Mechanistic Clinical Trial of PCSK9 Inhibition for AAA

After being informed about the study and its potential risks, all patients giving informed consent will undergo a baseline visit and be randomized to received either evolocumab 140mg subcutaneously or placebo. This baseline visit includes a vital signs assessment, laboratory tests, medical history and medication review, a pregnancy test (if applicable), and training on how to perform drug injections. Participants will receive 3 doses/autoinjectors of study drug or placebo and be instructed to perform injections every 14 days starting 5 weeks prior to their scheduled AAA repair. If the baseline assessment occurs 5 weeks prior to their scheduled AAA, the first injection will be performed during this visit. Participants will have the option of coming back to the site for injections 2 and 3 or perform these injections at home under telehealth supervision. At the time of open AAA repair, participants will repeat laboratory tests and have a sample of aneurysm tissue taken. Participants will then have a follow up phone call 4 weeks after AAA repair to assess for any adverse events. At the conclusion of the study investigators will examine gene expression and protein levels in the aortic tissue to determine the impact of LDL-C lowering with evolocumab.

• Evolocumab (Drug): See arm description.
• Placebo (Drug): See arm description.

Primary outcomes

• Interleukin (IL)-6 in myeloid derived monocytes/macrophages from in AAA tissue [AAA Repair (Week 5)]: IL-6 expression will be measured in myeloid cells in the aortic tissue specimens using single nucleus RNA sequencing and confirmed by whole tissue ELISA.

Secondary outcomes

• Matrix metalloproteinase (MMP)-9 in myeloid derived monocytes/macrophages from in AAA tissue [AAA Repair (Week 5)]: MMP-9 expression will be measured in myeloid cells in the aortic tissue specimens using single nucleus RNA sequencing and confirmed by whole tissue ELISA and immunofluorescence activity assays.
• Infiltrating immune cell composition and their activation/inflammatory states in AAA tissue [AAA Repair (Week 5)]: Relative numbers of infiltrating immune cell type and their activation/inflammatory state as measured by a combination of bulk and single nuclear RNA sequencing
• Smooth muscle composition of AAA tissue [AAA Repair (Week 5)]: The relative numbers of smooth muscle cells and their contractile/proliferative state as measured by a combination of bulk and single nucleus RNA sequencing

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Abdominal aortic aneurysm (AAA) requiring open surgical repair
2. Age > 18
3. Provision of signed and dated informed consent form
4. Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

1. Prior use of a PCSK9 inhibitor (evolocumab, alirocumab, inclisiran) within 6 months of the baseline visit
2. LDL-C < 40 mg/dL (within 3 months of baseline visit)
3. Known allergy to PCSK9 inhibitor
4. Aortic dissection
5. Vascular connective tissue disorders
6. Type I-III or V Thoraco-abdominal Aortic Aneurysm
7. Vasculitis or inflammatory aneurysm
8. Pregnant or lactating women
9. Poorly controlled diabetes (A1C > 10%)
10. Chronic kidney disease Stage 4/5 or End Stage Renal Disease (ESRD) on hemodialysis (HD)
11. Liver Disease (alanine transaminase \[ALT\] or aspartate aminotransferase \[ALT\] > 3.0 x upper limits of normal) (within 3 months of baseline visit)
12. Known latex or naturally rubber allergy
13. Treatment with another investigational product within 30 days or 5 half-lives of the investigation drug before consent (whichever is longer) that would have an impact on endpoints associated with this trial.
14. Any other condition that the Investigator feels prohibits participants' ability to comply with study or follow up.

• Scott Damrauer, MD, Principal investigator, University of Pennsylvania

NIH grants: R01HL166991