An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context
Summary: Background: Angiopoietin-like protein 4 (ANGPTL4) inhibition is a promising approach to manage atherogenic dyslipidaemia and residual atherosclerotic cardiovascular disease (ASCVD) risk. Human ANGPTL4 loss-of-function (LoF) is associated with reduced plasma triglyceride (TG), remnant chole...
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Elsevier
2025-07-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425001926 |
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| author | Beryl B. Cummings Page R. Bouchard Mark N. Milton Peter F. Moesta Vyas Ramanan John W. Trauger Eleftheria Maratos-Flier Andrei Voznesensky Igor Splawski Amitabh V. Nimonkar Keith DiPetrillo Daniel LaSala Meihui Pan Meghan M. Flaherty Francois Huet Sukhdeep K. Sahambi Jijun Dong Deborah Knee Regis Cebe Thomas Huber Joshua Lehrer-Graiwer Rebecca A. Juliano Ethan J. Weiss |
| author_facet | Beryl B. Cummings Page R. Bouchard Mark N. Milton Peter F. Moesta Vyas Ramanan John W. Trauger Eleftheria Maratos-Flier Andrei Voznesensky Igor Splawski Amitabh V. Nimonkar Keith DiPetrillo Daniel LaSala Meihui Pan Meghan M. Flaherty Francois Huet Sukhdeep K. Sahambi Jijun Dong Deborah Knee Regis Cebe Thomas Huber Joshua Lehrer-Graiwer Rebecca A. Juliano Ethan J. Weiss |
| author_sort | Beryl B. Cummings |
| collection | DOAJ |
| description | Summary: Background: Angiopoietin-like protein 4 (ANGPTL4) inhibition is a promising approach to manage atherogenic dyslipidaemia and residual atherosclerotic cardiovascular disease (ASCVD) risk. Human ANGPTL4 loss-of-function (LoF) is associated with reduced plasma triglyceride (TG), remnant cholesterol (RC), and apolipoprotein B (ApoB) levels, and lower risk of type 2 diabetes and ASCVD, without observable safety concerns. However, development of ANGPTL4 inhibitors has been stalled by adverse findings in Angptl4 knockout mice fed a high-saturated-fat diet (HSFD), which show lipid accumulation in mesenteric lymph nodes (MLNs), systemic inflammation, severe adverse clinical signs, and reduced survival. Methods: Here, we present the development and preclinical characterisation of MAR001, a humanised monoclonal ANGPTL4 inhibitor antibody. We assessed single-dose MAR001 efficacy in hypertriglyceridemic (HTG) non-human primates (NHPs, n = 4), and safety in two NHP toxicology studies: a 15-week subchronic study with a standard or HSFD (n = 36), and a 9-month chronic study exclusively on an HSFD (n = 24). Findings: In HTG monkeys, single-dose MAR001 treatment reduced plasma TG by up to 58%, non-high-density lipoprotein cholesterol by 38%, ApoB by 30%, and RC by 59%. In safety studies, MAR001 was well tolerated without clinically adverse findings with either diet. Animals fed an HSFD exhibited minimal to moderate foamy macrophage formation in MLNs, but importantly, these histological findings did not progress to degeneration, necrosis, inflammation, fibrosis, or other reactive changes, and with no evidence of systemic effects, including no evidence of systemic inflammation or clinical adverse signs. Interpretation: MAR001 improved plasma lipid profiles in NHPs without clinical adversity, even during prolonged HSFD feeding. The favourable NHP safety profile aligns with human ANGPTL4 LoF findings, and contrasts with the severe pathology in mouse knockout models on an HSFD. These findings supported MAR001 clinical studies reported in our concurrent publication, which demonstrated robust lipid improvements without lymphatic pathology. Overall, these findings support continued development of MAR001 as a promising new therapy for ASCVD risk reduction. Funding: Marea Therapeutics. |
| format | Article |
| id | doaj-art-e6325ea9ad144fc8aaadcb2ef54c092d |
| institution | OA Journals |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj-art-e6325ea9ad144fc8aaadcb2ef54c092d2025-08-20T02:05:07ZengElsevierEBioMedicine2352-39642025-07-0111710574810.1016/j.ebiom.2025.105748An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in contextBeryl B. Cummings0Page R. Bouchard1Mark N. Milton2Peter F. Moesta3Vyas Ramanan4John W. Trauger5Eleftheria Maratos-Flier6Andrei Voznesensky7Igor Splawski8Amitabh V. Nimonkar9Keith DiPetrillo10Daniel LaSala11Meihui Pan12Meghan M. Flaherty13Francois Huet14Sukhdeep K. Sahambi15Jijun Dong16Deborah Knee17Regis Cebe18Thomas Huber19Joshua Lehrer-Graiwer20Rebecca A. Juliano21Ethan J. Weiss22Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USAMarea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA; Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USAMarea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA; Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USAMarea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USAMarea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USANovartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USAMarea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USAMarea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USAMarea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA; Corresponding author.Summary: Background: Angiopoietin-like protein 4 (ANGPTL4) inhibition is a promising approach to manage atherogenic dyslipidaemia and residual atherosclerotic cardiovascular disease (ASCVD) risk. Human ANGPTL4 loss-of-function (LoF) is associated with reduced plasma triglyceride (TG), remnant cholesterol (RC), and apolipoprotein B (ApoB) levels, and lower risk of type 2 diabetes and ASCVD, without observable safety concerns. However, development of ANGPTL4 inhibitors has been stalled by adverse findings in Angptl4 knockout mice fed a high-saturated-fat diet (HSFD), which show lipid accumulation in mesenteric lymph nodes (MLNs), systemic inflammation, severe adverse clinical signs, and reduced survival. Methods: Here, we present the development and preclinical characterisation of MAR001, a humanised monoclonal ANGPTL4 inhibitor antibody. We assessed single-dose MAR001 efficacy in hypertriglyceridemic (HTG) non-human primates (NHPs, n = 4), and safety in two NHP toxicology studies: a 15-week subchronic study with a standard or HSFD (n = 36), and a 9-month chronic study exclusively on an HSFD (n = 24). Findings: In HTG monkeys, single-dose MAR001 treatment reduced plasma TG by up to 58%, non-high-density lipoprotein cholesterol by 38%, ApoB by 30%, and RC by 59%. In safety studies, MAR001 was well tolerated without clinically adverse findings with either diet. Animals fed an HSFD exhibited minimal to moderate foamy macrophage formation in MLNs, but importantly, these histological findings did not progress to degeneration, necrosis, inflammation, fibrosis, or other reactive changes, and with no evidence of systemic effects, including no evidence of systemic inflammation or clinical adverse signs. Interpretation: MAR001 improved plasma lipid profiles in NHPs without clinical adversity, even during prolonged HSFD feeding. The favourable NHP safety profile aligns with human ANGPTL4 LoF findings, and contrasts with the severe pathology in mouse knockout models on an HSFD. These findings supported MAR001 clinical studies reported in our concurrent publication, which demonstrated robust lipid improvements without lymphatic pathology. Overall, these findings support continued development of MAR001 as a promising new therapy for ASCVD risk reduction. Funding: Marea Therapeutics.http://www.sciencedirect.com/science/article/pii/S2352396425001926MAR001ANGPTL4TriglycerideRemnant cholesterolNon-human primatesSafety |
| spellingShingle | Beryl B. Cummings Page R. Bouchard Mark N. Milton Peter F. Moesta Vyas Ramanan John W. Trauger Eleftheria Maratos-Flier Andrei Voznesensky Igor Splawski Amitabh V. Nimonkar Keith DiPetrillo Daniel LaSala Meihui Pan Meghan M. Flaherty Francois Huet Sukhdeep K. Sahambi Jijun Dong Deborah Knee Regis Cebe Thomas Huber Joshua Lehrer-Graiwer Rebecca A. Juliano Ethan J. Weiss An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context EBioMedicine MAR001 ANGPTL4 Triglyceride Remnant cholesterol Non-human primates Safety |
| title | An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context |
| title_full | An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context |
| title_fullStr | An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context |
| title_full_unstemmed | An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context |
| title_short | An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context |
| title_sort | angptl4 inhibitory antibody safely improves lipid profiles in non human primatesresearch in context |
| topic | MAR001 ANGPTL4 Triglyceride Remnant cholesterol Non-human primates Safety |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425001926 |
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