Highlight
– MEDI6570, an antibody antagonist of LOX‑1, produced dose-dependent reductions in soluble LOX‑1 (sLOX‑1) and lowered IL‑6 at higher doses in patients with recent MI and elevated hsCRP.
– The randomized phase 2 GOLDILOX‑TIMI 69 trial (n=423) found no effect of MEDI6570 on the primary imaging endpoint — change in noncalcified plaque volume in the most diseased coronary segment (NCPVMD) — or on global noncalcified or low‑attenuation plaque volume.
– MEDI6570 was well tolerated with similar rates of serious adverse events to placebo; trial results emphasize the gap between favorable pharmacodynamic biomarker changes and absence of short‑term plaque regression on CT angiography.
Background — disease burden and rationale
Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. After myocardial infarction (MI), residual inflammation — commonly identified by persistent elevation of high‑sensitivity C‑reactive protein (hsCRP) — predicts recurrent events. Clinical trials targeting inflammation have shown that selective anti‑inflammatory strategies can reduce cardiovascular events (for example, canakinumab in CANTOS and low‑dose colchicine in COLCOT and LoDoCo2), validating inflammation as a therapeutic target in atherosclerosis and post‑MI care.
Lectin‑like oxidized low‑density lipoprotein receptor‑1 (LOX‑1) is a scavenger receptor expressed on vascular endothelium, macrophages and smooth muscle cells. LOX‑1 binds oxidized LDL (oxLDL) and mediates proinflammatory signalling, endothelial dysfunction and plaque instability in preclinical models. Soluble LOX‑1 (sLOX‑1), shed into the circulation, has been proposed both as a biomarker of vascular inflammation and as a pharmacodynamic readout of LOX‑1 blockade.
MEDI6570 is an antibody designed to antagonize LOX‑1. The GOLDILOX‑TIMI 69 trial tested whether antibody‑mediated LOX‑1 inhibition in patients with recent MI and residual inflammation would reduce coronary atherosclerotic plaque burden measured by coronary computed tomography angiography (CTA).
Study design
GOLDILOX‑TIMI 69 was a randomized, double‑blind, placebo‑controlled, dose‑finding phase 2 trial. Key features:
- Population: Adults 30–365 days post‑MI with residual inflammation defined as hsCRP ≥1 mg/L. 423 patients were randomized (75 women, 348 men).
- Intervention: Subcutaneous MEDI6570 at doses of 50 mg, 150 mg or 400 mg, or placebo, given every 4 weeks for 32 weeks.
- Primary endpoint: Change from baseline to end‑of‑treatment in noncalcified plaque volume in the most diseased coronary segment (NCPVMD) assessed by coronary CTA.
- Secondary endpoints: Global noncalcified plaque volume and low‑attenuation plaque volume on CTA. Exploratory endpoints included circulating free sLOX‑1 and inflammatory markers such as interleukin‑6 (IL‑6).
- Safety assessments: Adverse events, serious adverse events, and laboratory monitoring.
Key findings
Primary and imaging outcomes
After 32 weeks of therapy, MEDI6570 did not significantly change the primary imaging endpoint. Placebo‑adjusted differences in change in NCPVMD were not statistically significant at any MEDI6570 dose (all P > 0.05). Secondary imaging endpoints — global noncalcified plaque volume and low‑attenuation plaque volume — likewise showed no significant placebo‑adjusted reductions at any dose.
Biomarker and exploratory outcomes
MEDI6570 produced robust, dose‑dependent reductions in circulating free sLOX‑1 from baseline: placebo −44.8%, 50 mg −85.8%, 150 mg −94.0% and 400 mg −96.4%. Placebo‑adjusted comparisons for all active doses reached statistical significance (P < 0.001), supporting target engagement and a clear pharmacodynamic effect.
Inflammatory biomarkers responded variably. IL‑6 levels decreased slightly in the placebo arm (−2.9%) and 50 mg arm (−3.0%), and showed larger reductions with the 150 mg (−18.9%) and 400 mg (−21.5%) doses. Placebo‑adjusted reductions in IL‑6 were statistically significant at 150 mg and 400 mg (P < 0.05), indicating a downstream anti‑inflammatory signal at higher doses.
Safety
MEDI6570 was generally well tolerated. Rates of serious adverse events were similar between MEDI6570‑treated groups and placebo. No new safety signals of concern were reported in this trial.
Expert commentary — interpretation and limitations
The GOLDILOX‑TIMI 69 results are informative and instructive. They demonstrate that robust pharmacologic LOX‑1 inhibition with MEDI6570 can substantially lower circulating sLOX‑1 and reduce IL‑6, yet these biomarker changes did not translate to measurable short‑term reductions in coronary noncalcified plaque volume by CTA.
Several mechanistic and methodological explanations can account for these discordant results:
- Timing and biology: A 32‑week treatment window may be too short to expect measurable regression of established noncalcified plaque volume, even when anti‑inflammatory effects are present. Structural plaque remodeling and calcification dynamics occur over months to years.
- Endpoint sensitivity: Noncalcified plaque volume on CTA quantifies gross plaque burden but may be insensitive to biologically meaningful changes in plaque composition or vulnerability (for example, caps stability, macrophage content, necrotic core remodeling) that could reduce events without large volume changes. Low‑attenuation plaque is a surrogate for vulnerable plaque but may still miss subtle stabilizing effects.
- Patient selection: The study enrolled patients with residual inflammation post‑MI (hsCRP ≥1 mg/L), a reasonable high‑risk group, but heterogeneity in lipid‑lowering therapy, time since MI, and baseline plaque characteristics could dilute measurable treatment effects on imaging endpoints.
- Biomarker versus clinical effect: Reduction of circulating sLOX‑1 and IL‑6 confirms target engagement and downstream anti‑inflammatory signaling, but it remains unproven whether LOX‑1 blockade will reduce hard cardiovascular events. Prior trials show that biomarker improvement does not always predict clinical benefit unless the intervention addresses pathophysiologic mechanisms causally linked to events.
- Statistical power and effect size: While the trial was large for a phase 2 imaging study, the anticipated effect size may have been optimistic. Failure to detect an effect does not exclude smaller or clinically meaningful benefits that require larger or longer outcome trials to detect.
Compared with prior anti‑inflammatory cardiovascular trials, GOLDILOX‑TIMI 69 adds important nuance. CANTOS showed that IL‑1β inhibition reduced events without changing lipids, linking cytokine biology to outcomes. Colchicine trials (COLCOT, LoDoCo2) demonstrated modest event reductions with inexpensive therapy. MEDI6570 differs mechanistically — targeting a vascular scavenger receptor implicated in oxLDL signalling — and its lack of short‑term plaque regression suggests that LOX‑1 blockade may require a different outcome framework or combination strategies to show clinical benefit.
Implications for clinical practice and future research
For clinicians, GOLDILOX‑TIMI 69 does not support adopting anti‑LOX‑1 therapy to reduce coronary plaque volume in the short term after MI. However, the trial provides important pharmacodynamic and safety data that will inform future development:
- Soluble LOX‑1 appears to be a robust pharmacodynamic biomarker of target engagement for LOX‑1 antagonists.
- Higher doses produced larger reductions in IL‑6, suggesting dose‑dependent downstream anti‑inflammatory effects that may be relevant for event reduction.
- Future studies should consider longer durations, event‑driven designs, or alternative imaging and molecular endpoints (e.g., PET imaging of vascular inflammation, intravascular imaging for plaque microstructure) that may be more sensitive to biologically meaningful changes.
- Combination approaches (for example, LOX‑1 blockade plus potent lipid‑lowering or antiplatelet strategies) may be necessary to translate biomarker changes into reduced events.
Conclusion
The GOLDILOX‑TIMI 69 phase 2 trial shows that antibody‑mediated LOX‑1 inhibition with MEDI6570 achieves clear pharmacodynamic effects, lowering sLOX‑1 and, at higher doses, IL‑6, with an acceptable safety profile. Despite these promising biomarker data, MEDI6570 did not reduce noncalcified coronary plaque volume over 32 weeks in patients with residual inflammation after MI. These findings underscore the complexity of translating mechanistic and biomarker improvements into measurable structural plaque regression within a short timeframe, and they highlight the need for longer, adequately powered outcome trials and refined mechanistic endpoints to determine whether LOX‑1 blockade can reduce cardiovascular events.
Funding and clinicaltrials.gov
Trial registration: EudraCT 2020‑000840‑75. Funding and full trial protocol details are provided in the original publication (O’Donoghue et al., Nat Med 2025).
References
1) O’Donoghue ML, Morrow DA, Vavere AL, et al.; GOLDILOX‑TIMI 69 Trial Investigators. Antibody‑mediated LOX‑1 inhibition in patients with residual inflammation after myocardial infarction: a randomized phase 2 trial. Nat Med. 2025 Oct;31(10):3553–3559. doi:10.1038/s41591-025-03951-w. PMID: 40999229.
2) Ridker PM, Everett BM, Thuren T, et al.; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119–1131. doi:10.1056/NEJMoa1707914.
3) Tardif J‑C, Kouz S, Waters DD, et al.; COLCOT Investigators. Colchicine in Patients with a Recent Myocardial Infarction. N Engl J Med. 2019 Jun 20;381(26):2497–2505. doi:10.1056/NEJMoa1912388.
Author note
This article was written to interpret and contextualize the findings of the GOLDILOX‑TIMI 69 trial for clinical and scientific audiences. Readers should consult the original publication for full methodological and supplementary details.