Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH

Loomba, Rohit; Sanyal, Arun J.; Kowdley, Kris V.; Bhatt, Deepak L.; Loomba, Rohit; Frías, Juan P.; Bédossa, Pierre; Harrison, Stephen A.; Lazas, Donald J.; Barish, Robert J.; Gottwald, Mildred D.; Feng, Shibao; Agollah, Germaine D.; Hartsfield, Cynthia L.; Mansbach, Hank; Margalit, Maya; Abdelmalek, Manal F.

doi:10.1056/nejmoa2304286

Cited by 146 publications

(54 citation statements)

References 29 publications

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“…The results from the trial also indicate that treatment with an FGF21 analogue may positively affect some of the classical traits of metabolic derangements, including adiponectin, serum triglyceride and HDL cholesterol levels. 37 The results from the outlined trials support the idea that treatments targeting the FGF21 pathway may have dual beneficial effect for the many people with ArLD who also carry metabolic risk factors. 38 Our results demonstrate a decrease in systemic levels of FGF23 in the ArLD group, but not in healthy controls or the NAFLD group.…”

Section: Discussionmentioning

confidence: 71%

Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation‐related markers

Stankevic,

Israelsen,

Juel

et al. 2023

Liver International

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BackgroundFrequent binge drinking is a known contributor to alcohol‐related harm, but its impact on systemic and hepatic inflammation is not fully understood. We hypothesize that changes in immune markers play a central role in adverse effects of acute alcohol intake, especially in patients with early liver disease.AimTo investigate the effects of acute alcohol intoxication on inflammation‐related markers in hepatic and systemic venous plasma in people with alcohol‐related liver disease (ArLD), non‐alcoholic fatty liver disease (NAFLD) and healthy controls.MethodsThirty‐eight participants (13 with ArLD, 15 with NAFLD and 10 healthy controls) received 2.5 mL of 40% ethanol per kg body weight via a nasogastric tube. Seventy‐two inflammation‐related markers were quantified in plasma from hepatic and systemic venous blood, at baseline, 60 and 180 min after intervention.ResultsAlcohol intervention altered the levels of 31 of 72 and 14 of 72 markers in the systemic and hepatic circulation. All changes observed in the hepatic circulation were also identified in the systemic circulation after 180 min. Only FGF21 and IL6 were increased after alcohol intervention, while the remaining 29 markers decreased. Differences in response to acute alcohol between the groups were observed for 8 markers, and FGF21 response was blunted in individuals with steatosis.ConclusionAcute alcohol intoxication induced changes in multiple inflammation‐related markers, implicated in alcohol metabolism and hepatocellular damage. Differences identified between marker response to binge drinking in ArLD, NAFLD and healthy controls may provide important clues to disease mechanisms and potential targets for treatment.Clinical trial number: NCT03018990

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Section: Discussionmentioning

confidence: 71%

Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation‐related markers

Stankevic,

Israelsen,

Juel

et al. 2023

Liver International

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“…Learnings from this study were incorporated in the ENLIVEN study, in which three expert NASH pathologists scored liver biopsies separately and independently, and a consensus score reached by an objective algorithm that minimised need for adjudication. 16,24 In conclusion, pegozafermin had pleiotropic beneficial effects on hepatic and metabolic parameters and was well tolerated over 20 weeks. Learnings from this proof-of-concept study have been instrumental to inform the design of the recently published phase 2b…”

Section: Discussionmentioning

confidence: 85%

“…The effects of pegozafermin on liver histology in subjects with biopsy-confirmed NASH have been further investigated in the randomised, controlled, phase 2b ENLIVEN study (NCT049483). 16 The use of a single central reader for liver biopsy analysis was also a limitation. Learnings from this study were incorporated in the ENLIVEN study, in which three expert NASH pathologists scored liver biopsies separately and independently, and a consensus score reached by an objective algorithm that minimised need for adjudication.…”

Section: Discussionmentioning

confidence: 99%

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Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy‐confirmed nonalcoholic steatohepatitis

Alkhouri,

Lazas,

Loomba

et al. 2023

Aliment Pharmacol Ther

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SummaryBackgroundAn approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need.AimTo investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy‐confirmed NASH.MethodsThis proof‐of‐concept, open‐label, single‐cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21–75 years) with NASH (stage 2 or 3 fibrosis, NAS≥4) and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) ≥8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability.ResultsOf 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of ≥2‐point improvement in NAFLD activity score with ≥1‐point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least‐squares mean relative change from baseline in MRI‐PDFF was −64.7% (95% CI: −71.7, −57.7; p < 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths.ConclusionsPegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH. ClinicalTrials.gov: NCT04048135.

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“…and 44 mg q2w met the primary histological endpoints, along with an HFF reduction of ≥ 50%. 24 The most common adverse events associated with pegozafermin therapy were nausea and diarrhea.…”

Section: Articlementioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis

Tseng,

Balic,

Charlton

et al. 2023

Clin Pharma and Therapeutics

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Pegozafermin is a long‐acting glycoPEGylated analog of fibroblast growth factor 21 (FGF21) in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. In a phase Ib/IIa placebo‐controlled, double‐blind, multiple ascending dose study in patients with NASH (NCT04048135), administration of pegozafermin resulted in clinically meaningful reductions in hepatic fat fraction (HFF), with a favorable safety and tolerability profile. We aimed to characterize the relationship between pegozafermin dosing, exposure and effects on HFF reduction. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling of data from the phase Ib/IIa study to identify model parameters and covariates affecting the exposure–response relationship. Clinical simulations were performed to help support dose selection for larger studies. Pegozafermin exposure was adequately described by a one compartment PK model, with one additional transit absorption compartment. PK/PD modeling demonstrated that HFF reduction was significantly related to pegozafermin exposure. HFF outcomes were correlated with average pegozafermin concentrations regardless of weekly dosing (q.w.) or dosing every 2 weeks (q2w). The significant PK/PD model covariates included baseline body weight, alanine aminotransferase level, and liver volume. Simulations showed that the 30 mg q.w. dose approximated the full PD effect; almost all patients would benefit from a greater than or equal to 30% HFF reduction, suggesting fibrosis regression. Furthermore, 44 mg q2w dosing (~22 mg q.w.) appeared to be an effective regimen for HFF reduction. Our modeling supports the feasibility of q.w. and q2w dosing for achieving favorable treatment outcomes in patients with NASH, and provides the rationale for dose selection for the phase IIb ENLIVEN study (NCT04929483).

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Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH

Cited by 146 publications

References 29 publications

Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation‐related markers

Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation‐related markers

Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy‐confirmed nonalcoholic steatohepatitis

Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis

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