Targeting Lp(a): therapeutic insights and novel developments

Targeting Lipoprotein(a), it's exciting. We've learned a lot about the impact of high Lp(a) on risk. Now the big question in the clinical mind is if we measure, if we recognize the risk, will we be able to attenuate the risk by optimal therapy?

Well, the first question before we actually address treatment is, do we know how much lowering of Lp(a) is required in order to achieve a clinically meaningful risk reduction? Well, there are several estimates which have tried to quantitate this issue. First one is from genetic data. If you look at very large genetic data sets, you can see that here the first estimate was actually that we might need as much as 200 nanomoles of Lp(a) lowering in order to achieve a risk reduction comparable to 1 millimolar of LDL. Later on, because the genetic data were predominantly in healthy primary prevention, the Danish groups actually looked in the Copenhagen studies, and they came with more moderate estimates, maybe 100 nanomoles, which would already give you a clinical meaningful--We need very large Lp(a) reductions, and the exact number is still out and waits for the trials.

What's currently available to lower Lp(a)? Well, not a lot. You can see that statins may even increase by 10% to 15% the Lp(a) concentration, not relevant, but they at least don't lower it. On the right, you can see that there are multiple agents which may have an impact on Lp(a), but eyeballing, you can see that none of them is very potent. I'll briefly discuss through the most important ones.

First, PCSK9 inhibition. We've learned a lot about the impact of PCSK9 on Lp(a) lowering. One of the most challenging and interesting findings was presented by Greg Schwartz and coworkers, where they reported the post hoc analyses of the ODYSSEY OUTCOME study, where they looked at the impact of alirocumab on Lp(a). Actually what they found is that as expected, PCSK9 antibody reduced Lp(a) modestly by 20%-25%, but if you look in the quartile distribution, you can see that the patients with the highest Lp(a) at baseline responded best to the beneficial impact of alirocumab. They showed the largest risk reduction. Now, there are two scenarios. One, because Lp(a) increases risk, the patients with the highest risk have the highest benefit. That's just a way of math, or a second one could be that the 20% to 25% risk reduction, Lp(a) reduction, may actually contribute to the benefit besides the potent LDL reduction offered by alirocumab. In a statistical analysis, they actually estimated that in fact the latter scenario may be true. Obviously, it's the statistical analysis on estimated true cholesterol, et cetera. There are drawbacks, but it may be that actually already a minute Lp(a) lowering does offer some benefit, we'll have to wait for the true outcome trials.

A second way to treat Lp(a) is predominantly performed in Germany, that's the lipoprotein apheresis. If Klaus Parhofer has a lot of patients where he performs Lp(a) apheresis in the high-risk patients, here you can see what happens to the Lp(a) concentration. We recognize the saw tooth phenomenon, so it's not a stable reduction, but there are several studies suggesting that indeed this lipoprotein apheresis which is not selective, so it's difficult to only attribute this to Lp(a) reduction, but there are some benefits, albeit non-placebo controlled trials, is some suggestion that indeed in very high-risk patients, Lp(a) apheresis may be beneficial.

Then there's some more novel data about CETP inhibition. These are data in progress from the ROSE study where one of the last surviving CETP inhibitors, the obicetrapib, they showed that not only does LDL decrease by 50% but also Lp(a) seems to decrease by 50%. This needs further validation and mechanistic studies, but if this is true, it might be very interesting for the future. Also, we will wait the ongoing PREVAIL Outcome Study to see how this translates to potential cardiovascular benefit.

Then, last but certainly not least, finally are highly selective potent interventions to really lower Lp(a) by substantial amounts but then we actually are talking about RNA-targeting strategies. RNA targeting is no longer new in cardiovascular medicine. We know the antisense mechanism seen on the right, which works in the nucleus. Then there's the siRNA, silencing RNA, which works in the cytoplasm. The antisense strategy in the HORIZON trial is far advanced. I'll briefly discuss that first. Here, you can see the antisense molecule, pelacarsen. Pelacarsen is linked to the GalNAc molecule, a sugar chain, which results in very rapid uptake by the liver. Not only is the antisense very selective, by linking it to sugar, it's also directly taken up by the liver where you further minimize the potential for unexpected side effects. One of the earliest studies published already in 2016 was where it was the second generation of this molecule, which showed that indeed the antisense for apo(a) gives you a very marked reduction of Lp(a) and was quite interesting to see that here we already showed that the inflammatory behavior of circulating white blood cells decreases if you decrease Lp(a), so yes, Lp(a) lowering does have a beneficial biological effect in patients. Further development made it more selective. Here, you can see that 20 milligrams every week or 80 milligrams once a month gives you an 80% reduction in Lp(a). This is actually the compound that's currently being studied in the HORIZON trial. HORIZON trial is a large cardiovascular outcome trial, fully enrolled, and the data are expected in 2025.

In parallel, other strategies are ongoing. That's the silencing RNA strategies. Here, you can see the double-strand silencing RNA going into the cytoplasms and not into the nucleus, and actually the guidance strand goes into the RNA-induced silencing complex. Now, this RISC complex is evolutionary well conserved, and the big advantage is that this guidance strand is very stable for a prolonged period of time, so you only need to administer this siRNA two to three times a year, offering clear advantages. The data on the silencing approach for Lp(a) is also very impressive. Here, you can see the Olpasiran data published by Koren in Nature Medicine, and you can see that a single administration gives a massive reduction in Lp(a) of more than 90% and look at the duration of this effect. Indeed, fully as predicted, you can see that one administration not only gives you a potent but also a very prolonged effect in Lp(a) lowering. Good part is also to see that it's very, very selective. There's no change in corrected LDL, only a minor reduction in ApoB, no change in HDL, so a very selective potent repression. The last molecule is also a silencing RNA. Also, they show similar data, very potent reduction after one single injection, more than 90%, and had prolonged effect. Active potent interventions are here to stay. Luckily again for the silencing RNA approach, very low adverse event rate and no worry signals.

In summary, targeting Lp(a) is getting very, very hot. We know now that in every patient having a cholesterol check we should measure Lp(a) because we need to know whether Lp(a) is increased, because this will have clinical consequences for the patient. The data genetically, observationally, and the incomplete interventional data all are very supportive of a beneficial effect of Lp(a) lowering on cardiovascular outcome. Now with the advent of the RNA-targeting strategies, we have highly selective potent ways of massively lowering Lp(a). We look forward to the outcome trials, which will hopefully show that we get a further potent suppression of cardiovascular residual risk in these patients.

Thank you for your attention.