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Clinical Trial
. 2023 Jul;29(7):1782-1792.
doi: 10.1038/s41591-023-02427-z. Epub 2023 Jun 24.

The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial

Deepak L Bhatt  1 , Harold E Bays  2 , Michael Miller  3 , James E Cain 3rd  4 , Katarzyna Wasilewska  5 , Nabil S Andrawis  6 , Teresa Parli  7 , Shibao Feng  7 , Lulu Sterling  7 , Leo Tseng  7 , Cynthia L Hartsfield  7 , Germaine D Agollah  7 , Hank Mansbach  7 , John J P Kastelein  8 ; ENTRIGUE Principal Investigators
Affiliations
Clinical Trial

The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial

Deepak L Bhatt et al. Nat Med. 2023 Jul.

Erratum in

Abstract

Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses (n = 67; 52 male) versus placebo (n = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl-1 and ≤2,000 mg dl-1). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo -43.7%, 95% confidence interval (CI): -57.1%, -30.3%; P < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (-10.5% and -18.3% for pooled doses compared to 1.1% and -0.6% for placebo (95% CI: -21.5%, -2.0%; P = 0.019 and 95% CI: -30.7%, -5.1%; P = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment (n = 17) versus placebo (n = 6; -42.2% pooled pegozafermin, -8.3% placebo; 95% CI: -60.9%, -8.7%; P = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186).

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Conflict of interest statement

D.L.B. serves on the following Advisory Boards—AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences and Stasys. D.L.B. is on the Board of Directors of the following—Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care and TobeSoft. D.L.B. is the Inaugural Chair of the American Heart Association Quality Oversight Committee. D.L.B. is a Consultant at Broadview Ventures and Hims. D.L.B. is on the following Data Monitoring Committees—Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial). D.L.B. has received the following Honoraria—American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees) and Wiley (steering committee). Additional disclosures for D.L.B. include Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent—Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); Research Funding—Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89bio Inc.; Royalties—Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator—Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee—American College of Cardiology; Unfunded Research—FlowCo and Takeda. H.E.B. reports the following competing interests: Consulting Fee—89bio Inc., Amgen, Esperion; Research Support—89bio Inc., Akcea, Allergan, Alon Medtech/Epitomee, Amgen, Anji Pharma, AstraZeneca, Axsome, BioHaven, Bionime, Boehringer Ingelheim, CinCor, Civi, CSL Behring, Eli Lilly, Esperion, Evidera, Gan and Lee, Home Access, Lexicon, Matinas, Merck, Metavant, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Satsuma, Selecta and TIMI; Speaker Bureau; E.M.M.: Advisory Board Member and Consulting fees—Amarin and 89bio Inc. J.E.C.III: has no disclosures to report. K.W. has no disclosures to report. N.S.A. has no disclosures to report. The following are employees of 89bio Inc., and may own stock: T.P., S.F., L.S., L.T., C.L.H., G.D.A. and H.M. J.J.P.K. reports the following competing interests: Consulting Fee—CIVI Biotechnology, Cincor, CSL Behring, Draupnir, Esperion, Inversago, Madrigal Pharmaceuticals, North Sea Therapeutics, Novartis, Regeneron, RegenXBio, Scribe therapeutics, Staten Biotech, and 89bio Inc.; Omeicos part-time employee: NewAmsterdam Pharma.

Figures

Fig. 1
Fig. 1. Patient flow diagram.
CONSORT flow diagram showing participant disposition and data analysis sets, including reasons for discontinuation. Of the 85 participants treated, 75 (88.2%; n = 59 in pegozafermin and n = 16 in placebo) completed treatment. QW, once-weekly; Q2W, once every 2 weeks.
Fig. 2
Fig. 2. Effect of pegozafermin on serum TGs.
a, Median percent change in TGs from baseline to week 8 (the primary endpoint). b, Proportion of participants who achieved TG responses of <500 mg dl−1, <150 mg dl−1 or a ≥ 50% reduction from baseline to week 8. c–f, TG subgroup analysis among participants (not on background LMT (c), on background LMT (d), without T2DM (e) and with T2DM (f). Data are based on the full analysis set population (defined as all randomized participants who received at least one dose of study treatment, had baseline and at least one postbaseline TG value) and analyzed using the van Elteren test for pooled pegozafermin groups and the Wilcoxon rank-sum test for individual pegozafermin dose groups. n represents independent participants examined at baseline and four postbaseline timepoints for TG-related graphs. All P values are two-sided and based on comparison to the placebo arm. PBO, placebo; PGZ, pegozafermin; QW, once weekly; Q2W, once every two weeks.
Fig. 3
Fig. 3. Effect of pegozafermin on serum lipids.
a–e, LS mean (±s.e.) or median (ApoC3) percent change in non-HDL-C (a), apolipoprotein B (b), apolipoprotein C3 (c), LDL-C (d) and HDL-C (e) from baseline to week 8. Data are based on the full analysis set population (defined as all randomized participants who received at least one dose of study treatment, had baseline and at least one postbaseline TG) and analyzed via MMRM. n represents independent participants examined at baseline and two postbaseline timepoints for lipid-related graphs. All P values are two-sided and based on comparison to the placebo arm. PBO, placebo; PGZ, pegozafermin; QW, once weekly; Q2W, once every two weeks.
Fig. 4
Fig. 4. Effect of pegozafermin on hepatic steatosis.
a, LS mean (±s.e.) percent change from baseline to week 8 in liver fat fraction assessed by MRI-PDFF. b, MRI-PDFF images depicting changes in liver fat fraction from representative participants with elevated baseline liver fat fraction defined as >25%. c, Proportion of participants who achieved liver fat normalization (that is, <5% by MRI-PDFF), ≥30% or ≥50% relative reduction in liver fat after 8 weeks. Data are based on full analysis set population (defined as all randomized participants who received at least one dose of study treatment, had baseline and at least one postbaseline TG) and analyzed using MMRM or the van Elteren test for pooled pegozafermin groups and Wilcoxon rank-sum test for individual pegozafermin dose groups. n represents independent participants examined at baseline and one postbaseline timepoint for liver fat graphs. All individual MRI-PDFF images in b were generated as 384 × 288 mm and color corrected to a common color scale to allow direct comparison across images. MRI-PDFF, magnetic resonance imaging whole liver proton density fat fraction; PBO, placebo; PGZ, pegozafermin, QW, once weekly; Q2W, once every two weeks.
Extended Data Fig. 1
Extended Data Fig. 1. Study design.
Study design showing the main study and fibrate cohorts as randomized. The 6-week screening period consisted of a 4-week medication/lifestyle stabilization period followed by a 1- to 2-week TG qualification period. EOS, end of study; EOT, end of treatment; MRI-PDFF, magnetic resonance imaging whole liver proton density fat fraction; TG, triglycerides; QW, once weekly; Q2W, once every 2 weeks.
Extended Data Fig. 2
Extended Data Fig. 2. Effect of pegozafermin on serum TGs by subgroup.
Shown are the 95% CIs for median differences. If the percentage of participants within a subgroup was less than 33% of the overall cohort (n < 6), only descriptive analysis is presented. LMT, lipid modifying therapy; PGZ, pegozafermin.
Extended Data Fig. 3
Extended Data Fig. 3. MRI-PDFF imaging.
MRI-PDFF images depicting liver fat fraction at baseline and at follow-up (~day 57) in all participants with available data (23 out of 24). Images were generated using a common color-scale for all participants.
Extended Data Fig. 4
Extended Data Fig. 4. Waterfall plot.
Waterfall plot showing the effect of pegozafermin on liver fat fraction assessed via MRI-PDFF. Data presented for individual participants showing relative change in liver fat from baseline to week 8. Per protocol, the week 8 follow-up MRI-PDFF assessment was to be completed within ±7 days of last dose of study drug, participants noted in asterisks (*) had follow-up MRI-PDFF performed >21 days from date of last dose. The dashed line represents a 30% reduction in liver fat which is commonly used to denote a meaningful change.
See this image and copyright information in PMC

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