Proteomic changes associated with vupanorsen therapy in TRANSLATE-TIMI-70
R Bansal, A Bellavia, P Jarolim, J F Kuder, S Verma, W Wojakowski, M S Sabatine, B A Bergmark, D A Morrow, N A MarstonAbstract
Background
ANGPTL3 is a potential therapeutic target for reducing residual risk of cardiovascular events, with genetic evidence that supports a causal role in the progression of atherosclerosis. Vupanorsen is an injectable antisense oligonucleotide that inhibits synthesis of ANGPTL3. In the TRANSLATE-TIMI 70 trial,1 vupanorsen treatment significantly decreased non-HDL cholesterol and other lipid parameters compared with placebo over 24 weeks.
Purpose
To use multiplex protein profiling to characterize proteomic changes associated with ANGPTL3 inhibition by vupanorsen.
Methods
We analyzed 92 candidate biomarkers in samples collected at baseline and 24-week follow up among 221 patients who remained on investigational therapy. The Olink platform reports relative concentrations of each biomarker in the sample as a normalized protein expression value (NPX) in log2 units, where each unitary increase reflects a doubling in protein signal. We compared the change in proteomic profile between these timepoints across randomized treatment arms (combined vupanorsen vs. placebo). Multiplicity was addressed using a Benjamini-Hochberg correction for false discovery (adj P value <0.05). We used cubic splines to depict dose-response between selected markers and ANGPTL3 levels at week 24.
Results
8 biomarkers demonstrated significant placebo-adjusted changes with vupanorsen (Fig 1). In the placebo group, all significant biomarkers had minor (<5%) changes in expression signal relative to baseline, while 5 biomarkers had larger (>5%) changes relative to baseline in the treatment group only (Fig 2). These 5 were fibroblast growth factor 21 (FGF21), angiotensin-converting enzyme 2 (ACE2), interleukin-4 receptor subunit alpha (IL4RA), carbonic anhydrase 5A mitochondrial (CA5A), and 2-hydroxyacid oxidase 1 (HAOX1). Of these biomarkers, the changes in HAOX1 and CA5A demonstrated strong graded associations with the degree of ANGPTL3 inhibition.
Conclusions
A targeted proteomic approach identified a set of novel protein biomarkers associated with treatment using vupanorsen and the degree of ANGPTL3 inhibition . These proteins reflect physiological pathways related to cellular response to stress, small molecule transport, lipid and heme metabolism, and immune response. Future work exploring the relationship between these proteins and the ANGPTL3 pathway is warranted.Fig 1:Volcano plot vupanorsen biomarkersFig 2:Percent change 8 biomarkers