The growing epidemic of “The Silent Liver Disease”
Non-alcoholic fatty liver disease (NAFLD) is experiencing a meteoric rise globally. NAFLD is the umbrella term for a range of non-alcoholic liver conditions that occur as a result of fat in the liver. NAFLD also encompasses a spectrum of diseases which consist of two distinct subtypes: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). This chronic medical condition affects approximately 25% of the worldwide population and over 100 million individuals in the United States (1).
NASH is the more serious subtype impacting 20% of NAFLD patients and as high as 30-40% in some regions (2). Estimates show that this condition impacts 3-6% of the global population today. This is expected to increase 63% by 2030 (3). Moreover, estimates indicate that NASH costs $103 billion each year in healthcare costs in the U.S. alone (4) and is the primary cause of liver transplantation in the country. A recent study found that 11% of patients with NASH are at risk of death from liver-related illness (5).
Patients with NASH typically have no or few symptoms – particularly in the early stages of the disease which is why it is often known as “The Silent Liver Disease”. It can also be challenging for physicians to impress the real dangers of this condition on their patients who may be largely asymptomatic. One company, Genuity Science, is ready to help the global biopharma industry tackle NASH by uniquely unlocking the underlying biology of this disease.
Risk factors are on the rise
The leading risk factors for NAFLD – obesity and type 2 diabetes – are also on the rise growing at a similar rate to NAFLD. Other risk factors include age, hypertension or a high fructose diet (6). In obese or diabetic individuals, prevalence of NAFLD is much higher, up to 60-70% for NAFLD and 20-25% for NASH (7). While no effective treatments are currently available, caffeine, physical activity, and a low-fat, Mediterranean diet have shown to be effective lifestyle interventions when treating NAFLD (8).
Several genetic predisposing factors are related to NAFLD and NASH. Heritability estimates (20-70%) vary depending on diagnosis methods, ethnicity and environmental factors (9-11). Hereditary modifiers also have a significant impact on the susceptibility to NAFLD and the risk for progression to more advanced disease. While most patients will have NAFL only, others may progress to NASH; a subset of NASH patients will then develop liver fibrosis leading to the feared complications of NASH – cirrhosis or hepatocellular carcinoma (HCC). Studies have identified a number of common genetic variants in distinct genes which associate with NAFLD, including PNPLA3, TM6SF2, HSD17B13, GCKR, LYPLAL1 and TRIB1.
A significant unmet medical need
Despite much investment and many clinical trials of candidate drugs to treat NASH, there are still no approved therapeutics on the market, and there have been numerous, high-profile clinical trial failures. Gilead’s selonsertib failed at Phase III and Conatus Pharmaceuticals’ emricasan failed in the first of three Phase II trials the company is running with Novartis. Most recently, French biotech, Genfit’s Phase III trial of its lead drug candidate elafibranor did not meet its primary endpoint. Thus, this means a growing population of NASH patients must now wait even longer for an approved treatment.
Success has been elusive for many reasons; NAFLD is such a multifactorial disease, the NAFLD phenotype is infamously hard to define since the diagnosis methods vary and the gold standard, an invasive liver biopsy, is not widely available or applicable. Additionally, although NASH affects a high proportion of the population, disease awareness has been low, largely as a result of the “silent” nature of the disease. These factors make it difficult not only to study the disease but also to successfully recruit diagnosed NASH patients for participation in clinical trials. In a recent Labiotech article, writer Helen Albert posits “the continued failure of NASH trials does beg the question of whether a different approach might be needed.”
A different approach – targeting disease biology
Genuity Science hopes to buck the trend on NASH clinical trial failures by taking a different approach and giving the global biopharmaceutical industry better insight into the disease, by targeting the complex underlying biology of the NASH/NAFL. It aims to determine why only a portion of NAFLD patients progress to severe NASH with high fibrosis.
Genuity is combining several thousands of NASH and NAFL patients with deep clinical data, whole genome sequencing and liver tissue multi-omics to define which genes distinguish high fibrosis NASH patients (high risk) from low or no fibrosis NAFLD patients (low risk). Analysing this cohort of patients will allow Genuity to identify the driver genes or pathways that have genetic variants with the highest effect on liver fibrosis. The company has compiled the world’s largest whole genome sequenced NASH/NAFL cohort with rich clinical phenotype data which they believe will lead to significantly better understanding of the disease biology of fibrosis and other aspects of NASH, and ultimately approved drugs to treat the disease.
Uniquely, the Genuity Science NASH/NAFL cohort of 6,000 patients (and growing) has 5 to 15 years of extensive longitudinal clinical data, including a large portion with liver biopsies, documenting the degree of liver fibrosis and inflammation. The cohort also has an average of 8 non-invasive measures of liver fibrosis per patient, enabling Genuity to define and compare rapid progressors of fibrosis vs. slow progressors to find biomarkers of fibrosis progression. These markers may be useful to enrich NASH clinical trials with patients more likely to progress.
The cohort is also enriched to look at links to other risk factors for NASH with roughly 20% of 6,000 NASH/NAFL patients having had bariatric surgery. This allows Genuity Science to look for the effects of extreme weight loss on NAFLD, and explore if there are obesity-dependent and obesity-independent forms of NAFLD, and determine if they are driven by different genes. More interestingly, another several hundred patients in the cohort are not overweight, having normal or lean body mass indices (BMI). Having such a distinctive, large-scale discovery resource will allow Genuity and collaborating researchers to define severe and less severe disease subtypes, compare rapid progressors versus slow progressors, and examine earlier onset and later onset subtypes.
“Analysing NAFLD at varying stages of disease severity is key to uncovering novel driver genes – looking at whole genome sequences and detailed clinical data at population scale enables us to uncover rare and low frequency variants with high effect sizes which wouldn’t have been possible with genotyping chips that measure common variants or even whole exome sequence analysis alone,” said Genuity Science co-founder and Chief Scientific Officer, Jeff Gulcher.
As a part of the advanced analysis the Genuity researchers are conducting, they also apply artificial intelligence and machine learning to multiomic and single nuclei RNA sequencing data from NASH and NAFL liver biopsies to find driver genes of steatosis, inflammation, hepatocyte death, and fibrosis. Genuity’s research will be used to support new candidate targets or support validation of pre-existing targets and also to identify biomarkers which may define the difference between slow progression and more rapid progression of fibrosis.
“Our ambition is to complement WGS association by combining powered, bulk multi-omic liver tissue datasets, single nuclei RNAseq and methylation datasets, and AI analysis in order to understand the clinically important aspects of fibrosis using human genomics,” continued Gulcher.
Genuity Science sees another key factor to successful NASH clinical trials in their efforts – their highly-powered NASH dataset can be utilised to stratify patient populations – a critical enabler for trial reliability and response rates which is unique to the approach often taken today.
For more information, Dr Jeff Gulcher will be presenting his talk, “Identifying Novel High Fibrosis NASH Drug Targets Using Detailed Clinical Omics Data,” at the NASH Summit on Wednesday, December 16, 2020, 12.00 EST / 9.00 PST.
References:
- The NASH Education Program (n.d.). How prevalent is NASH? https://www.the-nash-education-program.com/what-is-nash/how-prevalent-is-nash/; accessed July 9, 2020.
- GI Society, “The Dangers of Non-Alcoholic Fatty Liver Disease” (2014). https://badgut.org/information-centre/a-z-digestive-topics/the-dangers-of-non-alcoholic-fatty-liver-disease/
- Kumar et al. (2019). Non-alcoholic Fatty Liver Disease: Growing Burden, Adverse Outcomes and Associations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132013/
- Shetty et al. (2019) Health and Economic Burden of Nonalcoholic Fatty Liver Disease in the United States and Its Impact on Veterans. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366581/
- European Association for the Study of the Liver (April 2019). High rates of liver disease progression and mortality observed in patients with NAFLD/NASH. https://medicalxpress.com/news/2019-04-high-liver-disease-mortality-patients.html
- Barrera & George, The role of diet and nutritional intervention for the management of patients with NAFLD (2014). https://pubmed.ncbi.nlm.nih.gov/24274867/
- Ahmed, Non-alcoholic fatty liver disease in 2015 (2015). https://pubmed.ncbi.nlm.nih.gov/26085906/
- Gomez et al. (2017), Treatment of NAFLD with diet, physical activity and exercise. https://www.journal-of-hepatology.eu/article/S0168-8278(17)32052-4/pdf
- Loomba et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study (2015). https://pubmed.ncbi.nlm.nih.gov/26299412/
- Schwimmer et al. Heritability of nonalcoholic fatty liver disease (2009). https://pubmed.ncbi.nlm.nih.gov/19208353/
- Palmer et al. Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent (2013). https://europepmc.org/article/pmc/pmc3782998
Image credit: By Andrii Zastrozhnov – canva.com
