Video
ACC 2025: ALPACA Phase 2: Lepodisiran, an Extended Duration Small-interfering RNA Targeting Lipoprotein(a)
Published: 30 Mar 2025
-
Views:
91
-
Likes:
0
Average (ratings)
No ratings
ACC 2025 - 540-day follow up of lepodisiran in patients with elevated lipoprotein(a) (Lp(A)) shows the extended duration of action of lepodisiran will allow infrequent dosing in the ongoing cardiovascular outcome trial.
Dr Steven Nissen (Cleveland Clinic, Cleveland, US) joins us onsite at ACC to discuss the ALPACA phase 2 trial (NCT05565742), investigating the safety and efficacy of lepodisiran, an extended duration small-interfering RNA for elevated lipoprotein(a). The primary outcome measure was the percent change from baseline in time averaged Lp(a).
Findings showed that lepodisiran reduced time-averaged Lp(a) by 93.9% from day 60 to 180 following a dose of 400mg with no major safety concerns. Lp(A) reduction from days 30 to 360 was 88.5% after a single dose, and 94.8% after 2 doses (at baseline and day 180). Lp(A) levels remained 53.4% below baseline at 540 days after a single dose, and 74.2% at 360 days following a second dose.
Interview Questions:
- What is the reasoning behind the ALPACA phase 2 trial?
- What was the study design and patient population?
- What were the key findings?
- What are the take-home messages for practice?
- What further research is needed in this area?
Recorded on-site at ACC in Chicago, 2025.
Editors: Yazmin Sadik, Jordan Rance
Videographers: Dan Brent, David Ben-Harosh
Support: This is an independent interview produced by Radcliffe Cardiology.
I'm Dr Steven Nissen. I am the Chief Academic Officer at the Heart, Vascular and Thoracic Institute at the Cleveland Clinic.
What is the reasoning behind the ALPACA phase 2 trial?
Lepodisiran, which is the drug we studied, is an unusual small interfering RNA that targets lipoprotein(a). It has a very long duration of action, and we needed to know how to dose this drug in phase three.
Phase three is actually underway, and we designed it in such a way that the results of the phase two trial would be used to inform the dose and dosing interval in the ongoing phase 3 trial.
What was the study design and patient population?
So we included people over the age of 40 who had a lipoprotein(a) level greater than 175 nanomoles per litre. We studied doses from 16 milligrammes to 400 milligrammes, and in the 400 milligramme dose group, we studied both a single dose of 400 milligrammes and two doses at 180 day intervals and then followed the patients out to 540 days.
What were the key findings?
The primary endpoint was the time-averaged reduction from day 60 to day 180. And we achieved a 93.9% reduction in lipoprotein(a) during that interval. But we also looked out to a year, and from 30 to 360 days there was an 88.5% reduction in lipoprotein(a). After two doses at a year, there was a 95% reduction and it was still reduced by 74% at 540 days. So a very durable effect on lipoprotein(a).
What are the take-home messages for practice?
Well, look, whenever you can have a drug that you need to give in frequently, adherence to the therapy is much better. And so a drug you can give twice or even once a year gives us a huge advantage over something you have to take more frequently. And so this design of this molecule that gives it a very durable effect is an important advance for patients because it makes it much more accessible and more likely to be used.
What further research is needed in this area?
We will, of course, have the phase three and that's underway and going very well. And we're going to look at the phase two carefully to see if we can identify who has the best response, who has the worst response, so that we can refine our understanding of how to use the drug when it eventually, hopefully, comes to market.
Comments