Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results
Background Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐af...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-02-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.122.027540 |
| _version_ | 1797672613068144640 |
|---|---|
| author | Andrea L. Vavere Marvin Sinsakul Emily L. Ongstad Ye Yang Vijayalakshmi Varma Christopher Jones Joanne Goodman Vincent F. S. Dubois Angelica L. Quartino Sotirios K. Karathanasis Liron Abuhatzira Anna Collén Charalambos Antoniades Michael J. Koren Ruchi Gupta Richard T. George |
| author_facet | Andrea L. Vavere Marvin Sinsakul Emily L. Ongstad Ye Yang Vijayalakshmi Varma Christopher Jones Joanne Goodman Vincent F. S. Dubois Angelica L. Quartino Sotirios K. Karathanasis Liron Abuhatzira Anna Collén Charalambos Antoniades Michael J. Koren Ruchi Gupta Richard T. George |
| author_sort | Andrea L. Vavere |
| collection | DOAJ |
| description | Background Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐affinity monoclonal blocking antibody to LOX‐1. Methods and Results This phase 1, first‐in‐human, placebo‐controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX‐1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half‐life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target‐mediated drug disposition. Dose‐dependent reductions in mean soluble LOX‐1 levels from baseline were observed (>66% at 4 weeks and 71.61–82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (−13.45 mm3 versus −8.25 mm3). Conclusions MEDI6570 was well tolerated and demonstrated dose‐dependent soluble LOX‐1 suppression and a pharmacokinetic profile consistent with once‐monthly dosing. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT03654313. |
| first_indexed | 2024-03-11T21:33:43Z |
| format | Article |
| id | doaj.art-4606a5cf507d406c8be0c7a8b37627a3 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-11T21:33:43Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-4606a5cf507d406c8be0c7a8b37627a32023-09-27T06:42:27ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-02-0112310.1161/JAHA.122.027540Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 ResultsAndrea L. Vavere0Marvin Sinsakul1Emily L. Ongstad2Ye Yang3Vijayalakshmi Varma4Christopher Jones5Joanne Goodman6Vincent F. S. Dubois7Angelica L. Quartino8Sotirios K. Karathanasis9Liron Abuhatzira10Anna Collén11Charalambos Antoniades12Michael J. Koren13Ruchi Gupta14Richard T. George15Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USAEarly Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USABioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USAEarly CVRM Biometrics, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USAEarly Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USAClinical Pharmacology & Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg SwedenClinical Pharmacology & Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg SwedenClinical Pharmacology & Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg SwedenClinical Pharmacology & Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg SwedenBioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USAEarly Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USAProjects, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gothenburg SwedenDivision of Cardiovascular Medicine, Radcliffe Department of Medicine University of Oxford United KingdomJacksonville Center for Clinical Research (JCCR) Jacksonville FL USABioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USAEarly Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca Gaithersburg MD USABackground Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐affinity monoclonal blocking antibody to LOX‐1. Methods and Results This phase 1, first‐in‐human, placebo‐controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX‐1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half‐life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target‐mediated drug disposition. Dose‐dependent reductions in mean soluble LOX‐1 levels from baseline were observed (>66% at 4 weeks and 71.61–82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (−13.45 mm3 versus −8.25 mm3). Conclusions MEDI6570 was well tolerated and demonstrated dose‐dependent soluble LOX‐1 suppression and a pharmacokinetic profile consistent with once‐monthly dosing. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT03654313.https://www.ahajournals.org/doi/10.1161/JAHA.122.027540atherosclerosiscardiovascular diseasecoronary CTAdiabetesLOX‐1 |
| spellingShingle | Andrea L. Vavere Marvin Sinsakul Emily L. Ongstad Ye Yang Vijayalakshmi Varma Christopher Jones Joanne Goodman Vincent F. S. Dubois Angelica L. Quartino Sotirios K. Karathanasis Liron Abuhatzira Anna Collén Charalambos Antoniades Michael J. Koren Ruchi Gupta Richard T. George Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atherosclerosis cardiovascular disease coronary CTA diabetes LOX‐1 |
| title | Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results |
| title_full | Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results |
| title_fullStr | Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results |
| title_full_unstemmed | Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results |
| title_short | Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results |
| title_sort | lectin like oxidized low density lipoprotein receptor 1 inhibition in type 2 diabetes phase 1 results |
| topic | atherosclerosis cardiovascular disease coronary CTA diabetes LOX‐1 |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.027540 |
| work_keys_str_mv | AT andrealvavere lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT marvinsinsakul lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT emilylongstad lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT yeyang lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT vijayalakshmivarma lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT christopherjones lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT joannegoodman lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT vincentfsdubois lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT angelicalquartino lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT sotirioskkarathanasis lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT lironabuhatzira lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT annacollen lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT charalambosantoniades lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT michaeljkoren lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT ruchigupta lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results AT richardtgeorge lectinlikeoxidizedlowdensitylipoproteinreceptor1inhibitionintype2diabetesphase1results |