October NASH News

Fatty liver disease (FLD) and non-alcoholic steatohepatitis (NASH) are increasing in prevalence worldwide, creating a major global public health crisis. To adequately educate patients, practitioners and policy makers, there is a need to collect, curate and share relevant information. NASH News, published on behalf of the Global Liver Institute’s NASH Council, intends to meet that need and to facilitate collaboration across the emerging NASH community on a monthly basis.

We would appreciate your feedback and content contributions. Please contact nash@globalliver.org

GLI Perspective

As reported in this issue of NASH News, there are great amounts of research and treatment development focused on NASH occurring worldwide. Recently, GLI President and CEO Donna Cryer, JD was invited to participate on a panel and present patient and policy perspectives on NASH at the ROTH Battle of the NASH Thrones Investor Conference in New York City. Among the points she made to the audience were:

Defining NASH currently as a biopsy-confirmed disease is the biggest barrier to appropriate quantification of the patient population and will be used against the community by payers to restrict access to treatment once approved — if we permit that to occur.
Diagnosis of NAFLD/NASH has three aspects: awareness/acceptance by the medical communities (including endocrinology and cardiology/lipids); clinical workflow/referral patterns; and technology (development of non-invasive tests by consortia such as NIMBLE and LITMUS or individual companies like Genfit or Gilead).
Pricing/Reimbursement will depend on multiple factors, but primarily two: will the therapy be prescribed for chronic use or a limited time, and is the expectation that a single drug will be sufficient or will a combination be necessary? Those involved in pricing should also consider that NASH patients will likely be on multiple therapies for other aspects of the medical syndrome and may also want to consider what a NASH care bundle may look like, comprising physician, imaging, weight management or other support services, as well as pharmaceuticals. Is the right reference point bariatric surgery or branded statins? What economic research is necessary to quantify the currently unrecognized impact of undertreated NAFLD/NASH to be able to demonstrate the value of care once therapies are approved?

These are among many considerations and potential barriers to overcome to ensure patient access to efficacious and quality NASH care.

GLI Updates

45 NASH Treatments in Clinical Trials

A September review conducted by GLI found 45 therapies in clinical trials for treatment of NASH/NAFLD. At the time of the GLI review, four treatments were in phase III clinical trials, 32 were in phase II, and nine were in phase I. Additional treatment candidates were identified in pre-clinical investigation. Of special interest and related to the apparent heterogeneity of NAFLD and NASH are the significant variety of treatment pathways, treatment targets and the means by which different treatments work. In a 2017 review for Virology Education, Dr. Sanjay Bhagani of the Royal Free Hospital in London, England, identified six NASH treatment pathways being tested in clinical trials and more he categorized as “Other.” The six are:

Lipid metabolism
Antifibrotic
Glucose metabolism
Anti-Inflammatory
Immunomodulatory
Oxidative stress

Following is a brief summary of the four treatments currently in Phase III trials:

Cenicriviroc (Allergan) inhibits macrophage accumulation in the liver. The recruitment of monocytes and macrophages to the liver promotes the progression of NASH and fibrosis. The drug seeks to impede inflammation and fibrosis.
Elfibranor (Genfit) is a dual agonist of the peroxisome proliferator-activated receptors (PPARs) alpha and delta. PPARs are nuclear receptors that modulate multiple activities involved in metabolism, diabetes, obesity, and cancer. Exercise increases PPAR activity and results in increased fat burning activity. Agonists of the PPAR system mimic this action to increase fatty acid oxidation. Agonists also increase HDL concentrations which reduce blood lipid levels.
Selonsertib (Gilead) is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. During oxidative stress ASK1 leads a phosphorylation (protein changing) stress response pathway that worsens liver inflammation and fibrosis. Selonsertib intervenes to end fibrosis and liver cell death.
Ocaliva (obeticholic acid, Intercept) is an agonist of the farnesoid X receptor. FXR is highly expressed in the liver and GI tract and is the main regulator of bile synthesis. FXR agonists decrease bile acid synthesis, decreases hepatic gluconeogenesis and lipogenesis. Ocaliva is FDA approved for treatment of primary biliary cholangitis.

The apparent heterogenous pathophysiology of NAFLD/NASH and the different approaches being developed to stop or reverse steatosis, inflammation and/or fibrosis are suggestive of the challenges for GLI’s NASH Council and other organizations seeking to guide physicians, patients and policymakers in the optimal personalized disease management approaches suitable for patients with differing medical histories, conditions and personal circumstances. For a recent research article on this topic see Obesity and Nonalcoholic Fatty Liver Disease: Current Perspectives.

Conference Outreach

Speaking at conferences and participating in panels addressing cutting edge patient-care issues is one way GLI advances liver health awareness and promotes patient-centered values. In addition to her presentation at the ROTH Battle of the NASH Thrones Investor Conference in New York, on October 18th, Donna Cryer moderated a panel focused on Health System Transformation and Patient Engagement at AcademyHealth Concordium 2018 in Washington, DC. She will also speak at the BIO Patient and Health Advocacy Summit on the Ensuring Patient Access and Affordability Panel, taking place on October 25 in Washington, DC.

If you are a NASH Council member and are engaged in public or professional education, please let us know about your outreach activities.

GLI will be attending the American Association for the Study of Liver Diseases (AASLD)’s The Liver Meeting 2018 in San Francisco on November 9-13. Hold the date for Friday, November 9 for a GLI evening event.

NASH Council

Save the date for Tuesday, December 4, when GLI’s NASH Council Policy workgroup will meet. With input from Gilead, the workgroup meeting will address strategies focused on NASH screening, diagnosis, prevention, and management.

Please email nash@globalliver.org with your new workgroup preferences. The workgroups are: Lifestyle Intervention, Clinical Workflow, or Policy.

View the membership list. Want to be a member? Fill out the membership Application Form.

NASH Fact of the Month

Prevalence of NASH is expected to increase by 63% by 2030 in the United States. A treatment for NASH is necessary to ease the future disease burden projected.

Source: Estes, C., Razavi, H., Loomba, R., Younossi, Z., and Sanyal, A.J. (2018). “Modeling the Epidemic of Nonalcoholic Fatty Liver Disease Demonstrates an Exponential Increase in Burden of Disease.” Hepatology, 68(1), 123-133. Doi: 10.1002/hep.29466

NASH Patient Insights

Kimberly Martinez with GLI President & CEO, Donna Cryer, JD at GLI’s Advanced Advocacy Academy

This month, we interviewed Kimberly Martinez, a 2018 GLI Advanced Advocacy Academy (A3) trainee. Kimberly discovered she had NASH when she lost weight to become a living kidney donor for her older brother, Paul.

If you could change one thing about how the healthcare system treats patients, especially those with liver disease, what would it be?

Early screening for liver problems should be as common as screenings for diabetes. Then, [once] liver problems are diagnosed, education for the patient is pivotal. ...They need to be aware of what stage of liver disease they have [and] what can be done by changing their lifestyle. I believe the liver patient should not only have a gastroenterologist but also be referred to a hepatologist.

I wish I would have been told that cirrhosis could be caused by things other than drinking or drug abuse. I was clueless, and no one told me [that] being heavy my whole life was most likely the reason I developed cirrhosis. I only found out my diagnosis, NASH, from my discharge papers. I found out what NASH was by looking it up on Google. I definitely would have benefitted from point-of-care patient counseling.

What do you most want people to know about your life with liver disease?

My life with liver disease is a triumphant story. I was told I had a terminal disease that would eventually take my life [and] my future. With the help of my incredible support system, my family and friends, and the doctors and nurses from that first night in the ER, to the team at Nazhi Zuhdi Transplant Center, I am forever in their debt. But, without an organ donor, there is no triumphant story to tell. I would not be here without my donor. One of her last wishes on this earth was to save someone’s life. I thank my donor and her family for today and every day.

I am post transplant about two and a half years. I am active, I play volleyball and pickleball, I still attend a Zumba class. I am feeling better than I have for years.

As far as my future, I am not waiting. I am an advocate for others. I hope by sharing my story, I can help someone else avoid getting to the point of transplant or…losing their life to liver disease. [My story] is a worthy legacy to leave. I also would love to be the answer to someone else’s prayer; I am registered to be an organ donor.

Industry News

Oramed Pharmaceuticals

After promising preclinical and clinical studies showing the positive effects of its oral insulin capsule for reducing liver inflammation in NASH patients, Oramed recently announced the enrollment of the first patient in a three month study.

Samil and Galmed Pharmaceuticals

Korea’s Samil Pharmaceuticals and Israel’s Galmed Pharmaceuticals joined forces to create Aramchol, a drug that is anticipated to be a treatment for NASH. It is currently in phase 2b clinical trials and is expected to soon begin phase 3. Treatment with Aramchol produced a statistically significant reduction in liver fat as well as ALT and AST levels when compared to a placebo.

Sanyal Biotechnology

A Norfolk-based company was licensed by the Virginia Board of Pharmacy and the U.S. Drug Enforcement Agency to use cannabidiol (CBD) in medical research and examine its effects on obesity and NASH. Sanyal received the broadest license available to conduct its research; further implications on the future scheduling of CBD could be addressed by the federal government.

Regulatory

Clinical Trials

161 clinical trials globally recruiting for NAFLD
153 clinical trials globally recruiting for NASH

Research & Studies

Finland

A research team is looking into the relationship between lipids, fatty liver, and the blood brain barrier. Using data they’ve found regarding lipids, they are seeing if there is a connection between NAFLD and metabolic comorbidities, which might relate to psychotic disorders.

Korea

After conducting a prospective cohort study, researchers discovered that obesity and weight gain were independently associated with an increased risk of fibrosis progression in the liver. They stated that this study reinforced that physicians should encourage patients with NAFLD to maintain a healthy weight and prevent weight gain to keep the disease from progressing.

Poland

This review discovered that there may be a need to monitor bone density in patients with NAFLD. The researchers suggested that the positive effects of vitamin D in helping manage it could be due to a shared pathogenesis between osteoporosis and NAFLD.

Sweden

Researchers found that patients with NAFLD are at higher risk for ischemic heart disease, especially those with cardiovascular disease risk factors at baseline. They determined that risk for cerebrovascular disease was not significantly associated with NAFLD alone.

United States

At the American College of Gastroenterology Annual Meeting earlier this month, three presentations focused on liver disease. Dr. Reau of Rush University stressed the importance of further testing in pregnant mothers if changes in liver transaminase and bilirubin levels were observed; early detection of liver disease could save the lives of both the mother and the child. Dr. Singh of Stanford University presented on the new findings that patients with NAFLD and type 2 diabetes could see either a decrease in NAFLD severity or increase without any treatment. This indicated that the effects of diabetic medications on NAFLD needed further investigation to explain this bidirectionality. Dr. Zachry of Quantym Therapeutic Data discovered that FibroScan after an endoscopy diagnosed new patients with NASH or NAFLD. He stressed the importance of both screening and follow-up with high-risk patients.

Use of a nanosensor in mice livers demonstrates a noninvasive lipid accumulation measure. This could aid in drug development as well as provide a way to better understand the pathogenesis of liver disease. Researchers also identified a potential link between endolysosomal lipid accumulation and the progression of diseases like NAFLD.

A study conducted at Yale University including different ethnicities established that black adolescents are less prone to NAFLD. However, in cases where they already have NAFLD, these patients present with more severe metabolic syndromes.

NASH In The News

A coalition led by the Emirates Gastroenterology and Hepatology Society, Saudi Association for the Study of Liver Diseases and Transplantation, and European Association for the Study of the Liver signed a Call for Action supported by Gilead to raise awareness about NASH at this year’s third International Hepatology Summit. NASH is highly prevalent in the Middle East, affecting an estimated 32% of the population. The Call for Action aims to identify patients that are high-risk for developing NASH earlier and encourage lifestyle changes to prevent progression of the disease.