NASH resolves, fibrosis improves in 22% treated with growth factor analogue
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Fibroblast growth factor 19 analogue aldafermin showed dose- and duration-dependent reduction in liver fat with resolution of non-alcoholic steatohepatitis in more than one-fifth of cases, according to a presenter at the Digital International Liver Congress.
“Ultimately, looking at the study from cohort 4, the primary endpoint was met. Clinically significant improvements in histology regulatory endpoints of fibrosis improvement, resolution of NASH and the composite endpoint requiring achievement of both are very positive,” Stephen Harrison, MD, medical director of Pinnacle Research, said during his presentation. “Cohort 4 data suggest that the histologic effects previously observed at 12 weeks are durable and potentially amplified with extended treatment.”
For this phase 2 study, key inclusion criteria, determined by MRI-PDFF and biopsy at baseline, included biopsy-proven NASH with NAFLD activity score (NAS) of 4 or greater, stage 2 to 3 fibrosis and absolute liver fat content (LFC) of 8% or higher. This cohort received either placebo (n = 25) or aldafermin (NGM Bio, n = 52) for 24 weeks, at which time they were screened with MRI-PDFF and biopsy. Follow-up went to 30 weeks.
‘Very positive’ results
At week 24, treatment with aldafermin resulted in reductions in LFC: 68% of the aldafermin group achieved 5% or greater absolute LFC reduction vs. 24% in the placebo group (P < .001), which translated to 66% of the aldafermin group achieved 30% or more relative LFC reduction vs. 29% of the placebo group (P = .004).
“There was a rapid and consistent improvement in fibrosis and NASH resolution at week 24,” Harrison said.
A greater proportion of those receiving aldafermin achieved fibrosis reduction of 1 or more stage without NASH worsening (38% aldafermin vs 18% placebo) and NASH resolution with no worsening of fibrosis (24% aldafermin vs. 9% placebo). Additionally, more than one-fifth of those receiving aldafermin achieved both histological endpoints (22% aldafermin vs. 0% placebo; P = .015).
“If the F3 patient had a 30% reduction in liver fat content, 46% of them actually had an improvement of fibrosis by at least one stage with no worsening of NASH compared to 0 for placebo,” Harrison said.
Harrison showed that a similar pattern was seen in NAS reduction by two or more points: 62% of aldafermin group vs. 9% of the placebo group (P < .001) with significant improvement in each component. ALT also returned to “near normal” levels in in the aldafermin group at a higher rate (49% vs. 6%, P < .001), Harrison said.
‘Lipid optimization’
In this study, Harrison explained that they implemented “lipid optimization” in which the study design outlined the use of statins beginning at week 2 if there was an LDL rise of 10 mg/dL or more from baseline.
“An observation was made in this trial about suboptimal baseline management of these NASH patients,” Harrison said. “Approximately 61% of patients had diabetes and with this baseline risk, they met the [American College of Cardiology and American Heart Association (ACC/AHA )] guideline for statin therapy. However, only 32% were on statins at baseline.”
The aldafermin group saw a 3% decrease in the 10-year atherosclerotic CVD (ASDCVD) risk score while the placebo group saw only a 1% decrease (P = .032).
“Trying to find the sweet spot between efficacy and rise in LDL has been part of the development program. For me, knowing that we are going to raise LDL ... putting in a mitigation strategy that’s very prescriptive is important rather than leaving it up to the individual treater to decide whether or not to start a statin,” Harrison said. “Being prescriptive like that has allowed us to show we can decrease not only the ASCVD risk score but bring LDLs down to the below the baseline values. Knowing that 61% in this trial – which maybe applicable across the board – of patients actually meeting criteria to start a statin, ultimately, we need to manage these patients very proactively and very efficiently relative to their cholesterol anyway.”
Ongoing study
Harrison showed a consistent duration response in which 38% of patients receiving aldafermin for 24 weeks showed fibrosis improvement compared to 25% who received the same 1 mg dose for 12 weeks. Additionally, dose response was higher in the 3 mg dose: 42% of the 3 mg recipients vs. 25% of the 1 mg recipients showed fibrosis improvement at 12 weeks. Results of 3 mg at 24 weeks are forthcoming, he said.
“It really shows that there’s an improved chance of success moving to phase 3,” Harrison said.
Adverse events were mostly mild and moderate in severity.
Perspective
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Jamile’ Wakim-Fleming, MD, FACG, FAASLD
NAFLD and its subtype NASH are reported in both children and adults when fat is present in at least 5% of hepatocytes and when toxicity from excessive fat causes hepatocyte inflammation and deposition of fibrosis in the extracellular matrix. When this happens, accelerated damage to the liver occurs leading to the formation of cirrhosis, liver cancer, liver failure and death. Medications are in dire need that will decrease the deposition of fat in the liver and will be used in conjunction with other management modalities to fight this progressive and increasingly prevalent disease.
One of the agents researchers are testing for the treatment of NAFLD is aldafermin (NGM Bio), a fibroblast growth factor 19 analogue that regulates metabolic homeostasis and inhibits bile acid synthesis. In a phase 2, randomized, double-blind placebo-controlled clinical trial, conducted for 24 weeks by Harrison and colleagues, aldafermin has shown to significantly decrease fat in the liver compare with placebo. Further, there was a trend in decreasing NASH and fibrosis. No patient in the aldafermin group discontinued, whereas 4% did in the placebo group.
These results are very encouraging and while the drug is still in phase 2b, we hope that aldafermin will breakthrough and the trends seen in histological improvements will translate in significant implications on the overall prognosis of patients with NAFLD.
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Harrison S. LBO01. Presented at: The Digital International Liver Congress; Aug. 27-29, 2020.
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