Pegozafermin Shows Sustained Benefit for NASH in Phase 2b Extension Study

Hank Mansbach, MD

Credit: PR Newswire

89bio has announced positive long term data from the blinded extension phase of the phase 2b ENLIVEN trial evaluating the use of pegozafermin in patients with nonalcoholic steatohepatitis (NASH).

Announced on November 27, 2023, findings showed both 30 mg weekly and 44 mg biweekly pegozafermin demonstrated statistically significant improvements across key markers of liver health including fibrosis, inflammation, and fat through 48 weeks, consistent with benefits previously observed through week 24 in the main study.¹

“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,” said Hank Mansbach, MD, chief medical officer of 89bio.¹ “Notably, we observed consistent and robust benefits in F2-F3 NASH patients, as well as in subgroups of patients receiving concurrent GLP-1 therapy and F4 patients with compensated cirrhosis, validating pegozafermin’s anti-fibrotic effects across a broad spectrum of patients.”

A glycoPEGylated analog of fibroblast growth factor 21 (FGF21), pegozafermin regulates energy expenditure, glucose, and lipid metabolism. It has previously demonstrated direct anti-fibrotic and anti-inflammatory effects on the liver, reduced triglyceride levels, improved insulin resistance and glycemic control, and demonstrated a favorable safety and tolerability profile.¹

On September 21, 2023, the US Food and Drug Administration (FDA) granted pegozafermin Breakthrough Therapy designation for the treatment of NASH with fibrosis, supported by data from the main ENLIVEN study. Pegozafermin is advancing into a phase 3 trial for NASH and is also being studied for severe hypertriglyceridemia in the phase 3 ENTRUST trial.^1,2

A multicenter, randomized, double-blind, placebo-controlled trial, ENLIVEN assessed the safety and efficacy of weekly or biweekly pegozafermin for the treatment of patients with biopsy-confirmed NASH and NAS ≥ 4. For inclusion, patients were required to be aged 21-75 years, have biopsy-confirmed NASH with fibrosis stage F2 or F3, and have a NAS score ≥ 1 in steatosis, ballooning degeneration, and lobular inflammation. In total, 192 patients were included in the study and assigned to pegozafermin 15 mg weekly, pegozafermin 30 mg weekly, pegozafermin 44 mg biweekly, or placebo for 24 weeks.^1,3

Patients who entered the blinded extension phase were treated for an additional 24 weeks for a total treatment period of 48 weeks. A subset of patients in the placebo arm of the main study (n = 19) were rerandomized to receive pegozafermin 30 mg weekly during the extension phase. In total, 50 patients received pegozafermin 30 mg weekly, 45 received pegozafermin 44 mg biweekly, and 35 received placebo. Key endpoints included liver fat, noninvasive markers of liver fibrosis and inflammation, and metabolic markers.¹

According to the release, both 30 mg weekly and 44 mg biweekly pegozafermin demonstrated statistically significant improvements across key markers of liver health:

• MRI-PDFF for liver fat (-60% for 30 mg, P < .01; -47% for 44 mg, P < .05)
• ALT for liver injury/inflammation (-42% for 33 mg, P < .001; -35% for 44 mg, P < .01)
• AST for liver injury/inflammation (-39% for 33 mg, P < .001; -36% for 44 mg, P < .001)
• ELF score for liver fibrosis (-0.3 for 33 mg, P < .01; -0.4 for 44 mg, P < .001)
• FAST for liver fibrosis (-59% for 33 mg, P < .001; -51% for 44 mg, P < .001)

Patients on background GLP-1 therapy who received pegozafermin continued to experience greater improvements across markers of liver fibrosis, liver injury/inflammation, liver fat, and lipids compared to patients who continued GLP-1 therapy in the placebo group, consistent with results from the main study. Additionally, patients with compensated cirrhosis F4 who had previously demonstrated histological response and improvement in noninvasive measures at week 24 continued to do so at week 48. Patients on placebo in the main study who were rerandomized to receive pegozafermin 30 mg during the extension phase exhibited similar improvements after 24 weeks of treatment with pegozafermin following little to no change on placebo.¹

Pegozafermin continued to demonstrate a favorable safety and tolerability profile at week 48, consistent with previously reported data. Investigators noted the most common treatment-emergent adverse events were grade 1 or 2 gastrointestinal events and pointed out incidence rates of adverse events were stable between week 24 and week 48.¹

“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. 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," Mansbach said.¹

References:

1. 89bio. 89bio Announces New Positive Long-Term Data from the ENLIVEN Phase 2b Trial of Pegozafermin in Patients with Nonalcoholic Steatohepatitis (NASH). Press Releases. November 27, 2023. Accessed November 27, 2023. https://ir.89bio.com/news-releases/news-release-details/89bio-announces-new-positive-long-term-data-enliven-phase-2b
2. 89bio. 89bio Announces U.S. FDA has Granted Breakthrough Therapy Designation for Pegozafermin in Nonalcoholic Steatohepatitis (NASH). Press Releases. September 21, 2023. Accessed November 27, 2023. https://ir.89bio.com/news-releases/news-release-details/89bio-announces-us-fda-has-granted-breakthrough-therapy
3. Clinicaltrials.gov. Study Evaluating the Safety, Efficacy and Tolerability of BIO89-100 in Subjects With Biopsy-confirmed Nonalcoholic Steatohepatitis (NASH) (ENLIVEN). July 24, 2023. Accessed November 27, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04929483