WASHINGTON—New data are supporting the use of novel agents in the treatment of nonalcoholic steatohepatitis, according to late-breaking abstracts presented at The Liver Meeting 2022.

Research into three agents—efruxifermin (Akero), PXL065 (Poxel) and obeticholic acid—all resulted in improvements in fibrosis, NASH resolution and markers of liver injury. Two of the drugs, efruxifermin and PXL065, both in phase 2 trials, also were found to improve liver fat content. And new interim results from a phase 3 study data of obeticholic acid reaffirmed the agent’s antifibrotic properties over the long term with manageable side effects.

Fibrosis Improvement With Reduced Fat

A long-acting fibroblast growth factor 21 (FGF21) analog, efruxifermin significantly improved several outcome measures in patients with F2/F3 fibrosis due to NASH in the phase 2b HARMONY trial, according to principal investigator Stephen A. Harrison, MD, a visiting professor of hepatology at the University of Oxford, in England, and the medical director for Pinnacle Clinical Research and president of Summit Clinical Research, in San Antonio. Efruxifermin greatly reduced liver fat in the trial, unlike what has been seen with other FGF21 analogs in production (Nat Med 2021;27:1262-1271). In early December, the FDA granted a breakthrough therapy designation for efruxifermin for the treatment of NASH.

In the trial, Dr. Harrison and his co-investigators randomly assigned 128 patients with NASH and F2/F3 fibrosis to receive once-weekly doses of 28 mg (n=38) or 50 mg (n=34) efruxifermin or placebo (n=41) for 96 weeks. About 70% of patients had diabetes, 63% to 70% had F3 fibrosis, and hepatic liver fat content ranged from 17% to 18.5%. Liver biopsies were conducted at 24 weeks. Two pathologists blinded to the treatment arms scored the biopsy results independently.

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Both doses of efruxifermin achieved statistical significance on fibrosis improvement and NASH resolution. About 39% of patients taking the 28-mg dose and 41% of those taking the 50-mg dose had fibrosis improvement of at least one stage and no worsening of NASH at week 24, compared with 20% in the placebo arm (P<0.05). About 15% of patients in each efruxifermin arm achieved fibrosis improvement of at least two stages and no worsening of NASH. Both doses also were significant for a composite end point of fibrosis improvement and NASH resolution, seen in 29% of patients taking the 28-mg dose and 41% of those taking the 50-mg dose, compared with 5% in the placebo arm (P<0.01 and P<0.001, respectively).

Efruxifermin also had notable effects on other markers compared with placebo, including up to a 5.2 mcg/L reduction in Pro-C3 (P<0.001), up to a 0.7 reduction in enhanced liver fibrosis (ELF) score (P<0.001), and up to a 4.3 kPa decline in liver stiffness by Fibroscan (Echosens) (P<0.01). The drug resulted in significant improvements in markers of liver injury, including alanine transaminase (ALT), aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, as well as improvements in lipoproteins and glycemic control.

It also “substantially reduced and normalized liver fat,” Dr. Harrison reported, resulting in up to a 64% reduction in liver fat at week 24 compared with placebo (P<0.001) (Table). This targeting of liver fat shows the “potential to eliminate the underlying disease driver,” the investigators reported at the meeting.

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Table. Proportion of Patients Achieving Fat Reduction Thresholds at Week 24
OutcomePlacebo (n=42)Efruxifermin
28 mg (n=38)
Efruxifermin
50 mg (n=35)
Relative reduction in liver fat (to =50%), %263a77a
Normalization of liver fat content (to =5%), %034a51a
a P<0.001, versus placebo.
Source: The Liver Meeting 2022.

Efruxifermin generally was well tolerated, with transient mild to moderate gastrointestinal events, such as nausea, diarrhea or increased appetite. The data support initiation of a phase 3 program, Dr. Harrison said.

Advances Without Edema

A second study, the phase 2 DESTINY1 trial, found that PXL065, a deuterium-stabilized R-stereoisomer form of pioglitazone, demonstrated significant reductions in liver fat content and positive effects on inflammation and fibrosis in NASH patients.

Although pioglitazone is effective as a NASH therapy and is recommended by practice guidelines, some patients have developed edema and right-sided heart failure while taking the medication, said Dr. Harrison, who is also the primary investigator for this trial. The new agent is designed without the peroxisome proliferator-activated receptor gamma component that is linked to weight gain, fluid retention and other adverse events, he said.

The investigators randomly assigned 117 patients with biopsy-proven NASH and liver fat content of at least 8% to receive daily oral doses of 7.5 mg (n=21), 15 mg (n=23) or 22.5 mg (n=27) of PXL065, or placebo (n=24) for 36 weeks. Patients were a mean age of 53 years and had a mean body mass index of 36 kg/m2. The majority of patients (76%) had F2/F3 fibrosis, 40% had well-controlled diabetes, and average liver fat content was approximately 20%.

All doses of medication met the primary end point of a reduction in liver fat content of at least 30% by week 36. The higher the dose, the larger the effect, with reduction of liver fat content of 40% in the 22.5-mg group (P=0.07), 34.4% in the 15-mg group (P=0.07) and 32% in the 7.5-mg group, compared with 16.7% in the placebo arm. Greater improvements in ALT, biomarkers of fibrogenesis and fibrosis, such as Pro-C3, Procollagen III, N-terminal propeptide, ELF, and Fibrosis-4 score, also were noted in all dose arms over placebo. About 30% to 50% of participants taking PXL065 achieved at least a 1-point improvement in fibrosis without worsening of NASH, depending on the dose. Improvements in glycemic control also were noted.

Overall, the drug was well tolerated, with the most common adverse events being headache and some nausea, Dr. Harrison said.

The results are “very promising” and next steps include a pivotal trial design and dose selection, and pursuit of a 505(b)(2) pathway from the FDA, he said.

Review Confirms Results

In a third study presented at the meeting, a three-pathologist consensus panel confirmed interim results of the phase 3 REGENERATE study (Lancet 2019;394[10215]:2184-2196) of obeticholic acid—a farnesoid X receptor agonist—in the treatment of NASH. This analysis was done after a request from regulatory agencies to assess interim results reported in the ongoing study, which originally had just one pathologist reviewing an 18-month biopsy, said lead investigator Arun Sanyal, MD, MBBS, a professor of medicine and the executive director of the Education Core Center for Clinical and Translational Research at Virginia Commonwealth University, in Richmond.

Patients in the trial were randomly assigned to receive either placebo, or 10 or 25 mg of obeticholic acid daily. A total of 2, 477 patients are enrolled in the ongoing trial, some of whom have received the study drug for four years. The primary end point is achievement of fibrosis improvement by at least one stage without worsening of NASH, or NASH resolution and no worsening of fibrosis at 18 months.

Pathologists re-reviewed liver biopsies taken from the original 931 patients analyzed at the interim time point. Results were largely similar to the original pathologist review, indicating that the one-third of patients taking the 25-mg dose responded to treatment.

“The confirmed antifibrotic effect, together with extended exposure, supports the positive benefit … in patients with advanced fibrosis due to NASH,” Dr. Sanyal reported.

Obeticholic acid and resmetirom are among drugs for NASH likely to be approved by the FDA this year, commented Mazen Noureddin, MD, MHSc, the director of the Houston Research Institute, and a hepatologist at the Sherrie & Alan Conover Center for Liver Disease and Transplantation at Houston Methodist Hospital. “These will be hopefully followed in the near future with other very promising medications such as efruxifermin.”

The efruxifermin study showed “one of the highest NASH resolution numbers we have seen, with percentages in the 70s,” he said, as well as fibrosis improvement in the 40% range, “which is quite high for such a group of patients.” “There’s a lot of excitement behind this drug,” Dr. Noureddin said. “They’re moving to phase 3 studies that everyone is looking forward to.”

There are multiple other drugs in the space in phase 2 and 3 studies to watch, he added, including lanifibranor, belapectin and semaglutide, which already is approved for type 2 diabetes and obesity.

—Karen Blum


Dr. Harrison reported financial relationships with Akero, Intercept and Poxel. Dr. Noureddin reported no relevant financial disclosures. Dr. Sanyal reported a financial relationship with Poxel.

This article is from the March 2023 print issue.