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Growth factor improved fatty liver score in 84% of patients

PARIS — Patients who received NGM282, a novel growth factor, showed improved noninvasive markers of nonalcoholic steatohepatitis and a histologic response after 12 weeks of dosing, according to a presenter at the International Liver Congress 2018.

“There was significant and clinically meaningful reductions across noninvasive markers of NASH-related disease. A large percent of patients demonstrated histological improvement at week 12 with 68% of patients meeting early histopathologic responder criteria,” Stephen A. Harrison, MD, medical director of Pinnacle Clinical Research, San Antonio, said in his presentation.

In this exploratory 12-week study, researchers assessed early histologic changes on liver biopsy after patients received NGM282 (NGM bio) 3 mg. From week 2 through week 12, patients also received rosuvastatin if needed due to an increase in low-density lipoprotein cholesterol.

Patients underwent a LiverMultiScan MRI to measure fat (MRI-PDFF), iron (T2*) and fibroinflammation (cT1) proton density fat fraction prior to receiving medication, at week 6 of the medication regimen, at week 12 after finishing the regimen and again at week 18. Patients underwent biopsy prior to dosing and at week 12. At baseline, included patients had a nonalcoholic fatty liver activity score (NAS) greater than 4, stage 1 to 3 fibrosis, and liver fat content of 8% or greater on MRI-PDFF. Nineteen patients finished therapy and underwent both biopsies.

“We can say that there are significant reductions across multiple noninvasive parameters for NASH at week 12,” Harrison said. “One hundred percent of subjects had a greater than 5% absolute and greater than 30% relative liver fat content reduction with many of those patients achieving normalization of liver fat. The mean [alanine aminotransferase (ALT)] dropped by 60% and, again, approximately 60% of patients achieved normalization of ALT. We also saw significant improvement in the exploratory fibrosis markers.”

Harrison showed that C4 levels and total serum bile acids were both significantly lower at week 12 as compared to baseline, reflecting potent target engagement of NGM282. C4 decreased relatively by 93% (P < .0001) while total serum bile acids had a relative decrease of 64% (P < .0001).

When looking at liver fat content, Harrison showed that 100% of participants achieved the primary study endpoint of 5% or more absolute reduction and a decreased relative reduction of 30% or more at week 12. Additionally, 63% of the participants achieved normalized liver fat content.

Fibrosis markers, Harrison said, were significantly reduced as early as week 6 — enhanced liver fibrosis (ELF) score and PRO-C3 levels specifically. He said participants with more severe disease (ELF 10.1) decreased their ELF scores by 0.8 at week 12. MRI-PDFF showed consistent reductions in LIF and cT1 as well, he added.

“As a result of this, moving forward, we were very excited to see what the biopsies might show and how the noninvasive tests correlated with the pathology,” he said. “The histologic response aligns with decreases across noninvasive efficacy markers.”

NAS decreased in 84% (n = 16) of patients, steatosis decreased in 74% (n = 14); inflammation decreased in 42% (n = 8) and remained unchanged in 53%; and ballooning decreased in 53% (n = 10). Harrison also showed a “rapid regression” of fibrosis at week 12, with 42% of patients improving and a mean decrease from baseline of 0.5.

“We ... saw unprecedented antifibrotic activity at week 12 with three patients improving in particular from F3 to F1,” Harrison said.

Harrison and his group defined the “early histologic responders” as patients with a reduction in NAS of 2 or more, a reduction in fibrosis of 1 or more with no worsening of NASH or resolution of NASH where inflammation is between 0 and 1 while ballooning is at 0. He showed that 68% of patients (n = 13) fit this definition: 58% with the reduction of NAS, 42% with the change in fibrosis and 11% with total resolution of NASH.

One of the side effects of NGM282 was an increase in LDL cholesterol levels, reflecting potent CYP7A1 inhibition, Harrison said. This spike at week 2 was effectively managed with statin therapy for the following 10 weeks, he said. No new safety signals were reported, and the most common adverse event was mild GI symptoms.

“We think this is safe and well tolerated, consistent with other study populations and we believe the data support advancing NGM282 to phase 2b study in NASH,” Harrison said. – Katrina Altersitz

For more information:

Harrison S, et al. GS-014. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.

Disclosure: Harrison reports being on the speakers bureau for AbbVie and Alexion; acting as a consultant and participating on advisory boards for Allergan, Axcella, Capulus, Echosens, CiVi Biopharma, Bristol-Myers Squibb, Chronic Liver Disease Foundation, Cirius, Corcept, Cymabay, Galmed, Genfit, Gilead, HistoIndex, Intercept, IQVIA, Madrigal, MedPace, NGM Bio, Novartis, Novo Nordisk, Perspectum, Pfizer, Pharmaceutical Product Development, Prometheus, Second Genome; and he received grant or research support from Allergan, Cirius, Conatus, Galectin, Galmed, Genfit, Gilead, Immuron, Intercept, Madrigal and NGM Bio.

Editor’s note: This item has been updated with clarifications from the presenter.