Effects of IPE on Inflammatory Biomarkers in Patients With COVID-19

Transcript:

Deepak Bhatt, MD, MPH: What do you think about platelet adhesion and mechanisms targeting that mechanism of action in thrombosis? Do you have any feeling about whether that’s worth studying in COVID-19 [coronavirus disease 2019]?

C. Michael Gibson, MS, MD: You and I both talked a lot about antiplatelets. I always refer to the 3 As, Deepak. There’s activation, and there’s aggregation that our common drugs focus on. But before all that, there’s adhesion when the platelet lands on a damaged endothelial cell. It has a tail hook, and the platelet grabs on to von Willebrand factor. There are some von Willebrand factor inhibitors coming along that could block the platelet from landing on the endothelium, and this might be the time for some of those agents to get tested and to begin to be used. Some good things can come out of a pandemic as well. It can create the selection pressure for newer approaches to the same old problem.

Deepak Bhatt, MD, MPH: I’m optimistic about those agents, though I must say that I have been for years. I’ve always been a little surprised why they didn’t come out with something in that class sooner.

C. Michael Gibson, MS, MD: We tried once in ACS [acute coronary syndrome], and it was an aptamer. The aptamer caused complement activation and hypersensitivity, but there are some new generations. They’re going to take another shot at it.

Deepak Bhatt, MD, MPH: It’s definitely worth taking a shot. It could help uncouple, as no agent has done yet, the ischemic and bleeding risk: reducing thrombotic complications without raising systemic bleeding excessively. I’m excited about that.

We talked a bit about statins already and the observational data potentially showing associations with better outcomes in COVID-19 patients. There are potentially all sorts of measures confounding there. The fact remains that patients with cardiovascular risk should be on statins anyway irrespective of COVID-19 status but perhaps especially if they’ve already survived COVID-19. There has been some work showing that there is cholesterol in cell membranes that might help the coronavirus get inside, and that may provide a mechanistic underpinning for some of these observational data. Maybe it’s just spurious confounding. One thing that I’m not sure you and I have chatted about has to do with icosapent ethyl [IPE]. That is something you were quite involved in, the REDUCE-IT trial, leading the clinical events committee of that study. There, we showed that, in people with elevated triglycerides, icosapent ethyl substantially reduced cardiovascular risk.

What you may not be aware of is that a relatively recent pilot study has started in Toronto looking at icosapent ethyl and its effects on cardiovascular biomarkers. It’s a planned 100 or so patients, assuming that the surge continues in Toronto, but that’s at least the goal: about 100 or so patients who are randomized to receive icosapent ethyl or not. It’s an open-label trial, so icosapent ethyl or no icosapent ethyl, and there is an assessment of inflammatory markers at 2 weeks including things like high-sensitivity C-reactive protein. That is looking at COVID-19–positive patients, but it will be an assessment of icosapent ethyl and its effects on inflammatory biomarkers earlier than anyone has ever looked as far as I know.

We know that IPE reduces various inflammatory biomarkers at about 12 weeks and later time points, but no one has actually, to my knowledge at least, looked that early at 2 weeks. It’ll be interesting, in addition to the COVID-19–positive aspect, to see if there is an early effect on biomarkers from icosapent ethyl. It’s also studying a loading dose for the first time. The usual dose is a total dose of 4 g a day: 2 g twice a day with meals. The dose that’s being studied here is a loading dose for the first 3 days of 8 g per day total, so it’s twice the usual dosing regimen. It could be insightful to see how well tolerated that loading dose is, not just for COVID-19 purposes. Maybe it’ll pan out in COVID-19; maybe it won’t.

Potentially, if the loading dose is safe and well tolerated, it could be used as a loading dose in acute MI [myocardial infarction], in acute stroke, and in acute revascularization procedures. Those types of patients were, in fact, included in REDUCE-IT in terms of stable patients. I’m talking about initiation at the time of the ischemic event, revascularization, or perhaps other indications that I’ve not even considered where a loading dose might be felt to be theoretically useful. It opens the door for lots of other potential future studies of icosapent ethyl, having nothing to do with COVID-19. What are your thoughts about this line of investigation?

C. Michael Gibson, MS, MD: I said it before, Deepak, so I’ll say it again: The data that you showed relating IPE levels themselves to outcomes, for me, was probably 1 of the most provocative findings from your trial. If this is a disease of the endothelium, if this is an inflammatory response, and if this drug does do what I think it does–many people think it reduces some of that vascular inflammation—then this could be very effective in the COVID-19 patient.

You and I talked about how it’s not just the inflammation; it’s the nexus of the inflammation and the thrombosis. If you could reduce inflammation, you could probably further reduce thrombosis as well. I hadn’t heard this; I’d heard about it a bit, but I didn’t know the details. I’m excited about it, and I can’t wait to see what you guys find.

Deepak Bhatt, MD, MPH: I know enrollment just started a couple of weeks ago, so it’s still pretty early. Even if it turns out that there isn’t an effect on COVID-19–positive parameters per se, a lot of good science could be generated that is useful for further study of that compound in a variety of disease states.

C. Michael Gibson, MS, MD: That’s fascinating. I hope you’ll do some more things outside COVID-19 too. It’s exciting.

Deepak Bhatt, MD, MPH: There are other people and other regions of the world looking at things like inflammatory bowel disease, metastatic colon cancer, and dementia. There are other things going on with that particular drug, so it’ll be interesting to see. Certainly, in REDUCE-IT, we showed safety that was quite good and tolerability that was quite good beyond the cardiovascular benefits in that specific population. Perhaps the safety findings are useful when considering studying in other populations too.

Transcript Edited for Clarity