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Increasing Awareness of NAFLD/NASH – 2019 Is “the Year of NASH” According to Goldman Sachs

Non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH), is estimated to become the most common chronic liver condition in Western populations. It has been difficult for researchers and policymakers to accurately estimate the prevalence of NAFLD/NASH because the diseases are asymptomatic. However, I’ve seen published prevalence estimates in the United States of 20–30% for NAFLD and 2–5% for NASH.1 More particularly concerning is the expectation that the prevalence of NASH will increase by 63% by 2030. Because NASH increases the risk of cirrhosis and end-stage liver disease, it is also expected that it will be the leading cause of liver transplantation by 2020.2

Yet, we are struggling with awareness of the disease, its etiology, diagnosis, and treatment throughout the community – patients, health professionals, health providers, and researchers alike. This struck me during my discussions and while I listened to presentations at the recent NASH Summit in Boston. One presentation provided results from a recent survey indicating that only 6% of people with the highest risk of NASH in the US had heard of the disease.3 And, a national online survey provided information that nearly half of the responding primary care physicians were reportedly unfamiliar with the differences between NAFLD and NASH – of these, 58% indicated they were managing patients with NASH or NAFLD.4

How do we increase awareness and improve education? Perhaps a three-pronged approach would be the most effective method: international advocacy and national public health groups, patient advocacy and support groups, and continued innovation and clinical trials for disease understanding and treatment.

International advocacy and national public health groups

Advocacy and public health groups play important roles in raising money for research, educating health practitioners and the public, and issuing practice guidelines.

For example, the NASH Council, an initiative by the Global Liver Institute (GLI), aims to “shine a spotlight … around the urgency of developing mechanisms for quantifying and addressing the silent epidemic of fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in the U.S. and abroad.” The NASH Council has also taken on the responsibility for the 2019 International NASH Day, a public education campaign to raise visibility and urgency around NAFLD and NASH that was launched in 2018 by The NASH Education Program™, a Pittsburgh-based non-profit. In International NASH Day’s first year, over 50 events (liver health screenings, policy briefings, and education events) were coordinated online and in more than 25 cities across the globe.

Over the last few years, public health groups and government health organizations have published new or updated guidelines for the management of NAFLD/NASH including the EASL-EASDEASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease (2016), Nonalcoholic Fatty Liver Disease (NAFLD): Assessment and Management by the National Institute for Health and Care Excellence (NICE) (2016), Asia-Pacific Working Party on Non-Alcoholic Fatty Liver Disease guidelines (Part I and Part II) (2017), and The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases (2018).

It’s also encouraging to see the increasing number of conferences, most of which are still fairly new, as well as workshops and seminars for providers, such as these in 2019:

Patient advocacy and support groups

Similar to disease advocacy and public health groups at the national or international level, patient advocacy and support groups also contribute to research funding, general awareness, and patient education. At the NASH Summit, I listened to a presentation given by a patient advocate, Tony Villioti, who had previously been diagnosed with NASH and cirrhosis. After receiving a liver transplant, he founded the NASH Education Corporation to build patient and health practitioner awareness – one of their outputs is this NASH brochure that is available for download.

Patient support groups (e.g., American Liver Foundation NASH support group and the European Liver Patients’ Association) are important resources for patients and caregivers to feel empowered about disease-related decisions and to share information about their diagnosis and treatment. Historically, there has been a stigma associated with liver disease, as there was a perception that liver disease was related to alcohol or drug abuse. Patient advocacy groups play a key role in overturning this perception and in spreading the message that early detection and diagnosis is the key to preventing the more severe complications associated with end stage liver disease.

Research for NASH diagnosis and treatment

Unfortunately, an approved treatment for NAFLD/NASH does not yet exist, and this could also limit physician motivation to put patients through the burden of diagnosis, confirmation of which requires invasive liver biopsy. Reliable, non-invasive blood tests and scans are not currently available, and current guidelines do not recommend systematic screening. This is particularly unfortunate given that a delayed diagnosis can mean a direct path from receiving a diagnosis to the need for liver transplant, skipping the opportunity to slow or reverse any liver damage. Due to the lack of treatment options, standard of care involves only lifestyle interventions (exercise, weight loss, diet, abstinence from alcohol) to address the close relationship between NAFLD/NASH and metabolic syndrome. Factors limiting the development of a treatment include the multifactorial nature of NAFLD/NASH (hepatocyte lipotoxicity, inflammation, and fibrosis), an incomplete understanding of progression, and lengthy disease course, requiring long-term follow-up of treatment efficacy.

However, with the exciting recent developments in NAFLD/NASH clinical trials, Goldman Sachs recently declared that 2019 will be “The Year of NASH.”

Some of the innovation is around non-invasive screening and diagnostic tests. For example, Genfit recently presented about their NASH diagnostic NIS-4 algorithm – it looks at the levels of four circulating biomarkers (miR-34a, Alpha2 macroglobulin, YKL-40, and HBA1c) to identify patients with active NASH (NAS≥4) and significant fibrosis (F≥2).

There is also considerable interest in different molecules for treatment, with multiple drugs currently in Phase III trials and many more in the global pipeline. A quick search of clinicaltrials.gov resulted in 86 active Phase I-III trials for NASH. There are five drugs currently in Phase III trials, with hopes that FDA approval for the first drug will occur later this year.

 

Company

Drug

Mechanism

Status

Genfit

Elafibranor

Dual-PPAR alpha/delta agonist

Fast Track designation

Phase III RESOLVE-IT trial

Anticipated accelerated approval from the U.S. FDA end of 2019

Gilead Sciences

Selonsertib

ASK1 inhibitor

Phase III STELLAR-4 trial

Completed April 2019

Intercept Pharamaceuticals

Obeticholic acid (Ocaliva)

FXR agonist

Breakthrough Therapy designation

Phase III REGENERATE trial

Expected completion October 2022

Allergan

Cenicriviroc

CCR2/CCR5 inhibitor

Fast Track designation

Phase III AURORA trial

Expected completion July 2024

Madrigal

MGL-3196 (Resmetirom)

THR β-selective agonist

Phase III MAESTRO-NASH trial

Expected completion March 2024

 

It’s exciting to see that drug companies are working together in this competitive market to combine different molecules and drugs to provide a complete treatment path for NAFLD/NASH. For example, Novartis and Pfizer are bringing together Tropifexor to treat inflammation, fibrotic scarring, and fat accumulation with one or more Pfizer experimental drugs to treat steatosis. Novartis is also teaming up with Allergen to test the combined effect of Tropifexor and Cenicriviroc on NASH in the Phase II TANDEM study. Other companies are realizing that a single drug might not be enough – Gilead just completed a proof-of-concept study combining the FXR agonist GS-9674 with the ACC inhibitor firsocostat (GS-0976) to treat steatosis and liver stiffness in NASH.

The global market for these new drugs is estimated to reach $21.5 billion by 20255 – with each new development, media coverage of NAFLD/NASH has increased, bringing greater awareness.

As the community rallies around NASH, we’re sure to see even more exciting developments, just as we have for other significant chronic diseases such as cardiovascular disease and, for liver health, hepatitis.

As new tools and therapies are developed, access to a diverse patient population willing to commit to long-term trials will become increasingly important.

References

  1. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–285.
  2. Estes C, Razavi H, Loomba R, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123-133.
  3. Survey confirms NASH awareness remains low even among most-at-risk. Healio Hepatology. May 3, 2019. Available at: https://www.healio.com/hepatology/steatohepatitis-metabolic-liver-diseas...
  4. Polanco-Briceno S, Glass D, Stuntz M, et al. Awareness of nonalcoholic steatohepatitis and associated practice patterns of primary care physicians and specialists. BMC Res Notes. 2016;9:157.
  5. Jaiswal P, Shinde S. Non-alcoholic steatohepatitis (NASH) market by drug type (vitamin E & Pioglitazone, Ocaliva, Elafibranor, and Selonsertib & Cenicriviroc), and sales channel (hospital pharmacy, online provider, and retail pharmacy) - global opportunity analysis and industry forecast, 2021-2025. Allied Market Research. Available at: https://www.alliedmarketresearch.com/nonalcoholic-steatohepatitis-NASH-m...

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