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NASH meds: What could go wrong

May 2, 2017

The International Liver Congress in Amsterdam has officially wrapped up, but the energy and excitement around NASH – aka non-alcoholic steatohepatitis – persists.

Characterized by inflammation and scarring of the liver, NASH affects an estimated five percent or 15.9 million Americans. It comes as a progression of non-alcoholic fatty liver disease (NAFLD), believed to affect some 75-100 million people in the U.S. alone.

It’s a super-sized epidemic that many experts believe holds blockbuster therapeutic potential. That’s driven dozens of companies to enter the so-called “dash to NASH” in hot pursuit of the first FDA approval.

As could be expected, there are a number of hurdles standing in their way.

Peter Traber knows all about them. A former gastroenterologist and current adjunct professor at the Emory University School of Medicine, Traber has been studying livers and NASH since before it was even cool. He’s now president, CEO, and CMO of Galectin Therapeutics, which has a Phase 2B trial underway in NASH with cirrhosis.

Via phone Traber shared his thoughts on the some of the biggest challenges for companies in this space.

Patient recruitment

Last Monday, industry-frontrunner Genfit revealed that its Phase 3 RESOLVE-IT trial for liver fibrosis/NASH had been delayed for four to six months due to issues with enrollment. Genfit cited two broad reasons for the hold-up; the team has been strict with its enrollment criteria and it’s a particularly busy space.

Indeed, Clinicaltrials.gov lists 155 open studies involving NAFLD/NASH.

“If you look at the overall landscape, there are lots of companies enrolling lots of patients in NASH trials,” Traber said.

The problem is particularly acute in early NASH or NASH fibrosis, he explained, which includes late-stage prospects from Intercept, Genfit, and Allergan-Tobira; as well as candidates from Bristol-Myers Squibb, Gilead, and dozens of other early-stage bets.

“You are competing pretty dramatically for patients,” Traber stated. “And for the clinical trial sites that are the mainstays for enrolling patients.”

Top investigators and centers in the U.S. might be running six or seven different NASH trials that are all enrolling patients as we speak, he said. And if you go away from the tried-and-true clinical trial sites and into community-based practices, the organizations have less experience running efficient clinical trials.

In both settings, it’s a tough sell. These studies typically require invasive liver biopsies to confirm a NASH diagnosis.

Unsurprisingly, Genfit isn’t the only one to encounter enrollment issues. Intercept caught investors off-guard in February by announcing a change to the coprimary endpoints of its Phase 3 REGENERATE trial. Traber noted that the changes allowed Intercept to decrease its sample size from 1,400 patients to around 750.

The not-so-placebo effect

How often do you drink? It’s a question that frequently crops up in medical settings. It’s also pretty commonplace for people to underestimate or underreport their alcohol intake — sometimes drastically. One Canadian study that compared self-reported intake with alcohol sales data showed consumption of spirits was underestimated by approximately 66 percent, wine by 38 percent, and beer by 49 percent.

That’s a problem, Traber notes, because NASH is in many way a diagnosis of exclusion. It looks very much like alcoholic liver disease. The difference is that the alcoholic type usually resolves when the patient stops drinking.

“We usually rule out that the patient is using alcohol by talking to the patient and talking to their family members,” Traber said. “But people lie about that stuff.”

If doctors and companies running clinical trials rely on self-reported measures of alcohol intake, there’s a good chance some non-non-alcoholic steatohepatitis patients will enter the program.

It’s hard to gauge just how much of an effect this has, but according to Traber, NASH trials commonly report improvements in up to 20 percent of patients in the placebo arm.

It follows that as they begin the trial and sign up for regular monitoring, participants moderate their alcohol intake and allow their liver to recover on its own.

Work is currently underway to develop better objective tests for alcohol use and tools that can distinguish between the two forms of steatohepatitis.

The payer problem 

NASH is known as a silent epidemic, which creates an interesting situation with patients, payers, and the FDA. Uncertainty reigns supreme when it comes to the trajectory of the disease.

“Everybody recognizes that the presence of NASH leads to cirrhosis,” Traber stated. “But the natural history of any particular patient with a particular stage of NASH; it’s hard to predict who’s going to go on to cirrhosis, which is really the problem area.”

It’s one thing to treat late-stage NASH, which is potentially fatal. It’s another to recommend millions of patients with early-stage forms of the disease take preventive action. The side effect profile will have to be “pristine,” Traber said.

The situation almost mimics that of statins, which is good news and bad news for companies in this space. There’s a lot of money to be made (statins, such as Pfizer’s Lipitor, have raked in billions in sales). But the FDA and payers will need to see a lot of data connecting the dots between early-stage NASH and long-term health outcomes.

“Statins took a very long time and tens of thousands – if not hundreds of thousands – of patients to determine that a reduction in cholesterol related to statins had an impact on morbidity and mortality,” Traber said.

Safety in such a huge population will also be keenly watched.

And Traber believes there’s one more confounding factor for future healthcare stakeholders to wrangle with.

“It’s very clear that if people lose weight, say 10 percent of their body weight, a very high percentage of those people will resolve their NASH altogether,” he explained. “So you’re left with; do we get people to try and lose weight, or do we give them a pill for two decades?”

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