Progress on NASH Treatments, But No Home Run Yet

This month has brought considerable progress on NASH treatments. Yet it’s hard to know when we will have real progress in medical care for this silent epidemic. Getting FDA to yes on new treatments seems to be a challenge. Nonetheless, we have news of two new studies that suggest promise for new NASH treatments. One uses semaglutide – a GLP-1 agent already available for diabetes – by itself. The other study was a test of semaglutide in combination with two other experimental drugs for NASH.

These are both phase 2 studies, so they’re not the final word. But the results tell us that semaglutide may help with NASH. Also they offer evidence that by itself or in combination with these two newer drugs, it is reasonably safe. Still, however, much work remains to be done before any of these NASH treatments will be ready for FDA approval.

Three Doses of Semaglutide Daily

The first study appears in the New England Journal of Medicine, and it is the most impressive. It tests three different daily doses of semaglutide – 0.1, 0.2, and 0.4 mg sc injections. What it found was a good effect for the drug at the top dose. In fact, NASH resolved in 59 percent of patients with no fibrosis after 72 weeks. In the placebo group, only 17 percent resolved. For the lower doses, the numbers showed some improvement, but it wasn’t statistically significant.

On the secondary endpoint – improved fibrosis – the drug did not show an improvement at any dose. “It is possible that the current trial was not of sufficient duration for improvements in fibrosis stage to become apparent, especially since most patients had advanced fibrosis,” the researchers wrote.

Note that semaglutide is used for diabetes in a once weekly dose of up to 1 mg. In studies of the drug for obesity, the weekly dose is 2.4 mg. So in the top dose for the present NASH study, patients were getting a bit more semaglutide (2.8 mg) per week. Novo Nordisk has previously said that the company will be testing a once weekly dose in the pivotal phase 3 NASH studies.

Combinations with Semaglutide

The second study, presented at the AASLD meeting, told us that combinations of two new agents with semaglutide might have promise. It was a phase 2 study with five different treatment arms. It was also much shorter than the first study – only 24 weeks. So mainly it provides data showing that these combinations were safe. In combination with semaglutide, the study tested cilofexor and firsocostat. One arm was semaglutide alone. Two arms tested semaglutide in combination with different doses of cilofexor. Yet another arm was semaglutide with firsocostat. Then the final arm was all three drugs together.

The bottom line is that these three drugs seem to be reasonably safe together. On efficacy, there’s not much to say. The study wasn’t big enough or long enough to prove much about clinical outcomes. All we know is that these combination therapies are reasonable and might show some benefit in a subsequent trial.

No Home Runs Yet

As we’ve noted before, NAFLD and NASH are mostly complications of untreated obesity. Because semaglutide is helpful for obesity, and possibly for NASH, too, we are hopeful. Perhaps the pivotal studies will show a real benefit in NASH.

But make no mistake, NASH is a tough disease to treat. The best bet for now is to do a better job of treating obesity so that hepatic steatosis might not progress to NASH.

Click here for the study in NEJM and here for further perspective on it. For the combo therapy study, click here, and then here for further perspective.

Hepatic Steatosis, image by the Department of Pathology at Calicut Medical College / Wikimedia

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November 22, 2020