NGM's closely watched NASH prospect flops, cutting shares in half and spurring R&D rethink

A phase 2b trial of NGM Biopharmaceuticals’ aldafermin in nonalcoholic steatohepatitis (NASH) has missed its primary endpoint, sending shares in the biotech tumbling. NGM has pulled plans to enter phase 3 in light of the midstage failure of the FGF19 analog.

California-based NGM ramped up expectations for aldafermin last year when it delivered midphase data linking the drug to a significant reduction in absolute liver fat content and improvements on a clutch of other measures. Yet, like other NASH drug developers before it, NGM has now found that a positive biomarker result can fail to translate into improvements in histology outcomes.

The study randomized 171 patients with biopsy-confirmed NASH and stage 2 or 3 liver fibrosis to take placebo or one of three doses of aldafermin. After 24 weeks of daily injections, people on aldafermin performed no better than their peers on placebo against key measures. 

Notably, there was no statistically significant difference in the number of patients who experienced a one stage or greater improvement in fibrosis without the worsening of NASH. In the aldafermin arms, 15% to 31% of patients experienced such improvement, with the highest rate seen in the group who received the lowest dose. Nineteen percent of placebo patients improved by that measure.

A lack of dose response and failure to improve significantly on placebo was also seen in an endpoint that looked at the rate of fibrosis improvement and NASH resolution. NGM reported a significant improvement in NASH resolution with no worsening of fibrosis in the high-dose arm and success on other secondary measures, but those hints of efficacy failed to save aldafermin.

“ALPINE 2/3 achieved statistical significance on multiple non-invasive measures of NASH at the two higher doses. That said, given the failure to meet the primary endpoint, we have decided to shift resources that had previously been reserved for a phase 3 F2/F3 NASH development program toward advancing our other programs,” NGM CEO David Woodhouse, Ph.D., said in a statement.

Woodhouse expressed surprise about the lack of fibrosis improvement, pointing to “the consistency of histology findings previously seen with aldafermin” in an earlier trial to make his case, but has decided there are better ways for NGM to spend the more than $400 million it had in the bank at the last count. NGM has treatments for geographic atrophy and metastatic pancreatic cancer in phase 2 trials. A phase 2 trial in NASH patients with stage 4 fibrosis is continuing to recruit patients.

Shares in NGM fell 47% in premarket trading.