Pelacarsen

In your story, you refer to the press release heard around the world.

So in early September, drug manufacturer Novartis announced that its promising lipoprotein A, or Lp little a-lowering candidate called pelacarsen, failed to prevent major adverse cardiovascular events in a phase III trial of participants with cardiovascular disease.

So before we get into the trial, what is Lp little a and why is it important?

Right.

But what happened in the trial?

Well, we don't know the full results yet.

So far, there's only been the press release from Novartis, which said that although pelacarsen did reduce Lp little a levels, the findings did not demonstrate that this translated into reduced cardiovascular risk in the overall study population.

For many, this is a huge disappointment.

But, you know, somebody has LP... elevated Lp(a) for sixty years, uh, they've accumulated a lot of damage.

So when Pelacarsen missed its endpoint, yeah, it left questions about did the antisense modulate Lp(a) enough and for long enough? But there's this other question, too, of how much risk through this pathway can you really kind of take out of the disease at this point? And the gap I think I'm kind of interested in is the modeling one.

Like, what does it take for the field to sort of precisely model how much benefit is still left to be, to be gained from a particular pathway at a particular stage of disease?

So, so wouldn't that also, talk about modeling, raise a question of whether we get to a place where people can be confident about models about early, much, much earlier intervention? So, you know, it's not practical to do an intervention in somebody when they're very young that's expected to have an impact on them when they get to be old.

If it meets all the, you know, pre-specified criteria, we'll probably know that towards the end of the first quarter of next year.

That's one to watch.

The other thing to watch for is really the full Pelacarsen dataset, right?

Mm-hmm.

It lowered, uh, Lp(a) by eighty-six percent in phase two, and it's now in phase three outcomes trial.

The Pelacarsen result raises the bar for all of them, but the deeper reductions and the inclusion of earlier-stage patients mean that these are genuinely different experiments.

And I think that this is the part most people are gonna wanna screenshot.

So someone gets their labs back, and Lp(a) is flagged as high.

They were given monthly injection of pelacarsen, 80 milligrams for a placebo.

They were followed for about six years.

Pelacarsen's mechanism in action is interesting because it is an ASO, an antisense oligonucleotide, goes directly into the hepatocytes.

So it's fairly clean, decreased the LP levels by 80%, and at the end of the day, we got the top-line results that it was a neutral trial.

And so the big question now is where do we go from here? Why, why do we think this happened, and what can we learn from this?

So let's go to our next question.

Which lipid fraction do pelacarsen and olpasirin reduce? Is it LDL-C? Is it lipoprotein A? Is it non-HDL-C? Is it triglyceride? Or I am not sure.

The correct answer is pelacarsen and olpasirin reduce lipoprotein A.

So let's talk about some of the therapies that are in late-stage clinical trials for lipoprotein A.

And we have different categories.

One of them is pelacarsen, which is an antisense oligonucleotide that prevents synthesis of lipoprotein A.

Then we have small interfering RNAs, including olpasirin, zurlasirin, lepodisiran, that really work at the messenger RNA level and reduce synthesis of lipoprotein A.

Then we have an oral small molecule, uh, molvolapolin That hinders the interaction between ApoA and ApoB100 and prevents the assembly of lipoprotein A.

[upbeat music] Welcome to the NACE Journal Club, where every month we go over some of the most important articles to come out in the medical literature relevant to primary care.

I'm Dr. Neil Skolnik, and this month, again, we have an exciting group of articles, beginning with top-line results for pelacarsen in patients with elevated Lp(a) and established cardiovascular disease.

This is one of those earth-shaking results.

Next, we're gonna discuss atorvastatin, cardiovascular events, and disability-free survival in older adults from the New England Journal of Medicine, addressing that question that we've all been asking for years.

Is giving statins to older people for primary prevention useful? And then we're gonna discuss an article that I think comes up every single day in the office, and it's an individual participant data meta-analysis.

Okay, that term is fancy, but what's important of how physical activity relates to mood in daily life, and that is from the journal Nature Human Behavior.

And to discuss our first topic, which is the top-line results for pelacarsen, an Lp(a) lowering medication in patients with elevated Lp(a) and established cardiovascular disease, is Dr. Alec Sauer, who is a resident at the Jefferson Health Abington Family Medicine Residency Program.

Alec, welcome to the NACE Podcast.