<p>Drugs targeting PCSK9 and small interfering RNA (siRNA) are US Food and Drug Administration (FDA) approved for patients with elevated low-density lipoprotein (LDL) cholesterol. Several other PCSK9- and lipoprotein(a) (Lp[a])–targeted therapies remain under investigation, and researchers at the <strong>American College of Cardiology 74th Annual Scientific Session & Expo (ACC.25)</strong> presented data from some of these studies.</p> <p><br></p> <p><em>Following these presentations, featured expert Deepak L. Bhatt, MD, MPH, MBA, FACC, FAHA, FESC, MSCAI, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Rick Davis, MS, RPh. Clinical perspectives from Dr Bhatt on these findings are presented here.</em></p>

We know from many studies that long-term adherence to drugs such as statins, even in patients following myocardial infarction, is very poor. Registries have shown that fewer than 50% of patients in the secondary prevention setting remain on their statin at 2 years, and adherence is even worse in the primary prevention setting. So, the idea of long-acting therapies for LDL lowering, and now for Lp(a) lowering, is appealing.

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The FDA-approved, PCSK9-targeting monoclonal antibodies (mAbs) alirocumab and evolocumab reduce cardiovascular (CV) risk and also reduce Lp(a) levels modestly, providing an advantage in patients with both elevated LDL levels and elevated Lp(a) levels. The more recently FDA-approved therapy inclisiran is an siRNA targeting PCSK9 gene expression. It lowers LDL cholesterol like the mAb PCSK9 inhibitors, but with the advantage of being given every 6 months after the second dose instead of every 2 or 4 weeks. Inclisiran is an appealing therapy for patients who have difficulty adhering to daily pills or to an mAb injection every 2 or 4 weeks. In fact, research by Robert S. Rosenson, MD, and colleagues presented at ACC.25 was focused on the effect that improved adherence with inclisiran might have on CV events. An investigational siRNA, lepodisiran, is being studied as a potential Lp(a)-lowering drug. In the recently reported ALPACA trial evaluating lepodisiran, also presented at ACC.25, patients demonstrated a large reduction in Lp(a) levels. So, we can envision potentially giving such patients an siRNA to lower their LDL cholesterol and Lp(a) levels, with long-lasting effects and, hopefully, better treatment adherence than we are currently seeing.

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Pills could be a good option for patients who are unwilling to receive an injection, and, in addition to the injectable PCSK9 inhibitors, several oral PCSK9 inhibitors are being studied in phase 2 and 3 trials. In a featured clinical research session at ACC.25, research by Michael J. Koren, MD, FACC, and colleagues was presented from the PURSUIT trial, a phase 2 study of the investigational, once-daily, oral PCSK9 inhibitor AZD0780. There was an approximately 50% reduction in LDL cholesterol, and it appeared to have efficacy even with background statin therapy, including high-intensity statin therapy. Although a phase 3 trial is necessary, this appears to be another potential option for lowering LDL cholesterol. We are finding that these agents lower LDL cholesterol fairly well in patients who do not want to get an injection but are willing to take a pill every day, and oral PCSK9 inhibitors can fill that particular clinical need. I think that, eventually, there will be many different options for PCSK9 inhibitors that lower LDL and also provide some additional Lp(a) lowering. However, for patients with markedly elevated Lp(a) levels, that degree of Lp(a) lowering may not be enough.

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I think that results from CV outcomes trials are important to determine if there is an advantage to using the investigational oral therapies over the FDA-approved mAbs and siRNA. CV risk reduction in clinical trials does not always translate into the real world, though. In a clinical trial, if someone is receiving pills, there is infrastructure to promote adherence, but we know that in real life, this adherence to daily pills is not as good compared with adherence to injections, especially if they are given in a doctor’s office. For patients who are willing to receive an injection, mAbs offer the advantage of already having CV outcomes data from the FOURIER and ODYSSEY OUTCOMES trials, and the siRNA inclisiran has the advantage of dosing every 6 months to lower LDL cholesterol plus the promise of randomized outcomes trial data soon to come. However, for someone with an elevated Lp(a), a dedicated Lp(a)-lowering drug would still be needed, assuming that the CV outcomes trials show benefit.