Novel injectable agent lowers Lp(a) by more than 80% at 36 weeks
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Key takeaways:
- Zerlasiran lowered lipoprotein(a) by more than 80% at 36 weeks compared with placebo.
- The results were sustained at 60 weeks, and there were no serious adverse events related to the study drug.
CHICAGO — Zerlasiran, a novel injectable small interfering RNA molecule, lowered lipoprotein(a) by more than 80% compared with placebo at 36 weeks, according to the results of the ALPACAR trial.
The phase 2 ALPACAR trial, results of which were presented at the American Heart Association Scientific Sessions and simultaneously published in JAMA, included 178 patients (mean age, 63.7 years; 25.8% women) with an Lp(a) concentration of at least 125 mmol/L (median, 213 mmol/L) and stable atherosclerotic CVD who were randomly assigned to placebo or one of three regimens of zerlasiran, formerly known as SLN360 (Silence Therapeutics): 450 mg every 24 weeks, 300 mg every 16 weeks or 300 mg every 24 weeks.
‘A consistent reduction’
“Zerlasiran was able to lower lipoprotein(a) between 80% and 85%, time-averaged over 36 weeks of treatment, when given relatively infrequently, either every 16 weeks or 24 weeks, and it produced a consistent reduction with very little in the way of any adverse effects,” Healio | Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said in an interview.
Compared with the placebo group, the least-squares mean time-averaged percent change in Lp(a) concentration between baseline and week 36 was 85.6% in the zerlasiran 450 mg every 24 weeks group, 82.8% in the zerlasiran 300 mg every 16 weeks group and 81.3% in the zerlasiran 300 mg every 24 weeks group, Nissen said during the presentation.
All three zerlasiran groups had their Lp(a) lowered by at least 90% between baseline and 36 weeks, according to the researchers.
Compared with placebo, the zerlasiran groups had LDL reduced between 25.1% and 31.9% and apolipoprotein B reduced between 9.9% and 15% at 36 weeks, Nissen said during the presentation.
The results were similar at 48 weeks and 60 weeks, he said.
The most common treatment-emergent adverse events were headache and nasopharyngitis, and there were no serious adverse events deemed to be related to the study drug, Nissen said during the presentation.
CV outcomes trial may be next
“We have established the extent to which the doses lower lipoprotein(a), the magnitude of duration and effect,” Nissen told Healio. “Then it will be up to ... Silence Therapeutics to determine whether they want to proceed with a phase 3 cardiovascular outcome trial. The FDA has made it clear that they will only approve these new therapies for lipoprotein(a) if they show an effect on cardiovascular morbidity and/or mortality.
“These drugs, as they cross the finish line, will be the first time in history that we can treat this disorder that causes a lot of morbidity and mortality,” he told Healio. “They all have a different pattern of response. But overall, all of the nucleic acid-based therapies in development do a good job of lowering Lp(a), so they all have promise as potential agents. Essentially what we have here are five shots on goal with different therapies. What we hope is that one or more of them will reduce morbidity or mortality. If we can ... that is one of the most important developments of the decade.”
Reference:
For more information:
Steven E. Nissen, MD, MACC, can be reached at nissens@ccf.org.
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Nissen SE, et al. LBS.08. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
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