The $35 billion race to cure a silent killer that affects 30 million Americans

At the Mayo Clinic in Jacksonville, Florida, the liver transplant group is busy handling an onslaught of patients who have come from all over the country in hopes of a chance at life. For many, a liver transplant is their last hope, after being diagnosed with a deadly disease sweeping the nation at epic proportions. People crowd the unit and undergo scores of testing and evaluation in an effort to get on the hospital's coveted transplant list. It's a program with a 94 percent survival rate after liver transplant, one of the highest in the nation.

For many the culprit is a serious form of fatty liver disease called nonalcoholic steatohepatitis, also known as NASH. An outgrowth of the obesity epidemic in the Western world and around the globe, it causes scarring and inflammation that can lead to liver cirrhosis, cardiac and lung complications, liver cancer and death. Yet few people know about it.

Across the United States, millions of people of all ages suffer from this silent killer that slowly morphs from nonalcoholic fatty liver disease, a condition that now affects 89 million in the U.S., according to the Center for Disease Analysis. The National Institutes of Health estimates as many as 30 million people, or 12 percent of U.S. adults, now have NASH.

The effects of the disease — which include fibrosis, ascites (fluid accumulation in the abdomen), bleeding varices in the esophagus and liver cancer — are devastating. "By 2020 NASH will overtake hepatitis C as the No. 1 cause of liver transplantation in the U.S.," says Dr. Maria Yataco, a gastroenterologist who is conducting research on NASH and liver disease at the Mayo Clinic in Jacksonville.

What is even scarier is the fact that liver specialists are seeing patients that are younger and younger with this disease due the rising obesity rates. "Today we are seeing people in their 20s and 30s with NASH," says Dr. Leona Kim-Schluger, a hepatologist and professor at the Recanati/Miller Transplantation Institute at Mount Sinai Hospital in New York. "There is even NASH in the pediatric population."

"Right now it is estimated the U.S. is spending $5 billion annually in health-care costs related to the disease, which include chemotherapy, transplants, tests and hospitalizations," says health-care economist Home Razavi, managing director of the Center for Disease Analysis, who is working with ministers of health around the world to gather data and help them develop a national health strategy for NASH. "But the costs will rise to $18 billion by 2030 if this disease goes unchecked."

In spite of the large U.S. patient population at risk, the CDC has not addressed the crisis, and there is no FDA-approved treatment available, experts point out.

Even worse, signs of the disease are asymptomatic, so a person often is not diagnosed with NASH until it advances to a late stage, when cirrhosis begins to ravage the body, according to Dr. Laurent Fischer, senior vice president and head of global drug development at Allergan.

By that point the only option is a transplant to avert death. That's because physicians typically do not screen for fatty liver disease as part of the annual physical they give patients when they analyze for other life-threatening conditions, like heart disease, diabetes, breast and colon cancer.

Wayne Gagne a 67-year-old locomotive engineer in Nashua, New Hampshire, can attest to that. Now on hospice care, he found out he had NASH totally by accident in 2011 after going to the emergency room at his local hospital for heart problems. There doctors did a battery of tests to diagnosis his issues, including an ultrasound of his abdomen, and found he had the disease. "By then he had cirrhosis of the liver, and his only option was a transplant," says his wife Gigi. But his heart condition precluded him from being a candidate.

"Routine checkups never revealed he had NASH," Gigi recalls, "all the blood tests of his liver enzymes were fine, so no one knew. We just thought if he lost weight and had a healthy life style he would be OK."

Since then Wayne has suffered with a host of complications including acities, varices in his esophagus and severe muscle loss and muscle cramps. His heart condition is worsening, another complication from NASH.

Stories like this abound. Many people fall through the cracks with no diagnosis. That's what happened to Evans Kavallines in Lake Mary, Florida. His gastroenterologist told him he had a fatty liver in 2015, but he thought nothing of it, since he was in good health. It wasn't until seven months ago that he reached a tipping point and his health began to slide. The 71-year-old got ascites, varices in his esophagus and severe muscle cramps. Three months later he was diagnosed with liver cancer at Mount Sinai Hospital after his family decided to take him to its Recanti/Miller Transplant Institute in New York City for evaluation.

"I feel like my hometown doctors let me down," he says, now grateful to be on the liver transplant lists at both Mount Sinai and the Mayo Clinic in Florida. "For the most part, the medical community is not addressing this horrible disease, testing for it or offering any treatment."

But that could change in the not-too-distant future. The race is on in the pharmaceutical industry to develop drugs to treat NASH.

"After successfully curing hepatitis C with a whole new class of blockbuster direct-acting antiviral drugs — i.e. Gilead Sciences' Sovaldi and Harvoni — this is the next big frontier in liver disease to conquer," says Veronica Miller, professor at the UC Berkeley School of Public Health and executive director of the Liver Forum. The nonprofit is a global initiative for collaborative research among Big Pharma, physicians, regulators and academia that is trying to fast-track drug development in NASH on all continents.

Mayo Clinic Jacksonville, Florida

Dr. Maria Yataco is conducting research on potential therapies and drugs for the treatment of NASH at the Mayo Clinic in Jacksonville, Florida

Industry experts estimate the global market for these new drugs is $35 billion. Several drugs are in late-stage testing, and dozens more are in the global pipeline. BioMedtracker, a product from business intelligence firm Informa, counts 55 NASH drugs in clinical trials: 19 at Phase 1, 33 at Phase 2 and four at Phase 3.

According to medical experts, obesity and Type-2 diabetes are the major causes of NASH, but the disease can also be triggered by high accumulation of triglycerides, carbohydrates and high-fructose corn syrup.

Scientific research from the National Institutes of Health shows that "fructose is a weapon of mass destruction" that increases fatty liver disease and is poorly absorbed by the gastrointestinal tract and almost entirely metabolized by the liver, since cells don't use fructose for energy.

Leading the drug discovery effort

Right now four companies are leading efforts to commercialize a drug to reverse the effects of NASH: Intercept Pharmaceuticals, Gilead Sciences, Allergan and French biotech GENFIT. All are in Phase 3 clinical trials.

The first to make a significant breakthrough in 2016, Intercept already has a drug called Ocaliva (obeticholic acid) that has been approved by the FDA to treat another liver disease, called primary biliary cholangitis, an autoimmune disease that can lead to cirrhosis that primarily affects women. The drug works by targeting the farnesoid X receptor, a key regulator of bile acid, inflammatory, fibrotic and metabolic pathways involved with digestion and liver function.

"It is a molecule 100 times more potent than human bile acid that amplifies the liver's ability to regenerate," says Dr. Mark Pruzanski, president, CEO and director of Intercept. "What we're doing is trying to build a future without liver cirrhosis so people can avoid transplants."

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The company now is in its Phase 3 trial to evaluate the safety and effectiveness of obeticholic acid or OCA for people with advanced-stage NASH. It hopes the interim analysis of the trial will be completed in the first half of 2019. "It's the population with the highest unmet need," said Dr. Pruzanski, who notes he hopes after providing the FDA with the findings he can get accelerated approval for the drug.

"After successfully curing hepatitis C with a whole new class of blockbuster direct-acting antiviral drugs — i.e. Gilead Sciences' Sovaldi and Harvoni — this is the next big frontier in liver disease to conquer."-Veronica Miller, executive director of the Liver Forum

Gilead Sciences, which was the first to market Hep C drugs and capture a first-to-market advantage, is now in a late-stage study for Selonsertib in hopes it could become the first drug to win approval for treating NASH next year. It could follow up with other NASH drugs — FXR agonist GS-9674 and ACC inhibitor GS-0976. The company is hopeful that one of the combos of the drugs it is studying will advance to Phase 3 clinical trials in 2019.

Allergan is in Phase 3 of a global clinical trial of its drug, Cenicriviroc, which helps reduce fibrosis in NASH patients It has enrolled 2,000 patients to evaluate the effectiveness of the drug.

GENFIT is currently evaluating a drug called Elafibranor, which it claims reverses NASH to prevent fibrosis progression while giving patients cardioprotective benefits. It works by aiding proteins that maintain liver homeostasis and helps stop the main cells responsible for liver fibrosis. Elafibranor is currently being evaluated in a clinical Phase 3 study Resolve-It so it can get marketing approval based on the analysis of 1,000 patients after 72 weeks of treatment.

Partnering to fast-forward innovation

As efforts in drug development heat up, many companies are joining forces in the quest for treatments and a cure.

A good example is the collaboration between Pfizer and Novartis to bring together their NASH therapies in a bid to find treatments to slow the disease. The two drug titans have a clinical development agreement that includes a study combining Tropifexor, a multi-modal drug that fights inflammation, fibrotic scarring and fat accumulation and one or more Pfizer experimental medicines for the treatment of NASH aimed at steatosis, or fat accumulation in the liver.

"NASH is a complex disease difficult to treat with a single drug or compound," says Eric Hughes, global development unit head, immunology, hepatology and dermatology. "We believe combination therapy will be the best way to tackle this condition."

At the same time, Novartis is doing research to help the large population of people with late stage NASH and cirrhosis. It has an exclusive licensing agreement with Conatus Pharmaceuticals, a biotech focused on liver disease, to help fund the development and commercialization of a drug called Emricasan. The drug originally invented in 1998 by Idun Pharmaceuticals is a pan-caspase inhibitor that helps stop cell death and reduces inflammation associated with the disease.

"The goal is to prove the drug can stabilize the liver and then reverse the progression of cirrhosis," says Steve Mento, president and CEO of Conatus. "The liver is one of the few organs that can regenerate. If you can stabilize it the liver can repair itself."

Right now scientists and pharmacists are optimistic that a breakthrough in the field is just a few years away. "I think the first wave of new drugs and treatments may come two to three years from now," says Weidong Zhong, PhD., president and CEO of Terns Pharmaceuticals, a start-up incubated by Lilly Asia Ventures focused on developing drugs to treat NASH and cancer. Dr. Zhong should know. He is an industry veteran who played critical roles in Hep C drug discovery at Gilead, Novartis and Schering-Plough.

"This is a major global problem, especially in China. In the past 20 years, obesity rates are soaring there and 43 percent of the population now has fatty liver disease," Zhong said.

He believes a global cooperative effort among regulators, drug companies and academia is needed to fast-track a cure. The world is waiting.