There is no approved drug for nonalcoholic steatohepatitis (NASH), the buildup of fat in the liver that’s predominantly caused by obesity rather than alcohol misuse. But it irks hepatologist Tarek Hassanein, M.D., when people equate that to a lack of treatment options.
“When someone says we don’t have anything to manage NASH—no, we have the key thing, which is lifestyle modification,” said Hassanein, a professor of medicine and director of outreach services for liver transplantation at the University of California San Diego School of Medicine.
Doctors currently treat NASH patients with diet and exercise: they help overweight patients lose weight and get their other conditions, such as diabetes or high cholesterol, under control. Depending on how much weight they lose, patients can tamp down on liver inflammation and even reverse liver scarring.
So, why is everyone piling into NASH?
Leaders at companies developing NASH drugs pointed to patients whose fatty liver has led to scarring that can’t be reversed with weight loss.
“First off, weight loss via diet and exercise is difficult to achieve and difficult to maintain in all patients. But we know that in patients with advanced fibrosis, the ability of weight loss to regress the fibrosis is limited,” said Rob Myers, vice president and clinical fibrosis research lead at Gilead Sciences. “If you have earlier-stage disease, weight loss can achieve that, but when you progress to the advanced stages it’s not effective. And that’s why, for this patient population, therapies like the ones we’re developing are necessary.”
For other patients, weight loss can be helpful, but can’t get patients all the way back to health. Gail Cawkwell, M.D., Ph.D., Intercept’s senior vice president of medical affairs, compares patients with NASH to those with high cholesterol. A NASH drug wouldn’t be a silver bullet for the disease, but it could be another tool to help patients get their liver back to normal.
“When I was a child, it was not unusual, particularly for a man in their 50s, to have a sudden cardiac event that was often fatal and certainly devastating. Now, it’s actually more unusual because we’re very good at monitoring for cholesterol and blood pressure and treating it,” Cawkwell said. “Diet and exercise can really help your cholesterol, but it rarely brings it to normal... so medicines like statins have made a huge difference in helping people beyond diet and exercise.”
In a similar vein, Aetna Wun Trombley, president and chief operating officer at NGM Biopharmaceuticals, thinks medicines could reverse scarring in advanced patients and bring them to a point where diet and exercise could make a difference.
“Where weight loss, diet and exercise has shown an effect on disease is when you have a long-term, sustained weight loss,” Trombley said. But patients with “well-established” fibrosis may not live long enough to achieve that kind of weight loss.
“Time matters for these patients, particularly the ones who are already cirrhotic. That is where you need a therapeutic intervention that can rapidly reverse the fibrosis, bring them back to [earlier stages of fibrosis] and a much healthier liver, which can regenerate,” she said. At this point, patients can work with diet and exercise to keep the disease at bay.
Developing a NASH drug and securing approval is just one piece of the puzzle. Another hurdle is getting it to everyone that could benefit. Often called a “silent” disease, NASH symptoms typically don’t show up until later in the disease.
“The problem right now is about identifying patients with a disease that is asymptomatic,” said Genfit CEO Pascal Prigent. “Today, we have no drug to treat NASH. When we talk to physicians, a lot of them say, fine, I can diagnose more and screen more, but then what do I do? There’s not a super high incentive to detect those patients because there is nothing.”
Prigent believes the advent of the first NASH drug will spur more doctors to diagnose the disease.
Genfit is working on a noninvasive test for NASH, which is designed to classify patients who are at risk of their disease getting worse.
“What we’re trying to do is go beyond ‘you do have NASH or you don’t have NASH.’ What we’re trying to say is, should you be treated, yes or no?” Prigent said.
Other companies are working on improving detection, too.
“Our medical affairs colleagues are trying to educate the community about NASH, what it is, who’s at risk and how to detect it,” said Gilead’s Myers. “Another piece is how can we identify the people who are really at risk of complications, like patients with advanced fibrosis? We’ve been generating evidence regarding noninvasive tests and how they could be used in the community to identify high-risk patients who could subsequently be considered for clinical trials, for example.”
Though invasive liver biopsy is still required in clinical trials of NASH drugs, doctors are using noninvasive measures, like blood-based tests, and imaging-based tests, like ultrasound to gauge liver stiffness, to diagnose patients.
“What is encouraging is there has been a huge increase in awareness within the broader medical community and a growing awareness in the public that this disease exists. The other positive momentum we’re seeing is with noninvasive tests,” said Intercept CEO Mark Pruzanski, M.D.