My name is Sanjiv Shah and I'm a heart failure cardiologist here in Chicago at Northwestern University.

What is the importance behind the ENDEAVOR trial?

The ENDEAVOR trial is really trying to modulate the immune system in HFpEF, reduce inflammation. And that's something that's been one of our main key goals for the last several years. We think that HFpEF, heart failure with preserved EF, really stems from comorbidities causing inflammation which then stresses the endothelium in multiple organs, causes microvascular dysfunction, and that the inflammation is really driving the pathogenesis of the syndrome and causing the cardiac dysfunction as well. So it's really the biggest trial to date that is testing an immune mediating, anti-inflammatory therapy or HfpEF.

Could you tell us about the mechanism of action behind mitiperstat?

Yeah. Mitiperstat is a myeloperoxidase inhibitor. And so what it does is it inhibits myeloperoxidase that is secreted by neutrophils. So normally we need this as part of our body's defense mechanism, our earliest or innate immune system defense against microbes, pathogens. But we think that in HFpEF, it's overdone. There's too much of this myeloperoxidase. It gets trapped in the, it gets trapped in the vascular wall and then that is where it causes damage, this sort of oxidative stress on the microvasculature and other cells.

What was the study design and patient population?

Yeah, the ENDEAVOR study was an international, randomized, double blind, controlled trial. It had three groups: mitiperstat 2.5mg, a lower dose; mitiperstat 5mg, a higher dose; and placebo. 709 total patients were randomized 1:1:1 in the three groups, and the primary outcome was KCCQ, total symptom score, and 6 minute walk distance at 16 weeks. But patients were treated for a full 48 weeks. And we followed them for heart failure hospitalisations, cardiovascular death, and a whole host of other parameters such as echocardiography, NT-proBNP, etc.

What were the key findings?

Well, contrary to our hypothesis that at 16 weeks it would improve both exercise function and symptoms, it was totally neutral on those endpoints. We looked as a pooled group together, both doses of mitiperstat individually, and we did not see any change. In addition, we looked at 24, 48 weeks as well. No change in those outcomes, no real reduction in NT-proBNP, and no change in cardiac structure and function. So we were quite disappointed in those results.

However, there was nearly a 35 to 40% reduction in heart failure hospitalisation over the 48 week trial. So that really was quite promising. Now it wasn't statistically, significantly different. There were not enough events, but certainly trend was there. And when we look at heart failure hospitalisation and death, all-cause death, similar trends. And so it's really a marked reduction in heart failure events. And really now we have to just understand was this a chance finding or is it real?

And we did a detailed proteomics analysis where we measured almost 3,000 proteins at baseline and at 16 weeks and looked at the change between the groups. And that's a big part of the story because that proteomic data I think support the reduction in heart failure hospitalisations because we're lowering the risk of the proteins that are normally associated with heart failure events. They're no longer associated with heart failure events. And we do a number of additional analyses to kind of show that the changing of the proteome with the drug compared to placebo is indicative of a more protective benefit for heart failure events.

What further research is needed in this area?

Yeah, I think it remains to be seen. I really hope that we're able to study it further and look at the effect of myeloperoxidase inhibition in a larger trial to reduce heart failure events. You know, for SGLT2 inhibitors, which we no longer question, it's a definitive therapy per HFpEF.

Had we done a phase two trial, it would have been neutral. And so we know that SGLT2 inhibitors work. And there's nothing to say that this also, you know, even though it doesn't improve 6 minute walk distance or KCCQ, it still very well may be an important drug for HFpEF. So I think a larger trial, but also we plan to do several analyses, take a deep dive into the ENDEAVOR data to figure out is there a specific responder subgroup and learn more about the drug and its effect.