ENLIVEN extension topline data: Pegozafermin sustains ‘robust benefits’ in NASH at week 48
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Key takeaways:
- Pegozafermin sustained statistically significant improvements for nonalcoholic steatohepatitis at week 48.
- Patients with compensated cirrhosis and those on background GLP-1-based therapy showed robust benefits.
Topline findings from an extension of the phase 2b ENLIVEN trial showed that pegozafermin sustained improvements in fibrosis and disease resolution for patients with nonalcoholic steatohepatitis at 48 weeks, 89bio announced.
Pegozafermin, a long acting glycopegylated recombinant fibroblast growth factor 21 analogue, has previously demonstrated direct anti-fibrotic and anti-inflammatory benefits for the liver, while maintaining a favorable safety and tolerability profile. Recently granted breakthrough therapy designation by the FDA, the drug is now being investigated for the treatment of NASH as well as severe hypertriglyceridemia.
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“We are very encouraged by these long-term efficacy and tolerability data which establish pegozafermin as the first FGF21 analog candidate to demonstrate positive, sustained benefits over a 48-week period in patients with advanced NASH,” Hank Mansbach, chief medical officer of 89bio, said in a press release. “Notably, we observed consistent and robust benefits in F2-F3 NASH patients, as well as in subgroups of patients receiving concurrent [Glucagon-like peptide-1] therapy and F4 patients with compensated cirrhosis, validating pegozafermin’s anti-fibrotic effects across a broad spectrum of patients.”
In the ENLIVEN phase 2b trial, a 24-week randomized, double-blind, placebo-controlled trial, patients with liver biopsy-confirmed NASH (n=192) were randomized to receive either weekly pegozafermin (15 mg or 30 mg), biweekly pegozafermin (44 mg) or placebo. Following the conclusion of the trial, patients were continued in a blinded extension phase for an additional 24 weeks, for a total of 48 weeks. Additionally, a subset of patients who had been assigned to the placebo group during the trial were re-randomized to receive pegozafermin 30 mg weekly in the extension trial.
The primary endpoints of the ENLIVEN extension phase included liver fat, non-invasive markers of fibrosis and inflammation and metabolic markers.
According to topline results, both the 30 mg weekly and 44 mg biweekly pegozafermin doses demonstrated statistically significant improvements across key markers of liver health at 48 weeks, consistent with results observed at 24 weeks.
The researchers observed that patients who had been re-randomized to receive 30 mg weekly during the extension phase exhibited robust improvements in noninvasive tests of liver fibrosis, liver injury/inflammation and liver fat following 24 weeks of pegozafermin after exhibiting “minimal to no change” during their time on placebo.
Additionally, patients who were prescribed background GLP-1 therapy and received pegozafermin continued to exhibit greater benefit for markers of liver fibrosis, liver injury/inflammation, liver fat and lipids vs. patients prescribed GLP-1 therapy in the placebo group. Similarly, patients with biopsy-confirmed compensated cirrhosis who had previously exhibited histological response and improvement at week 24 continued to demonstrate robust and sustained improvements in these measures at week 48.
“The sustained improvement in observed key liver health markers could lead to greater histological response rates, which we will aim to confirm in phase 3 development,” Mansbach said in the release. “We are working with the regulatory agencies and look forward to providing additional details of our phase 3 NASH program before the end of this year.”
Perspective
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Jamile’ Wakim-Fleming, MD, FACG, FAASLD
Our understanding of the pathophysiological mechanisms associated with the development of metabolic dysfunction-associated steatohepatitis, formerly NASH, has led to the development of drugs that target each of these mechanisms. Several drugs are in phase 2 trials and show promise in treating MASH; however, none are FDA-approved for that purpose yet.
Insulin resistance is the major driver underlying the development of this disease, leading to decreased glucose uptake by hepatocytes and an increase of free fatty acid uptake in the liver. Pegozafermin regulates glucose and lipid homeostasis.
These findings are very encouraging. Looking ahead, I hope that future research will include a more diverse population and longer duration of the clinical trials.
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