The competition’s heating up over a $35 billion market to treat NASH, a ‘silent disease’ millions are living with. But the early results look mixed.

Liver transplant
A piece of healthy liver that was removed from Jean Carlos Fernandez rests in a bag before being transplanted into his son Yin Carlos at Caracas’ Policlinica Metropolitana in Venezuela.
AP

Millions of people are living with a disease they’ve likely never heard of.

NASH, short for nonalcoholic steatohepatitis, is a type of liver disease in which liver fat builds up in people. NASH has become more common in recent years, and it’s estimated to affect about 16 million Americans.

It’s often called a “silent” disease because most people don’t know they have it until it leads to problems like cirrhosis and liver failure.

While the term NASH was coined in 1980, research into it didn’t ramp up right away, partly because the disease was regarded as a mild one. It’s a disease linked with our eating habits, or at least exacerbated by them. Although you might not know someone officially diagnosed, people with obesity, Type 2 diabetes, and insulin resistance have an elevated risk of developing the disease. Its links to other conditions have researchers specializing in everything from the liver to diabetes and obesity interested in seeing if there are ways to treat the condition earlier.

NASH is set to surpass viral hepatitis as the biggest reason for liver transplants by 2020, and the eventual size of the market for treating the disease is expected to be anywhere between $20 billion and $35 billion, according to a report from Reuters.

Read more: Trump just promised to end the HIV epidemic. This map shows the areas of the US that are home to the most people living with the disease.

In the meantime, the competition is heating up to see who can find a way to treat it, with companies taking a range of approaches to treat it at different stages, varying based on the specialties of the scientists looking into the treatments.

The first few results for late-stage NASH drug trials look mixed

In 2019, we’re starting to get the first batch of late-stage trial readouts, though so far, it hasn’t been too positive. In February, Gilead said that its first late-stage NASH trial for its drug selonsertib had failed. Analysts at RBC Capital Markets said the company’s appetite to tackle the NASH market has only intensified.

On Tuesday, Intercept said that its drug, obeticholic acid, had succeeded in improving liver fibrosis, though the late-stage trial wasn’t able to show that the treatment resolved NASH in patients compared to the placebo group. Wall Street saw this as a win all the same, and the stock jumped 23% on Tuesday morning in early trading.

Jefferies analyst Michael Yee said in a note Tuesday that the results were “near best case scenario.”

More late-stage trial results are expected in 2019 from rival Genfit, with a drug from Allergan also in a phase 3 trial.

“It’s like everybody’s feeling a different part of the elephant,” Morrie Birnbaum, senior vice president and chief scientific officer of internal medicine at Pfizer told Business Insider last year.

This liver has a prominent (centrilobular) macrovesicular steatosis (white/clear round/oval spaces) and mild fibrosis (green).
Wikimedia Commons

Why it’s so hard to diagnose

The biggest hurdle to treating NASH, other than finding a drug, is diagnosing it in patients.

Most people in early stages aren’t symptomatic, and to know conclusively if a person has NASH requires a liver biopsy — which involves sticking a small needle into your liver and extracting a few cells. Even if they do have it, some might not want to know, since there’s no way to treat it.

Researchers are working on imaging and blood tests that could either determine whether people need to take the next step and get a liver biopsy, but those can pick up only certain levels of fibrosis, or tissue scarring.

That means there’s no simple blood test to track how the drugs are doing, as there is with cholesterol-lowering medications or diabetes medications.

Even with the hurdle to find patients, the looming issue has led to a rush to develop new treatments, and a hot area for biotech investments, from smaller biotechs like Madrigal, Genfit and Intercept to major drugmakers like Novo Nordisk, Gilead, Novartis, Bristol-Myers Squibb, Allergan, and Pfizer.

Hopes to treat it early

Pfizer built out its NASH program with Birnbaum’s help out of a diabetes program that hadn’t been panning out. The team started to look at whether the targets they were going after for diabetes could work instead for NASH.

Pfizer’s approach is to treat the condition early by clearing out fat that’s accumulated in the liver. Birnbaum said the company may have a way to look instead at fat accumulation in the liver via MRI — a much less invasive way than the biopsy — to determine who to treat. Pfizer’s farthest along program — a drug known as an acetyl CoA-carboxylase inhibitor — is in a phase 2 trial.

Starting earlier can be trickier to prove in clinical trials though, where you need to show benefit that the drug is improving the patient’s disease over a set period of time, Dr. Scott Friedman, dean for therapeutic discovery at the Icahn School of Medicine at Mt. Sinai who has consulted with drug companies on NASH drugs including Pfizer, told Business Insider in April. If it’s possible that some people in the placebo group will spontaneously get better, it could lead to a failed trial.

It poses a tricky question: “When in the course of NASH does it stop being a biomarker and start being a disease?” Birnbaum said.

And there’s another challenge: If it’s used earlier by a bigger group of people who at the time don’t have many symptoms, like drugs to lower cholesterol, it’ll have to be really safe.

“For a metabolic unit like our unit here that historically has developed drugs for diabetes, that has no change for us. We’re used to that high bar of safety,” Birnbaum said. “If you were a liver group working on hepatitis C, the bar for safety would be very different.”

Genetic and microbial factors

One thing that might help drugmakers who are looking to treat the disease earlier: finding people with a genetic link to NASH.

It’s something researchers are starting to get a better picture of. Mutations in the PNPLA3 gene, particularly in Hispanic populations, have been associated with an increased risk of NASH and fatty liver disease. And in March 2018, biotech giant Regeneron said it found a variant on the HSD17B13 gene associated with protection from liver disease and a reduced risk of NASH. Regeneron’s plan is to partner with Alnylam to find potential drugs that can do something similar in people who don’t have the variant.

Another factor people are looking to crack, Friedman said, is the microbiome, or the collection of bugs that live in and on you. When it comes to our genes, they haven’t changed all that much — at least not to the point where NASH has ramped up so suddenly. What has changed, on the other hand, is our diets and our use of antibiotics, both of which impact our microbiome.

“To me, that’s the most compelling,” Friedman said.

Already, companies have tapped into this. Second Genome, a company focusing on microbiome-based therapies, has a treatment for NASH that’s based on the microbiome that’s launched into phase 2 trials in 2019.

This post was initially published in April 2018 and has been updated.

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