Innovative diagnosticsand therapeuticsfor metabolic disease

About

CellMade’s goal is to contribute to health innovation by addressing unmet medical needs in NAFL-NASH overcoming development of related comorbidities.

CellMade is an early-stage biopharmaceutical company dedicated to the discovery and development of innovative diagnostic and early, preventive nutraceutical therapies in metabolic diseases with unmet medical needs.

Targeting metabolic diseases with unmet medical needs

Non-Alcoholic Fatty Liver Disease (NAFLD) is defined by the presence of a determined hepatic steatosis, which corresponds to an accumulation of triglycerides in hepatocytes representing more than 5% of the total weight of the liver, in the absence of significant alcohol consumption, of the use of steatogenic drugs (tamoxifen or amiodarone) and of another liver pathology (viral or autoimmune hepatitis, hemochromatosis, Wilson's disease, …) (Chalasani et al. 2012; Neuschwander-Tetri 2003). NAFLD distinguishes liver steatosis (non-alcoholic fatty liver, NAFL) from non-alcoholic steatohepatitis (NASH) (Chalasani et al. 2012).

NAFL, which corresponds to the first stage of NAFLD and is considered to be a benign, asymptomatic and reversible condition, is defined by the presence of hepatic steatosis (≥ 5%) without evidence of hepatocytes ballooning (Chalasani et al. 2012; Neuschwander-Tetri 2003; Spengler and Loomba 2015). In some patients, NAFL may progress to a serious and irreversible pathological condition, non-alcoholic steatohepatitis (NASH), which is characterized by the presence of hepatic steatosis associated with inflammation and hepatocytes ballooning that causes their dysfunction and death. This condition, which may or may not be accompanied by the presence of fibrosis, may progress to cirrhosis, liver failure and, in rare cases, to liver cancer (Chalasani et al. 2012; Spengler and Loomba 2015).

Based on an epidemiological study that identified NAFLD cases in published scientific studies, the overall prevalence of NAFLD is 25% (Younossi et al. 2016). In a worrying way, this prevalence increased sharply, from 15 to 25% between 2005 and 2010 (Younossi et al. 2016). While NAFL remains considered as a benign and poorly symptomatic condition, its progression to NASH and the onset of co-morbidities, such as atherosclerosis or type 2 diabetes mellitus (T2DM), are major health problems. Among the leading causes of death in NAFLD patients, cardiometabolic complications are extremely common, including coronary heart disease and T2DM (Rafiq et al. 2009).

Early Diagnosis of NAFL-NASH

Nowadays, the standard method for diagnosing and assessing the severity of NAFLD remains liver biopsy, where hepatic steatosis, lobular inflammation, hepatocytes ballooning, and fibrosis are semi-quantitatively scored (Jennison et al. 2019; Lee 2017). However, this invasive procedure is associated with potential complications (such as bleeding), and the small sample volume could be responsible for sampling error, especially for mild steatosis (Jennison et al. 2019; Lee 2017). In addition, a poor reproducibility among different pathologists has been observed (Lee 2017). For these reasons, liver biopsy is not suitable for large scale diagnosis of NAFLD, but also for patient follow-up and analysis of the efficacy of a treatment. As a result, many studies have sought to develop new non-invasive methods for the reliable diagnosis of NAFLD. Many imaging methods have been developed (Jennison et al. 2019; Lee 2017). Computed tomography scan (CT-scan), although less dangerous than liver biopsy, is associated with radiation exposure, and is not adapted for mild steatosis (Jennison et al. 2019; Lee 2017). If ultrasonography is free of radiations and widely available, the sensitivity and specificity for detecting mild steatosis are poor and there is substantial intra- and inter-pathologist variability (Jennison et al. 2019; Lee 2017). Transient elastography demonstrates a better sensitivity and specificity for mild, moderate and severe steatosis than ultrasonography, but failure of examination has been observed in about 7 % of cases, particularly in obese individuals (because of larger skin capsular distance) (Jennison et al. 2019; Lee 2017). Magnetic resonance spectroscopy and imagery demonstrate an excellent diagnostic performance to detect and grade steatosis and are free of radiation, but the limited availability and the high cost of examination limit the utilization of these technics for large scale screening of subjects at risk to develop NAFLD (Jennison et al. 2019; Lee 2017). Based on blood samples, the Fatty Liver Index (that includes BMI, waist circumference, gamma-glutamyltransferase, and triglycerides) and the NAFLD Liver Fat Score (that includes the presence of MetS, T2DM, fasting serum insulin, aspartate aminotransferase, and the aspartate aminotransferase/alanine aminotransferase ratio) have been developed, but these scores have not been validated against liver histology (Jennison et al. 2019). In summary, no method allowing the early detection of NAFL is validated so far. New diagnostic methods for large scale screening of early-stage NAFLD but also to evaluate the efficacy of a treatment need to be developed.

Treatment of NAFL-NASH

To date, no pharmacological treatment can cure NAFL, which clearly promotes the further development of NASH and related comorbidities (El-Agroudy et al. 2019). According to the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD), and the European Association for the Study of Obesity (EASO), the current guidelines for the management of NAFL recommend lifestyle modification as the strategy of choice for preventing and improving NAFL, including caloric restriction and physical activity (Anon 2016). If lifestyle modifications are effective to improve the outcome of NAFL, or at least to limit its progression to NASH and other comorbidities, the evidence from both dietary and exercise interventions is limited regarding the effectiveness in more advanced stages, such as NASH (El-Agroudy et al. 2019). In addition, patients' compliance with these types of intervention remains relatively low. Indeed, caloric restriction is difficult to practice in the long term and increases the risk of malnutrition, which explains, in particular, the low compliance of patients (Golbidi et al. 2017; Madeo et al. 2019). Therefore, there is a real need to treat NAFL patients early and at a stage when the disease is potentially still reversible.

CellMade’s pioneering approach to early diagnosis and preventive therapy of metabolic diseases

CellMade develops a revolutionary class of products. Our innovative products focus on the early diagnosis of NAFL-NASH and its preventive nutraceutical treatment overcoming the development of related comorbidites such as atherosclerosis and type 2 diabetes. From a medical point of view, the products developed by CellMade form part of a preventive and personalized therapy approach and are complementary to existing recommendations for healthy lifestyle.

Treatment of the onset of noxious pathways

Preventing or slowing down the progression of NAFL to NASH is potentially the best approach avoiding the onset of comorbidites such as atherosclerosis and T2M. In a patient-oriented approach, CellMade’s biomarker signature CLM-BM-101 is used for the early diagnosis of NAFL-NASH. CellMade’s lead therapeutic (nutraceutical) product CLM-101 intervenes on key factors that are at the basis of the onset of the diverse noxious pathways leading to progression of NASH and leading to the development of related comorbidites.

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