Lepodisiran and the Emerging Role of Oxidized Phospholipids in Lipoprotein(a) Risk

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Dr. Luke Laffin:

My name's Luke Laffin, and I'm a preventative cardiologist at Cleveland Clinic. It's my pleasure to have Dr. Steve Nissen join us today. We're going to talk today about an analysis of the ALPACA trial, and what it reveals about lepodisiran on oxidized phospholipids and lipoprotein(a). Dr. Nissen, why don't you tell us a little bit about what the ALPACA trial was and what lepodisiran is?

Dr. Steven Nissen:

So, lepodisiran is a very unusual small interfering RNA. It's a double-stranded RNA that has a tetra loop. The two strands are linked together by a loop structure. When tested in phase two, it produced profound reductions in lipoprotein(a) that extended out for a considerable period of time, really almost an entire year, but certainly for at least six months. The reductions were large, about 95% time average reductions out to six months or even out to a year with two injections. So, a very, very powerful small interfering RNA targeting lipoprotein(a), an important risk factor for atherosclerotic cardiovascular disease and aortic stenosis.

Dr. Luke Laffin:

So, what were the investigators, yourself among them, trying to look at when they did this analysis looking at oxidized phospholipids in addition to lipoprotein(a)? What's the interaction there and what's the point of this?

Dr. Steven Nissen:

Well, the issue here is: how is it that lipoprotein(a) is associated with these adverse cardiovascular outcomes? There's a lot of data to suggest that it's not necessarily entirely due to this lipid particle itself, but that it is due to some constituents of the lipid particle, namely oxidized phospholipids. There are data showing that oxidized phospholipids are associated with inflammation. Possibly, they're prothrombotic. They tend to be associated with development of aortic stenosis. All of the things that lipoprotein(a) does seem to be linked to the oxidized phospholipid content of the lipoprotein(a) particle.

Now, what we were looking at then in the phase two trial, which involved several hundred patients, and had shown us that we could reduce lipoprotein(a), was could we also reduce oxidized phospholipids? And were those reductions in parallel? Were they the same patients that got the reductions, different patients? Were they correlated?

It turns out that we got large reductions in oxidized phospholipids, again, extending out for many months. We measured at 240 days and 360 days, after injections at day 180 and day 360, and reductions were anywhere in the 80 to 90% range for the various forms of oxidized phospholipids.

Now, it's important to note that oxidized phospholipids are associated with two components of lipoprotein(a), apolipoprotein A and apolipoprotein B. Indeed, both sets of oxidized phospholipids associated with these lipoproteins were reduced in parallel, they were strongly correlated, and they show us the potential mechanism by which lepodisiran may reduce cardiovascular events.

Now, we are studying lepodisiran in a very large 17,300 patient phase three trial, now fully enrolled and due to be completed in the next couple of years. So, this hopefully tells us that we've got a very good opportunity here to show benefits, and we'll be able to link those benefits to the effect on oxidized phospholipids in the outcome trial, which will be the ultimate proof of whether oxidized phospholipids are in fact one of the major carriers in the lipoprotein(a) particle that is associated with increased cardiovascular risk.

Dr. Luke Laffin:

So, if trials such as the lepodisiran trial and other ongoing trials of Lp(a) lowering therapies, if they confirm its clinical benefits, so reduction of atherosclerotic cardiovascular disease events, how do you envision this really changing cardiovascular prevention over the next five to 10 years?

Dr. Steven Nissen:

Well, the lepodisiran phase three trial known as ACCLAIM is the first trial to include patients that both have existing cardiovascular disease and are at risk for cardiovascular disease. So, both primary and secondary prevention. If a trial like ACCLAIM is successful, then we will be able to take people earlier in life who have increased lipoprotein(a), and prevent first events. And we'll be able to take people that have had an event and hopefully prevent a second event. This is kind of the last frontier in lipid therapy. We really don't have anything right now for lipoprotein(a), and we're really eager to find this kind of therapy that works. 20% of the global population has elevated levels. This involves over a billion people on our planet that have this disorder, and we are very eager to find a solution that will help these patients prevent cardiovascular events.

Dr. Luke Laffin:

Both you and I still see patients regularly in clinic. Thinking about that, there's a lot of patients that are getting their lipoprotein(a) checked now, particularly with some of the new changes in the guidelines. Can you speak to that, Dr. Nissen?

Dr. Steven Nissen:

Well, the guidelines are now emphasizing measuring lipoprotein(a), and several guidelines around the world suggest that it be measured in everybody at least once in their lifetime. Unfortunately, we've got a long way to go. The fraction of the population that is having their lipoprotein(a) level measured is still relatively low. It is increasing due to good efforts at public education, but we have a long, long way to go.

Dr. Luke Laffin:

Yeah. I think there's just a lot of momentum around it right now, understanding one's cardiovascular risk and doing what we can, be it with lifestyle, diet and currently approved medicines. Then, if someone has something, for example, like elevated lipoprotein(a), getting involved in clinical trials as well. Do you have any other final take home messages for the cardiologists or other medical professionals listening?

Dr. Steven Nissen:

I do. My message is: in people at risk, for sure, measure lipoprotein(a). If they have an elevated level, treat every other risk factor, take it off the table. Get their LDL down, get their blood pressure down, make sure their diabetes is treated, get them down to a good body weight, and get them off the couch and exercising. That's what we can do for people right now.

Dr. Luke Laffin:

Well, I think I speak for all of cardiology, we're looking forward to the results of those phase three trials, and want to congratulate you on a really important publication about ALPACA and oxidized phospholipids and lipoprotein(a). Thanks very much, Dr. Nissen.

Dr. Steven Nissen:

Thank you.

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