Zerlasiran for the Treatment of Atherosclerotic Cardiovascular Disease—Reply

In Reply Ms Wu and colleagues raise the concern that use of PCSK9 inhibitors may have resulted in underestimation of the lipid-lowering effect of zerlasiran in our trial. 1We think this is highly unlikely.Although PCSK9 inhibitors slightly reduce lipoprotein(a), the trial protocol (posted with the article), required trial participants receiving lipid-modifying therapy at trial entry (including statins, PCSK9 inhibitors, and ezetimibe) to be taking a stable, maximum-tolerated regimen for a minimum of 8 weeks with no changes to existing regimens, and introduction of new lipid-modifying regimens was not permitted after screening. 1For monoclonal antibody PCSK9 inhibitors, a stable dose was defined as at least 4 doses at a consistent dose level.Given the requirement for stable background lipid-lowering therapies, the effects of zerlasiran on lipoprotein(a) reduction was not likely influenced by use of PCSK9 inhibitors.Wu and colleagues also question the effect of participants' sex on the zerlasiran trial results and point out that there were more male than female participants in the trial, with most female participants likely being postmenopausal.The authors are correct that most female participants in the zerlasiran trial were postmenopausal; only 2 participants were individuals of childbearing age.Increases in lipoprotein(a) concentrations have been reported following menopause in several studies. 2 Because of the moderate size of the current study, we intentionally did not prespecify analysis of subgroups, including differences in response to zerlasiran, by sex or menopausal status.Male and female individuals both have an increased risk of major cardiovascular events associated with elevated lipoprotein(a). 3It is likely that some trial participants were taking hormone therapy, which does reduce lipoprotein(a) concentrations.However, there is no evidence that responses to small-interfering RNA (siRNA) therapies differ by sex and at least 1 other siRNA reported nearly identical lowering of lipoprotein(a) in both male and female participants. 4The increased risk of elevated lipoprotein(a) does not appear to be influenced by hormone therapy. 3u and colleagues also suggest that the effect of genetic differences in response to this type of therapy should be explored.In a large study involving more than 500 000 participants in the UK, a genetic risk score strongly predicted lipoprotein(a) concentrations, but the genetic risk score did not provide incremental prognostic information. 5Nonetheless, we agree that genetic analyses are potentially valuable and should be performed in larger phase 3 cardiovascular outcome trials studying the effects of RNA interference therapies targeting lipoprotein(a). 5u and colleagues also raise the issue of the effect of elevated hsCRP on the response to zerlasiran.Studies examining the association between hsCRP levels and the effect of elevated lipoprotein(a) on cardiovascular outcomes have reported conflicting results. 6The zerlasiran trial cannot contribute to understanding the relationship between hsCRP and response to siRNA therapy.The population in the zerlasiran trial had low levels of hsCRP, with a median baseline hsCRP of less than 1.0 mg/L.The low level of hsCRP precludes analysis of the effect of zerlasiran in individuals with elevated inflammatory markers.