkers.

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Fibrosis is a pathological condition characterized by the disruption of the balance between formation and degradation of extracellular matrix components (ECM), with an excessive accumulation of collagens leading to tissue scarring.

The formation of fibrotic (scar) tissue can affect different tissues including liver, lung, heart, kidney, skin, intestines, connective tissue, among others, resulting in permanent changes in tissue architecture which progress to loss of organ function and, ultimately death.

Understanding the molecular mechanisms behind fibrosis and monitoring relevant pathways associated to fibrogenesis and fibrolysis are extremely important to develop screening tools to identify patients at severe stages of fibrosis, patients who are at risk to disease progression as well as to develop and evaluate the efficiency of novel therapies to prevent and treat fibrotic conditions.

Biomarkers of the ECM, especially those based on collagens, are efficient tools to investigate fibrotic processes. Collagens are major components of ECM that are affected by fibrosis in the injured tissue, which produce unique fragments. These unique fragments, called neo-epitopes, are released in the bloodstream where they can be non-invasively measured by the Nordic ProteinFingerPrint Biomarker Technology™ to understand ECM turnover disruption. 

The FIB-NIT™ biomarker panel can guide drug development in fibrotic diseases.

The FIB-NIT™ panel includes three of the most prominent Nordic Bioscience developed biomarkers to understand fibrogenesis, fibrolysis and risk of outcome. NordicPRO-C3 (PRO-C3) and NordicPRO-C6 (PRO-C6) are both associated with fibrogenesis and excessive production of ECM, while the biomarker NordicCTX-III(CTX-III) is related to fibrolysis and degradation of fibrotic tissue.

When combined, these three biomarkers provide a unique solution to monitor the mass balance of ECM remodeling as well as fibrosis dynamics which can contribute to accelerated clinical trials. FIB-NIT™ achieves this by helping with patient selection and inclusion, identification of treatment responders, assessment and prediction of drug response without the need for invasive procedures like biopsy; or the use of expensive noninvasive screening tests that are commonly used in the clinical practice.

NordicPRO-C3™ (ADAMTS2 mediated release of the N-terminal pro-peptide of type III collagen) measures the formation of type III collagen which has been shown to be a key process behind fibrogenesis development and progression in different organs and tissues (liver, lung, kidney, heart, intestines, skin). Concentrations of PRO-C3 give an estimation of the level of active fibrogenesis and can be useful as a clinical research tool to identify patients at risk to develop outcomes and predict the incidence of liver related events.

PRO-C3, being a neoepitope differs from PIIINP, as the former is formation specific, while the latter measures both formation and degradation of type III collagen, yielding a less precise measurement.

Figure 1[1]. PRO-C3 levels allow to stratify patients with advanced liver fibrosis (F4) with a higher degree of active fibrogenesis and, consequently, at a higher risk to develop outcomes.

PRO-C3 has been widely used to monitor the response and pharmacodynamics of anti-fibrotic treatment and patients who are likely to respond to treatment, especially in the field of hepatic diseases such as MASH and obesity/metabolic phase 2 and 3 intervention studies.


Table 1. PRO-C3 levels dynamically change upon anti-fibrotic treatment with Efruxifermin allowing to monitor drug response and pharmacodynamics in phase 2 MASH intervention studies.

 

Table 2. PRO-C3 levels allow to monitor drug response and pharmacodynamics in phase 2 and 3 metabolic intervention studies with focus in MASH and obesity.

NordicPRO-C6™ (C-terminal of type VI collagen α3 chain; also known as Endotrophin) measures the formation of type VI collagen and the signaling molecule Endotrophin which correlates to fibrogenesis, fibroblast activity and, to metabolic processes. PRO-C6 acts as a driver of fibro-inflammatory processes, providing an efficient tool to predict outcomes (risk of cardiovascular events, HFpEF pathology; mortality; disease progression) in many different fibrotic diseases affecting liver, heart, kidneys, and the gastrointestinal system.


Figure 2. PRO-C6 as a marker of type VI collagen formation and Endotrophin signaling activity.

Endotrophin has a major role for the development and progression of metabolic disorders and is highly correlated to a pro-fibrotic, pro-inflammatory and angiogenesis endotype, allowing to identify patients with preserved ejection fraction (HFpEF) that are at risk of developing cardiovascular events and at risk of death.

Figure 3[2]. PRO-C6 levels indicate abnormal metabolic activity and can be used for identification of patients with cardiovascular (CV) diseases at risk of heart failure and death related to cardiovascular events. PRO-C6 outperforms standard biomarkers and scores used in the clinic for prognosis of cardiovascular diseases. Primary endpoint: CV death from CV causes, aborted cardiac arrest or hospitalization for HF. Data adjusted for age, gender, race, diabetes, history of MI & glomerular filtration rate (GFR).

Endotrophin measured through PRO-C6 levels has shown prognostic potential for predicting mortality in many different pathological conditions such as liver, cardiovascular, metabolic, respiratory, kidney diseases, diabetes and cancer.

NordicCTX-III™, (fragment of MMP degraded crosslinked type III collagen) measures the proteolytic degradation of cross-linked type III collagen, a process which indicates fibrolysis and fibrosis resolution. Interventions based on drug treatment and lifestyle changes can stimulate the production of proteolytic enzymes that cleave ECM excess, especially type III collagen, in fibrotic conditions, leading to improvement of fibrosis via resolution.

By measuring CTX-III, we may assess patients who have progressive, stable or regressive fibrosis. MASLD patients with higher concentrations of CTX-III have higher rates of fibrolysis and are more likely to present a more regressive endotype of fibrosis following interventions focused on improving liver health, for example, weight loss due to bariatric surgery.

 Figure 3[3]CTX-III separates regressors from stable and progressor patients.

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