Emergency icon Important Updates

In the first-in-human phase 1 trial of lepodisiran, a novel short-interfering RNA (siRNA) therapy, levels of lipoprotein(a) (Lp(a)) were reduced below the lowest limit of quantitation for nearly nine months. Steven Nissen, MD, summarizes these findings that were presented in a late-breaking science session at the American Heart Association Scientific Sessions 2023 and simultaneously published online in JAMA.

Subscribe:    Apple Podcasts    |    Podcast Addict    |    Buzzsprout    |    Spotify

Novel siRNA, Lepodisiran, Reduces Lipoprotein(a)

Podcast Transcript


Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Steven Nissen, MD:

I'm Dr. Steve Nissen. I am the Chief Academic Officer at the Heart, Vascular and Thoracic Institute within the Cleveland Clinic. Lipoprotein(a) is an important genetically determined risk factor for cardiovascular disease with no pharmacological treatments currently approved by regulatory authorities. The Lp(a) gene encodes for apolipoprotein(a), which is an essential component required for hepatic synthesis of lipoprotein(a). We studied lepodisiran, which is a short-interfering RNA designed to degrade the messenger RNA coding for apolipoprotein(a), thereby reducing translation of the Lp(a) gene.

Now, the study was performed in 48 participants with Lp(a) concentrations greater than 75 nanomoles per liter, which is the upper limit of normal. We studied six doses of four through 208 milligrams and placebo, and this is a subcutaneously administered drug. And we followed patients for 48 weeks. Of course, in Phase 1, one of the most important outcomes is safety, so we did collect treatment-emergent adverse effects in some safety laboratories. We also measured the effect of lipoprotein(a) serum concentrations through 337 days, or 48 weeks.

Now, the median Lp(a) for these patients was about 110 nanomoles per liter, clearly abnormal. What happened was the dose-dependent reduction in lipoprotein(a) over time. What was quite remarkable about the study is that by day 29, at the top dose of 608 milligrams, levels had dropped below the lower limit of quantitation, and they remained unmeasurable between day 29 and day 281. That's 9.4 months after administration. And even at 48 weeks, levels were still 94 percent below baseline. So, we were able to achieve nearly complete elimination of lipoprotein(a), and this reduction was long-lasting. There were no major adverse effects. Really, we saw virtually nothing except for a little bit of pain at injection sites that occurred in the treated patients, but also occurred in the placebo patients.

There were limitations of this study. It was a small, first-in-human Phase 1 trial. There were only 48 participants, and they did not have cardiovascular disease, so we can't comprehensively assess safety in such a small trial. Nonetheless, we think that we have established that this is a very potentially valuable addition to the therapeutic armamentarium, and there are many other, there are several other drugs of this type being developed for lipoprotein(a) with different approaches. The manuscript was published in JAMA, the Journal of the American Medical Association. It is available online.

So, in conclusion, after the 608-milligram dose, serum concentrations of lipoprotein(a) fell below the lower limit of quantitation for 9.4 months, and stayed more than 94 percent below baseline out to 48 weeks without any major safety issues. We think that this small study establishes the potential of lepodisiran to be effective as an once or twice-yearly therapy for elevated lipoprotein(a), a disorder suffered by 20 percent of the population that is responsible for considerable morbidity and mortality. Thank you very much.


Thank you for listening. We hope you enjoyed the podcast. We welcome your comments and feedback. Please contact us at heart@ccf.org. Like what you heard? Subscribe wherever you get your podcasts or listen at clevelandclinic.org/cardiacconsultpodcast.

Cardiac Consult

Cardiac Consult

A Cleveland Clinic podcast exploring heart, vascular and thoracic topics of interest to healthcare providers: medical and surgical treatments, diagnostic testing, medical conditions, and research, technology and practice issues.

More Cleveland Clinic Podcasts
Back to Top