Seeking Patients With Silent Liver Disease That Affects Millions

It reads like a recipe for a drug industry gold rush: a condition caused by ever-rising rates of obesity, the chance to save millions of patients from costly liver damage, and a market predicted to reach as much as $40 billion by 2025.

That blockbuster potential has put Intercept Pharmaceuticals Inc., Genfit and more than a dozen companies in a race to develop treatments for the liver disease known as NASH, or non-alcoholic steatohepatitis.

The only thing that’s missing? Patients.

The drugmakers are struggling to find enough people to fill the clinical trials needed to get the new drugs approved, according to executives and physicians overseeing the studies. Intercept managed to fully enroll one key trial this year only after making changes that enabled it to almost halve the number of participants required to 750. At Genfit, a late-stage study was delayed by months, and the French company is working with medical centers and doctors who can persuade patients to join.

“There is definitely still difficulty in finding patients for NASH trials,” said Robert Brown, a hepatologist at Weill Cornell Medicine and New York-Presbyterian who is an investigator in studies for Intercept and Gilead Sciences. Drugmakers testing more than 40 treatments are fighting for a relatively small pool of about 12,000 people, he said.

It seems counterintuitive for a disease that affects an estimated 3 percent to 12 percent of all Americans, a statistic so alarming that some studies predicted it could become the leading reason for liver transplants by 2020.

Yet the progressive disease is little known because it is virtually asymptomatic for years. Potential patients – most commonly people who are overweight or have diabetes – often live in rural areas with limited access to medical trials. And enrolling in late-stage NASH studies requires painful and invasive liver biopsies.

“Liver-biopsy trials are not that easy to recruit for,” said Dean Hum, chief science officer at Genfit. “There are more and more NASH trials coming on board now; we have to be more vigilant. There is some competition going on.”

The delays could set back plans to seek regulatory approvals, throw off drug launches and cost future revenue.

Companies that are able to fully enroll their studies first have a competitive edge, and Intercept is projected to be first to market. But the New York-based drugmaker faces challenges after 19 deaths in patients with a different, rare liver disease, were linked to its treatment Ocaliva. Shares have plunged 43 percent since the company reported the first deaths in September.

There’s a lot at stake for Intercept to get Ocaliva, its only product, approved for NASH: the $1.15 billion in revenue analysts now project for the drug in 2023 is almost entirely based on the disease.

“We’re in the lead and we’re confident we’ll maintain that lead,” Intercept Chief Executive Officer Mark Pruzanski said at a Dec. 14 conference.

NASH occurs after fat accumulates in the liver. It can lead to cirrhosis or liver cancer, but patients often don’t show symptoms until their livers are heavily damaged. Doctors say patients have been unwilling to undergo the rigors of a trial for a disease they might not have, or may not progress to serious stages.

The liver biopsy, an FDA requirement in late-stage studies, is holding back the development of drugs by three to five years, according to Hillel Tobias, a hepatologist at NYU Langone. In fact, half the patients who sign up for liver biopsies in the U.S. end up not having NASH, said Nezam Afdhal, a physician at Beth Israel Deaconess Medical Center in Boston.

Experts don’t expect biopsy mandates to change for several years, although noninvasive alternatives like blood tests and imaging are already being used in trials.

Companies testing drugs in patients with more advanced forms of the disease, which include Gilead and Galectin Therapeutics Inc., said they haven’t encountered issues. Sicker patients are more willing to participate in trials because they have fewer options.

Enrollment problems are seeping into earlier trials. Patients would prefer to opt into a late-stage study where there’s a better chance the drug will actually work, said Morrie Birnbaum, chief scientific officer at the cardiovascular and metabolic disease research unit of New York-based Pfizer Inc., which has at least three NASH drugs in early trials.

“Patient enrollment in trials is quite an issue because a lot of physicians are hesitant to biopsy patients without a proven therapy,” he said. “Finding patients is a major problem.”

Awareness of NASH remains especially low among primary doctors who don’t know to look for signs. The Center for Disease Control didn’t even mention the disease in a recent major report on diabetes in the U.S.

“Walk out on Fifth Avenue and ask somebody what NASH is,” said Stephen Harrison, a hepatologist and San Antonio, Texas-based consultant who oversees trials for many companies, including Gilead, Intercept and Genfit. “The only people who will know are probably the Wall Street folks that are investing in it.”