NGM282 shows equivalent efficacy in NASH at lower dose

SAN FRANCISCO — Although previously reported effective at a 3 mg dose, NGM282 showed similar efficacy in treating nonalcoholic steatohepatitis at 1 mg, according to data presented at The Liver Meeting 2018.

“NGM282 demonstrates improvement across histologic and noninvasive endpoints in NASH. There’s potent target engagement with C4 suppression and bile acids. There’s significant meaningful reductions across all noninvasive markers of NASH-related disease. And, ultimately, we see unprecedented antifibrotic activity at week 12 with both the 1 mg and 3 mg dose,” Stephen A. Harrison, MD, of University of Oxford, said during his presentation.

In this open label, 12-week paired liver biopsy study, Harrison and colleagues used MRI PDFF, Liver Multiscan and biopsies to measure the impact of NGM282 dosed in either 1 mg or 3 mg increments on patients with NAFLD activity score (NAS) of 4 or greater, stage one to three fibrosis and liver fat content (LFC) of 8% or greater. The primary endpoint was absolute change in LFC at 12 weeks and the novel data presented at this meeting was the 1 mg data for 12 weeks.

Noninvasive markers

In looking at suppression of C4 and serum bile acids, Harrison showed that the reductions were similar between 1 mg and 3 mg, although “slightly more robust with the 3 mg” dose vs. 1 mg.

Looking at the primary endpoint of MRI-PDFF, Harrison showed the 1 mg dose produced a significant reduction in liver fat “as early as week 6 that continues to improve through week 12,” which was similar to results seen with the 3 mg previously.

“The absolute reduction in liver fat was roughly 11% whether you used 1 mg or 3 mg,” Harrison said.

Nearly all patients achieved 5% absolute reduction in liver fat while 33% of patients in the 1-mg group completely normalized LFC (defined as less than 5% liver fat at week 12). This is compared with 63% normalized with 3 mg dosing, Harrison said.

“Ultimately, relatively similar relative reductions in liver fat content with approximately 90% to 100% achieving 30% relative reduction,” he said.

In looking at ALT and AST, “you see the same rapid and profound reductions in liver enzymes,” Harrison added. The absolute reduction in ALT with the 1 mg was 64 units per liter, equating to a relative reduction of 67%, he showed.

Additionally, enhanced liver fibrosis (ELF) showed significant reductions with NGM282, the ELF score dropping by 0.31 with the 1 mg and 0.56 with the 3 mg, Harrison said.

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“It’s important to note that there have been recent data that ELF scores have been shown to associate with disease progression and increased ELF from baseline associated with progression to cirrhosis,” Harrison said.

Lastly, in the noninvasive markers, he showed corrected T1(CT1) and novel multiparametric MRI (Liver Multiscan, Perspectum) with an absolute reduction in CT1 of 64 milliseconds at week 6, rising to 78 milliseconds at week 12, which Harrison said was consistent with the 3 mg dose

“I highlight that CT1 has been shown to correlate with improvement in the NAFLD activity score – 1 point for every 42 millisecond improvement in CT1,” he said.

Biopsy results

With the 1 mg dose, Harrison showed that 75% of people improved their NAS, 67% improved steatosis, 33% improved inflammation and 42% had improved ballooning.

At baseline, 42% of the cohort was F2, 38% had F3 and one patient was F4, Harrison said.

“When you look at the overall histologic response with the 1 mg dose at 12 weeks, 25% improved, 58% had no change and 17% had a 1-point worsening,” he said. One patient had a two-stage improvement” while previous 3 mg dosing had a similar result in three patients.

“When you compare the two doses, what we see very quickly is that the reductions in AST/ALT and the MRI-PDFF reduction are very comparable,” Harrison said. “When you go to biopsy – maybe it’s the small sample size or maybe it’s real – there does appear to be some improvement in the 3 mg group over the 1 mg, suggesting to me that we probably just need to treat longer in the 1 mg group to see a similar type benefit, thus the reason for the 24-week trial coming behind this.”– by Katrina Altersitz

Reference:

Harrison SA, et al. Abstract 104. Presented at: The Liver Meeting 2018; Nov. 9-13, 2018; San Francisco.

Disclosure: Harrison reports consulting relationships with Allergan, Axcella, Chronic Liver Disease Foundation, Cirius, CiVi, Corcept, Cymabay, Echosens, Galmed, Genfit, Hightide, HistoIndex, Innovate, Intercept, IQVIA, Madrigal, Medpace, Metacrine, Novartis, Perspectum, Pfizer, Pippin, PPD, Prometheus, NGM Bio, Novo Nordisk and Terns; receiving grant or research support from Allergan, Cirius, Conatus, Cymabay, Galectin, Genfit, Gilead, Immuron, Madrigal, Pfizer, NGM Bio, Novartis and Novo Nordisk; speaking and teaching relationships with AbbVie and Alexion; is a stock shareholder with Cirius, Genfit, Madrigal and Metacrine; and acts on the advisory or review panel for Gilead.