From Big Pharmas like Novartis and Gilead to liver specialists and one-asset biotechs, it seems like everyone in biopharma has some skin in the NASH game.
It makes sense, said Tarek Hassanein, M.D., a professor of medicine and director of outreach services for liver transplantation at the University of California San Diego School of Medicine. With the rise of obesity not just in the U.S. but all over the world, the number of people with NASH (nonalcoholic steatohepatitis) will only grow.
NASH is the most severe form of fatty liver disease stemming predominantly from obesity—that is, not from alcohol misuse. The buildup of fat in the liver can cause inflammation and scarring over time and in some cases, may lead to cirrhosis, liver failure and cancer. It has no approved drug and is currently treated with diet and exercise, an approach to which many patients respond well.
“If I get a patient to lose more than 5% of their body weight, their liver numbers are almost totally normal,” Hassanein said. “If they lose more than 10% of their weight, then fibrosis starts to improve, even without any medication.”
So, why have so many companies jumped into the NASH field?
Lifestyle changes don’t work for some patients, namely those with advanced disease whose scarring is too far gone, or who need a liver transplant.
“Even if they can implement diet and lifestyle changes and lose quite a bit of weight, it may be too late and not benefit them,” Intercept CEO Mark Pruzanski, M.D., said.
For others, lifestyle modifications can get them part of the way there, but they still need “something else” to regain liver health. Gail Cawkwell, M.D., Ph.D., Intercept’s senior vice president of medical affairs, likens these NASH patients to people who need statins to get their cholesterol under control.
Genfit CEO Pascal Prigent and NGM Bio CEO David Woodhouse, Ph.D., both said it can be difficult for patients to stick to a new lifestyle, even if it would benefit them.
“Adherence to diet and exercise is very low in this patient population,” Woodhouse said. “So, while it could work, I think it’s to the tune of 5% to 10% of these patients who can achieve the type of improvement that physicians are looking for. And so, it hasn’t really shown to be an effective way to tackle disease.”
“The fact that there is a way to avoid a disease does not mean people are capable of doing it,” Prigent said. “As we know, there is a huge diabetes market. And in theory, it could all be avoided with a different lifestyle. The same is true for NASH.”
Of course, it doesn’t hurt that some analysts see the NASH market raking in as much as $35 billion a year.
Intercept is leading the pack with obeticholic acid, also called OCA, which earned an FDA nod in 2016 for primary biliary cholangitis. The company filed the FXR agonist for FDA approval in NASH in September and plans to submit a European filing by the end of the year.
Genfit is following close behind with elafibranor, a PPAR alpha and delta agonist that’s in a phase 3 study due to read out in the first quarter of 2020. But the drug has a mixed track record, having missed the primary endpoint in a phase 2 study in 2015. Genfit blamed that failure on an enrollment error and the use of too many study sites. It designed the phase 3 program to focus on patients with more advanced disease, a move that some were skeptical of.
“That Genfit pushed into phase 3 based on a multiple post-hoc analysis of a failed trial is probably the biggest red flag here, though there are also mechanistic concerns when it comes to PPAR agonism,” Vantage wrote this summer.
A similar drug, seladelpar, fared worse. Cymabay recently ended studies in NASH and primary sclerosing cholangitis of the PPAR-delta agonist after biopsies showed liver damage in some patients.
“Is this a PPAR issue, a PPAR-delta issue or a seladelpar issue? … We think this may result in more scrutiny from the FDA around the PPAR class depending on the details of what exactly was seen on these biopsies,” Cantor Fitzgerald analysts wrote at the time. The setback may have implications for elafibranor and other drugs in the class, such as Inventiva Pharma’s lanifibranor, which hits PPAR alpha, delta and gamma.
Gilead’s ASK1 inhibitor selonsertib had been among the NASH front-runners until this spring, when it failed to improve fibrosis in two phase 3 trials involving more than 1,600 patients. Though selonsertib may be dead in the water as a monotherapy, the company is testing it in combination with its FXR drug cilofexor and its ACC inhibitor firsocostat in a phase 2 study that should yield data by the end of the year. And that’s not all: Gilead is also testing the firsocostat-cilofexor combo with Novo Nordisk’s GLP-1 drug semaglutide.
Selonsertib and seladelpar weren’t the only programs to falter in the NASH race. Shire cut short a phase 2 study of its prospect volixibat last year, while Conatus is scrambling to stay alive after its pan-caspase inhibitor emricasan flunked not one but three midphase trials. It was “hardly a surprise in the wake of two previous blow-ups,” Vantage wrote. “But emricasan was effectively all Conatus had, and similarly exposed NASH players should be looking on with trepidation at the company’s fate.”
Though Conatus might disagree, the failure of emricasan was useful for the field, Hassanein said: “They went after a very specific pathway of liver cells dying. They assumed if they prevented cells from dying, the liver would get better, but that didn’t help. It helped us to understand important mechanisms in patients with NASH.”
One mechanism that many have bet on is the farnesoid X receptor, or FXR. Intercept’s OCA may become the first approved FXR agonist for NASH, but there is still room for its earlier-stage competitors to catch up. In its phase 3 study, OCA missed one of its two co-primary endpoints and its most effective dose caused pruritis, or skin itching, in half of the patients. Enanta, Novartis and Gilead all have midstage prospects, while Terns Pharmaceuticals has a program in phase 1 and Allergan has a pair of preclinical assets. Any of these could compete with OCA if they can prove more effective or cause less itching.
As for other approaches, Allergan also plans to report phase 3 data for cenicriviroc, a dual CCR antagonist, in 2020, while NGM Bio expects to announce phase 2 data for aldafermin, an engineered version of the hormone FGF19, by the end of the year. Madrigal aims to start a phase 3 study of its THR-beta agonist resmetirom, based on phase 2 data.
Hassanein pointed to a trio of drugs that are perhaps outside of the usual suspects: drugs with mechanisms familiar to diabetes but that are being repurposed in patients with fatty liver. Zydus’ saroglitazar is a PPAR alpha and gamma agonist approved in India to treat patients with Type 2 diabetes. The drug didn’t affect NASH patients’ body weight much, but it did improve insulin resistance, liver enzyme levels and fat buildup in the liver, according to phase 2 data presented at this year’s American Association for the Study of Liver Diseases (AASLD) meeting.
AstraZeneca has cotadutide, a dual agonist of GLP-1 and glucagon, and Novartis has licogliflozin, an SGLT1/2 inhibitor. Both posted encouraging data at AASLD, improving enzyme levels and suggesting they might be advanced as treatments for NASH. Finally, Cirius Therapeutics is working on a second-generation thiazolidinedione, or TZD, a class of drugs used to treat diabetes.
When asked how a drug would fit into how he cares for NASH patients, Hassanein said that physicians should still focus on diet and exercise.
“I don’t want people to forget that the primary issue of NASH is the lifestyle issue. … We don’t want to just sit and wait for new drugs,” he said.
Doctors should keep doing what they’re doing: helping overweight patients lose weight and getting their other conditions under control, be they diabetes, high cholesterol or hypertriglyceridemia. Adding nutritionists to patients’ care teams—and getting insurance companies to cover them—would go a long way. Drugs would come in after that, Hassanein said.
“The big question will be: For each patient, at what level do we add medication?” Hassanein said. A patient with minimal scarring may not need a drug at all. But someone whose scarring is more severe, or whose disease is likely to worsen quickly, may need medication. All of these patients need to be identified, which requires better diagnostic and stratification tools.
At the end of the day, Hassanein said, new drugs won’t be a silver bullet for the disease: “New drugs alone won’t work without modifying the precipitating causes for the disease process.”
That said, read on to learn about eight prospects in the NASH pipeline. These include the front-runners knocking on the door of approval, as well as those waiting on midstage readouts and drugs developed for other ailments that could be useful in NASH.