While the FDA this week decides whether to grant its first-ever authorization for a metabolic dysfunction-associated steatohepatitis (MASH) drug to Madrigal Pharmaceuticals, one of its competitors said today it has begun a two-trial Phase III program designed to assess the safety and efficacy of its lead candidate for the liver disease.

89bio has initiated ENLIGHTEN by launching ENLIGHTEN-Fibrosis. The global Phase III, randomized, double-blind trial is designed to compare two dosages of pegozafermin to placebo in biopsy-confirmed non-cirrhotic MASH patients at fibrosis stage F2-F3. Approximately 1,000 patients will be randomized 1:1:1 to receive either 30mg of pegozafermin administered weekly, 44mg administered every two weeks, or placebo.

The co-primary endpoints of ENLIGHTEN-Fibrosis, to be assessed at week 52, are: A one-point or greater improvement in fibrosis with no worsening of MASH; and MASH resolution with no worsening of fibrosis. Data from the trial is intended to support a U.S. filing for accelerated approval and a European filing for conditional approval, both in non-cirrhotic patients.

Key secondary endpoints include additional histological endpoints, noninvasive tests (NITs) and metabolic and lipid assessments. Patients will continue to be treated beyond the 52-week assessment through outcomes to support full approval, 89bio added.  

Pegozafermin is an engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21) that 89bio is developing as a treatment for MASH as well as severe hypertriglyceridemia (SHTG), where it is under study in the ongoing Phase III Entrust trial (NCT05852431). FGF21 is an endogenous hormone that regulates energy expenditure, glucose, and lipid metabolism.

Pegozafermin is one of several drugs to reach Phase III for MASH or MASH-related indications. Others include aramchol (Galmed Pharmaceuticals), which targets stearoylCoA desaturase 1 (SCD1); belapectin (Galectin Therapeutics), an inhibitor of galectin-1 and galectin-3 with greater binding affinity to galectin-3; Novo Nordisk’s blockbuster drug semaglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist; and lanifabranor (Inventiva), a pan-peroxisome proliferator-activated receptor (PPAR) agonist.

Last month, Inventiva voluntarily paused screening and randomization of new patients in its Phase III NATiV3 trial (NCT04849728) to implement additional screening eligibility criteria recommended by the study’s independent Data Monitoring Committee, after a treatment–related Suspected Unexpected Serious Adverse Reaction (SUSAR) in which a patient showed elevated aminotransferases.

FGF21 analogs

Pegozafermin is among FGF21 analogs in mid- or later-phase clinical development for MASH indications; One is Boston Pharmaceuticals’ BOS-580, a fusion protein based on human IgG and FGF21, modified to provide an extended systemic half-life. According to BOS-580 is designed to have reduced immunogenicity due to expression in a mammalian cell line and proper glycosylation.

In January, Boston Pharmaceuticals presented 12-week data from a Phase II trial (NCT04880031) at the NASH-TAG 2024 conference in Park City, UT, showing that treatment with five different doses of BOS-580 mostly led to significant reductions in liver fat content, markers of liver injury and fibrosis, and numerically improved markers of metabolic health in patients with phenotypic MASH.

Results were measured across composite scores for Fibroscan-AST (FAST); Fibrosis-4 Index (FIB-4); Aspartate aminotransferase-to-platelet ratio index (APRI); and age, presence of diabetes, PRO-C3, and platelet count (ADAPT). Observed responses were within one to two weeks of treatment, and were sustained over the 12-week study, which according to the company suggests that BOS-580 treatment may lead to clinical benefit in MASH patients.

Another is Akero Therapeutics’ lead drug candidate efruxifermin (EFX), a once-weekly therapy that has also generated positive data in multiple clinical trials, by being shown to reduce liver fat and inflammation, reverse fibrosis, increase insulin sensitivity and improve lipoproteins.

Most recently on March 4, Akero released preliminary topline week 96 results from its Phase IIb HARMONY trial (NCT04767529) showing response rates of 75% for patients treated with a 50mg dose of EFX and 46% for 28mg EFX, compared to just 24% for placebo—up from 41%, 39%, and 20% after 24 weeks’ treatment.

HARMONY’s primary endpoint was the proportion of subjects achieving at least one-stage fibrosis improvement without worsening of MASH at week 24. At week 96, Akero evaluated several secondary measures, included ≥1 stage fibrosis improvement and no worsening of MASH, 2-stage fibrosis improvement without worsening of MASH, at least one-stage fibrosis improvement and MASH resolution, change from baseline in liver enzymes, noninvasive markers of liver fibrosis, glycemic control, lipoproteins, and body weight as well as safety and tolerability measures.

Both FGF21 analogs apply a different mechanism of action from Madrigal’s resmetirom, a once daily oral, liver-directed thyroid hormone receptor (THR) β-selective agonist designed to treat underlying causes of NASH in the liver, while improving multiple atherogenic lipid profiles.

Resmetirom is under review by the FDA, which has set a target action date of Thursday for Madrigal’s application under the Prescription Drug User Fee Act (PDUFA). If resmetirom is approved as expected, it would be the first treatment approved by the agency for adults with MASH with liver fibrosis.

Dosing advantage

Hank Mansbach, MD, 89bio’s chief medical officer, told GEN Edge that pegozafermin stands out from resmetirom and EFX by being able to be dosed either once weekly or once every two weeks, depending on the dosage.

“Once every two weeks seems like a small change. But for patients—and we’ve done market research to support this—it’s an advantage, because in one year, it’s 26 fewer injections. And the tolerability with every two weeks has been somewhat better,” Mansbach said. “So that also supports the idea that these are potentially therapies that patients may need to stay on for a long period of time.”

“MASH itself is an asymptomatic condition, until it becomes advanced cirrhosis. So, having a treatment that is better tolerated with a more patient friendly dosing interval could support better use of pegozafermin over a longer period of time as patients go about their busy lives,” Mansbach added.

In its endogenous state, FGF21 circulates at very low picogram concentrations with a very short half-life of less than two hours—compared to between now 55 to 100 hours when engineered into pegozafermin.

“Giving a much greater amount of the hormone is able to drive a couple of things: One, reduce energy expenditure. Two, improve lipids. Three, improve glycemic control. And then four, and most importantly in NASH, we’re seeing antifibrotic benefits and anti-inflammatory benefits,” Mansbach explained. “You can’t really test the hormone as a native hormone because it’s got such a short half-life and there’s so little of it that circulates.”

Boston Pharmaceuticals says BOS-580 could be an even longer-lasting treatment, having evaluated the drug at biweekly and even once-monthly doses, so far with positive results. The company’s Phase II trial (NCT04880031) is assessing once-monthly dosing of BOS-580 over 24 weeks for safety and efficacy in patients with biopsy-proven F2 or F3 MASH.

GLP-1 drugs

Also driving NASH drug development are GLP-1 drugs such as Eli Lilly’s tirzepatide, marketed in type 2 diabetes as Mounjaro® and in obesity as Zepbound®. Last month, Lilly announced positive topline results from the Phase II SYNERGY-NASH trial (NCT04166773) showing that tirzepatide met the study’s primary endpoint as up to 74% of participants achieved an absence of MASH with no worsening of fibrosis at 52 weeks, compared to nearly 13% of participants on placebo.

Another GLP-1 blockbuster, Novo Nordisk’s semaglutide—marketed to treat type 2 diabetes as Ozempic®and to treat obesity as Wegovy®—is in Phase III development as a once-weekly therapy for MASH.

Semaglutide is one of five MASH treatments in Novo Nordisk’s pipeline. A study published in 2021 in The New England Journal of Medicine (NEJM) found that patients treated with semaglutide in a Phase II trial (NCT02970942) experienced significantly more MASH resolution than those on placebo—40% in the 0.1-mg dose group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in placebo patients. But results proved inconclusive on the study’s secondary endpoint—improvement in fibrosis stage with no worsening of MASH—due to unusually high rates of response in the placebo group and overall small numbers.

Besides semaglutide, the only other Novo Nordisk candidate to advance beyond Phase I in MASH is an FGF21 analog also envisioned as a once-weekly therapy, now in Phase II.

“To our knowledge, there are no GLP-1 receptors in the liver and so the effect of GLP-1s on MASH is essentially indirect, by improving weight and improving glycemic control,” Mansbach said. “Whereas with an F21 therapy like our own, there are F21 receptors in the liver. There appears to be a more direct effect and that’s why we can see fibrosis improvement even within 24 weeks.”

Potential tolerability advantage

Another potential advantage of pegozafermin over EFX, Mansbach said, was tolerability, particularly adverse gastrointestinal (GI) events.

89bio reported no deaths and 10 serious adverse events among patients treated with any of three doses of pegozafermin in its Phase IIb ENLIVEN trial (NCT04929483), according to a study based on 24-week data published September 14, 2023, in NEJM—5% (one patient) in the 15-mg pegozafermin group, 4% (three patients) in the 30-mg pegozafermin group, and 11% (six patients) in the 44-mg pegozafermin group, compared with 4% (three patients) in the placebo group with the most common adverse events associated with the therapy being nausea and diarrhea.

In reporting 96-week data from its HARMONY trial earlier this month, Akero characterized EFX as “generally well-tolerated” based on no deaths, and reported 15 serious adverse events generally balanced across dose groups. Across both EFX groups, the most frequent adverse events were diarrhea, nausea, and increased appetite, which Akero said were transient in nature.

Three patients treated with EFX were discontinued due to adverse events between week 24 and week 96 (two in the 28mg group and one in the 50mg group), compared with none for placebo, according to Akero. At 24 weeks, a single drug-related serious adverse event of esophagitis was experienced by a patient in the 50mg group who had a history of gastroesophageal reflux disease, Akero said in September 2022.

89bio reported in the NEJM study that adverse events considered related to pegozafermin and that led to its discontinuation in ENLIVEN were seen in 5% of patients receiving the 15-mg dose of pegozafermin (diarrhea in one patient), in 6% of those receiving the 30-mg dose (diarrhea in two patients, nausea in one, and injection-site erythema in one), in 2% of those receiving the 44-mg dose (pancreatitis in one), and in no patients receiving placebo.

As of week 48 of ENLIVEN, 89bio reported last November, pegozafermin continued showing a favorable safety and tolerability profile, with the most common treatment-emergent adverse events being Grade 1 or 2 gastrointestinal events.

“Incidence rates of adverse events remained generally stable between week 24 and week 48 with no new patients on pegozafermin reporting diarrhea or nausea during the Extension Phase,” 89bio stated.

In ENLIVEN and other earlier clinical trials, pegozafermin had shown direct anti-fibrotic and anti-inflammatory effects on the liver, as well as reduced triglyceride levels, improved insulin resistance, and glycemic control, while continuing to demonstrate a favorable safety and tolerability profile.

Second Phase III trial planned

During the second quarter, 89bio plans to launch the second of its two trials under the Phase III ENLIGHTEN program. That trial, called ENLIGHTEN-Cirrhosis, is designed to evaluate the efficacy and safety of a 30mg weekly dose of pegozafermin in MASH patients with compensated cirrhosis (F4).

The trial—expected to start in the second quarter—consists of two portions. In the histology portion, the primary endpoint will be regression of fibrosis from F4 to an earlier stage, to be assessed at 24 months. However, the primary endpoint could be assessed earlier “based on the evolving clinical and regulatory landscape,” according to 89bio.

The company intends to incorporate data from the primary endpoint to support an accelerated approval filing in the U.S., as well as a conditional approval filing in Europe in F4 patients.

In the trial’s second portion focused on outcome, patients will continue to be treated in a blinded extension phase through clinical outcome events that the company expects will consist predominantly of decompensation events.

Alignment with the FDA on modified definitions of some of these events could allow ENLIGHTEN-Cirrhosis to reach its final number of events faster, and thus accelerate the timeline to trial readout—though the timing of topline data release has not been disclosed.

Positive results would support full approval in F4 patients and will also serve as confirmatory full approval in F2-F3 patients, 89bio said.

Patients will self-administer pegozafermin using the planned commercial liquid formulation delivered as a single subcutaneous injection. The trial will employ a three-panel consensus biopsy reading methodology, successfully used in the Phase II ENLIVEN trial.

The FDA has granted pegozafermin its Breakthrough Therapy designation for the treatment of MASH with fibrosis. The designation is designed to accelerate the development and review of drugs that are designed to treat a serious condition and have generated preliminary clinical evidence that they may have shown “substantial improvement” over available therapy on one or more clinically significant endpoints.

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