An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primatesResearch in context
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
Affiliations
Beryl B. Cummings
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA
Page R. Bouchard
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA; Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Mark N. Milton
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA; Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Peter F. Moesta
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA
Vyas Ramanan
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA
John W. Trauger
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Eleftheria Maratos-Flier
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Andrei Voznesensky
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Igor Splawski
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Amitabh V. Nimonkar
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Keith DiPetrillo
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Daniel LaSala
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Meihui Pan
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Meghan M. Flaherty
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Francois Huet
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Sukhdeep K. Sahambi
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Jijun Dong
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Deborah Knee
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Regis Cebe
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Thomas Huber
Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
Joshua Lehrer-Graiwer
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA
Rebecca A. Juliano
Marea Therapeutics, 131 Oyster Point Boulevard, South San Francisco, CA, 94080, USA
Ethan J. Weiss
Marea 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.
