Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study

Loomba, Rohit; Lawitz, Eric; Frías, Juan P.; Ortiz‐Lasanta, Grisell; Johansson, Lars; Franey, Bridgette Boggess; Morrow, Linda; Rosenstock, Moti; Hartsfield, Cynthia L.; Chen, Chao-Yin; Tseng, Leo; Charlton, R Will; Mansbach, Hank; Margalit, Maya

doi:10.1016/s2468-1253(22)00347-8

Cited by 53 publications

(44 citation statements)

References 34 publications

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“…These data also showed no clear correlation between safety profile and immunogenicity. 15 Furthermore, no neutralizing antibodies were found in patients included in this study. Pegozafermin also demonstrated a good safety and tolerability profile, with no treatment-related serious adverse events or deaths reported during the study.…”

Section: Discussionmentioning

confidence: 70%

“…Pegozafermin also demonstrated a good safety and tolerability profile, with no treatment-related serious adverse events or deaths reported during the study. 15 These encouraging findings raise the possibility of pegozafermin becoming an important therapeutic option for patients with NASH and warrants further investigation in larger clinical trials.…”

Section: Discussionmentioning

confidence: 93%

“…Results from the phase Ib/IIa trial of pegozafermin in patients with NASH indicate highly favorable outcomes in these patients. 15 Compared with placebo, 86% of patients receiving treatment with pegozafermin 27 mg q.w. reported clinically meaningful reductions (≥ 30% MRI-PDFF reduction) in HFF, with normalized (< 5%) HFF reported in 43% of these patients.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, baseline characteristics for key parameters were similar across the dosing groups (Table 1) and in patients with biopsy-confirmed NASH compared with those who had phenotypic NASH (data not shown). 15 Exposure-response (day 92 MRI-PDFF) model development A logistic regression model was used to describe the relationship between the serum levels of pegozafermin and the proportion of patients achieving ≥ 30% HFF reduction from baseline Figure 2 Exposure-response (a) parameter estimates, and (b) exposure-response curve. C avg , average serum concentration; EC 50 , half maximal effective concentration; E max , effect at maximal concentration; PDFF, proton density fat fraction; q.w., weekly; q2w, every 2 weeks; RMSE, root mean squared error; RSE, relative standard error; w, residual error (additive).…”

Section: Baseline Patient Characteristicsmentioning

confidence: 99%

“…Results from a phase I, first‐in‐human, single ascending dose study showed that pegozafermin had a relatively long half‐life (55–100 hours over the clinically relevant dose range) and a favorable safety and tolerability profile, as well as durable and robust effects on serum triglyceride (up to 51% reduction), high‐density lipoprotein cholesterol (up to 36% increase), and low‐density lipoprotein cholesterol levels (up to 37% reduction) when given as a single dose of 9.1 mg or higher 14 . A recent randomized, placebo‐controlled, double‐blind, phase Ib/IIa multiple ascending dose study (http://clinicaltrials.gov: NCT04048135) 15 reported that treatment with pegozafermin led to robust and clinically meaningful reductions in hepatic fat fraction (HFF) compared with placebo in patients with NASH with weekly dosing (q.w.) and dosing every 2 weeks (q2w).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Baseline Patient Characteristicsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Efficacy and Safety of Fibroblast Growth Factor‐21 Analogs for the Treatment of Metabolic Dysfunction‐Associated Steatohepatitis: A Systematic Review and Meta‐Analysis

Jeong,

Han,

Jeon

et al. 2024

Clin Pharma and Therapeutics

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Fibroblast growth factor (FGF)‐21 analogs are potential therapeutic candidates for metabolic dysfunction‐associated steatohepatitis (MASH). This systematic review and meta‐analysis aimed to assess the efficacy and safety of the FGF‐21 analogs, efruxifermin, pegbelfermin, and pegozafermin for MASH treatment. A comprehensive systematic review and meta‐analysis of randomized controlled trials from five major databases was conducted. Primary efficacy outcomes focused on liver histological improvement, while secondary efficacy outcomes encompassed reductions in liver fat content and improvements in biochemical parameters. Safety outcomes examined included treatment‐emergent adverse events (TEAEs), treatment‐related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Eight eligible studies involving 963 patients were included in this review. Compared with the placebo group, the FGF‐21 analog‐treated group exhibited significantly improved primary efficacy outcomes, specifically ≥1 stage improvement in fibrosis with no worsening of MASH (risk ratio [RR] = 1.83; 95% confidence interval [CI] = 1.27–2.62) and at least two‐point improvement in the non‐alcoholic fatty liver disease activity score with no worsening of fibrosis (RR = 2.85; 95% CI = 2.06–3.95). Despite an increased risk of TEAEs (RR = 1.17; 95% CI = 1.08–1.27) and treatment‐related adverse events (RR = 1.75; 95% CI = 1.40–2.19), FGF‐21 analogs exhibited an acceptable safety profile. FGF‐21 analogs were significantly better in achieving liver histological improvements and beneficial biochemical outcomes compared with placebo, with a tolerable safety pattern. These findings shed light on the efficacy and safety of FGF‐21 analogs and provide valuable evidence for their application as MASH therapeutics.

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Enhanced bioactivity and stability of a long-acting FGF21: A novel variant for the treatment of NASH

Ji,

Lu,

Duan

et al. 2024

Biochimie

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Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study

Cited by 53 publications

References 34 publications

Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis

Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis

Efficacy and Safety of Fibroblast Growth Factor‐21 Analogs for the Treatment of Metabolic Dysfunction‐Associated Steatohepatitis: A Systematic Review and Meta‐Analysis

Enhanced bioactivity and stability of a long-acting FGF21: A novel variant for the treatment of NASH

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