I am Dr steven Nissen. I am the chief academic officer of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic.

What is the importance behind the ALPACAR trial?

Well, first of all, the target is lipoprotein(a). And increasing amounts of research have linked elevated levels of lipoprotein(a) to two disorders, atherosclerotic cardiovascular disease and aortic stenosis. It's been an untreatable disorder for decades, and now with some contemporary science, it's treatable. And so there are a series of nucleic acid-based therapeutics, that's either DNA or RNA-based therapies, that can lower lipoprotein(a) by as much as 90%. And so having a treatment for an untreatable disorder is a very big deal.

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

So I'm reporting on the results of a phase two trial of 180 patients of a drug known as zerlasiran. This is a small interfering RNA that's given by injection to lower lipoprotein(a).

It's been studied in phase one, this is now the larger phase two, more definitive study to determine the best dose and dosing interval. We studied, there is a five-arm trial. We gave placebo every 24 or 16 weeks. We gave 450mg every 24 weeks. We gave 300 or 450mg every 16 weeks for several doses. And the question was, what was the most effective dosing regimen to go forward in phase three?

What were the key findings?

Well, first of all, the people we studied were typical patients with atherosclerotic cardiovascular disease. Their mean or median lipoprotein(a) levels were quite elevated, between 200 and 250nmol/L. A mixture of men and women, some black patients, although not many. Very important to have black patients because blacks or African Americans have higher levels of lipoprotein(a) than whites, about twice as high.

What we found, of course, the placebo didn't do anything, but the 450mg every 24 weeks and 300 or 450mg every 16 weeks produced a time average reduction in lipoprotein(a) of between 80 and 85%. So very effective knockdown of serum levels of lipoprotein(a). This now tells us that we can give this drug in phase three relatively infrequently. We can give it every 16 or perhaps even 24 weeks.

The other interesting finding is that with each additional dose, levels went lower. There was a cumulative effect, and that's an important finding. The other thing about phase two is you always want to have data on safety and the drug proved very safe. There were really no significant treatment-emergent adverse effects. We did see 5 to 10% of patients had transient injection site reactions during the first day after administration. That's true of every biologic, including vaccines. You get some pain or perhaps redness at the injection site, but otherwise very well tolerated. So we were very pleased.

One of the conclusions that I am telling the audience about is that we now need to find these patients, because therapies are coming. And I did a large study a few years ago that showed that only 13.9% of patients with atherosclerotic cardiovascular disease actually knew what their lipoprotein(a) level was. So we have this large group of people with a very serious disorder that don't know they have it. And we now have emerging therapies that are potentially going to reach approval in the next few years, but we have to find the patients.

What further research is needed in this area, and what are the next steps?

Well, the company that did this study, known as Silence Therapeutics, will now need to make a decision. Do they want to go forward with a very large phase three cardiovascular outcome trial, and how will they want to design that trial? As I'm sure everybody knows, these trials are big, they're very expensive. We needed to have phase two data that could give us a reliable dose and dosing interval, but now the big decision is whether they make the investment in a huge phase three trial, and I'm sure they will be considering that very carefully.