The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.
Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45 to 60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.
Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-mg and 600-mg doses.
In addition, for participants receiving the two highest doses, ApoB was reduced was 21% and 24%, respectively, and low-density-lipoprotein cholesterol (LDL-C), by 21% and 26%, respectively.
The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted,” said principal investigator Steven E. Nissen, MD, Cleveland Clinic, Ohio.
The results were presented in a late-breaking clinical trial session at the American College of Cardiology (ACC) 2022 Scientific Session and published simultaneously in the Journal of the American Medical Association.
Elevated Lp(a) is a powerful genetic risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).
SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.
Testing Vacuum
Nissen told that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.
“Someone comes in with an MI in their forties and we measure it and it’s 100, 150 (mg/dL), clearly abnormal, and often these patients don’t have a lot of other risk factors,” Nissen said. “So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it.”
During a media briefing, ACC.22 program co-chair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won’t be reimbursed because they don’t understand it.
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