Novo Nordisk's diabetes med semaglutide shows promise in NASH. Can it deliver in phase 3?

Drug development for non-alcoholic steatohepatitis has witnessed plenty of failures—and plenty of excitement as multiple players race toward market. Now, Novo Nordisk's popular GLP-1 diabetes drug semaglutide has racked up some encouraging clinical results that take it one step closer to the finish line.

A phase 2 NASH study testing the GLP-1 injectable semaglutide—sold under the brand Ozempic as a weekly diabetes therapy—hit its primary goal, Novo said Wednesday alongside its first-quarter earnings report.

Indeed, Novo touted the results as “the largest NASH resolution improvement so far,” confirming that the drug could be a potent anti-NASH agent. It will now assess the data and talk to authorities about how best to move forward with the clinical program, a company spokesperson told FiercePharma.

Industry watchers have some questions about—and expectations for—that phase 3 trial, particularly after a series of failures for other NASH hopefuls. And a would-be rival in the field from Intercept will see an airing at an FDA advisory committee hearing in June, which could potentially lead to an approval later this year.

But in the meantime, Novo has numbers to boast. In the phase 2 trial, a significantly higher percentage of patients on daily semaglutide injections saw NASH symptoms resolve—liver inflammation improved and liver cell ballooning eased—and no worsening in liver fibrosis than placebo patients experienced. After 72 weeks of therapy with the highest dosage tested (0.4 mg), 33 of 56 patients (59%) with fibrosis stages F2 to F3 could say that, versus 10 of 58 patients (17%) in the control arm.

All of the daily doses beat placebo in terms of resolution of NASH without worsening of fibrosis; among patients taking the 0.1 mg and 0.2 mg doses, 40% and 36% hit that goal, respectively.

As for the phase 3 dose, the spokesperson said decisions are being made but added that “further development would likely be once-weekly and a dose catered for that.”

In diabetes, Ozempic is given at 0.25 mg once weekly for the first four weeks and then increased to 0.5 mg per week. Dosing can be escalated to 1 mg if further blood sugar control is needed.

RELATED: Intercept's hotly anticipated NASH drug has to wait for its FDA hearing, thanks to COVID-19

In the universe of NASH drug development, semaglutide’s data are indeed impressive.

For Madrigal Pharmaceuticals’ oral THR-beta agonist resmetirom (MGL-3196), phase 2 showed 25% of treated patients achieved NASH resolution, compared with 6% on placebo. NGM Biopharmaceuticals’ daily injectable aldafermin achieved 24% after 24 weeks of treatment, versus 9% for placebo.

And let’s not forget a long list of trial flops, including Gilead Sciences’ ASK1 inhibitor selonsertib, ACC inhibitor firsocostat and FXR agonist cilofexor.

But as Jefferies analyst Michael Yee said in a Wednesday note to clients, Novo doesn’t yet have data on fibrosis, “which is the known gold standard endpoint for experts and specially F2/3 advanced fibrosis patients.”

On that matter, Intercept Pharmaceuticals’ repurposed obeticholic acid (OCA) has shown it can improve liver fibrosis in 23.1% of patients, almost double the 11.9% rate investigators observed with placebo. That med, with an FDA advisory committee meeting delayed to June 9 because of the pandemic, could be the first drug approved to treat NASH.

While improving NASH resolution could theoretically improve liver scarring, “it will be important to see this,” Yee said.

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Then there’s the problem of side effects. In its obesity study, in which semaglutide was administered as a daily injection, about 12% to 17% patients discontinued treatment due to adverse events, Yee noted. The drug comes with known gastrointestinal tolerability issues such as diarrhea and vomiting. In its Wednesday statement, Novo said the safety profile of semaglutide in the NASH trial was “consistent with the observed profile in other trials and disease areas.”

Meanwhile, Novo has partnered with Gilead to test a combination of semaglutide with the latter’s cilofexor and firsocostat. During a conference call on Wednesday, Novo chief scientific officer Mads Krogsgaard Thomsen said it doesn’t need to see the Gilead combo data before deciding whether to push semaglutide into phase 3. The drug looks like a “standalone or anchor” product, he said.

As for Ozempic, the diabetes drug sold DKK 4.76 billion ($688 million) in the first quarter, more than triple its haul of DKK 1.43 billion the same period last year, partly due to COVID-19-related stocking.

Editor's Note: Ben Adams also contributed to this story.