Reduction in Lp(a) possible with siRNA therapy: APOLLO

By Leah Kosyakovsky, MD on

Key Points:

  • In the Phase I APOLLO study, patients without known ASCVD and elevated Lp(a) ≥150nmol/L were treated with a novel siRNA therapy (SLN360) in a single ascending dose study. The primary outcome was degree of Lp(a) reduction at 150 days. Secondary outcomes included assessment of changes in LDL-C, apoB, oxidized LDL, inflammatory markers, plasminogen, and pharmacokinetics.
  • Treatment with SLN360 resulted in a persistent 70-80% reduction in Lp(a) at 150 days in the higher dose regimens (300 and 600mg). A 20-30% reduction in LDL-C and apoB was also observed. Further trials are warranted to determine the effect of a multi-dose regimen as well as to determine potential impact on the development of ASCVD.

Lipoprotein(a) is a critical risk factor for atherosclerosis with no currently approved treatments. Recently, a novel treatment targeting translation of the LPA gene (a silencing RNA, or siRNA, labeled SLN360) has been developed. In a breaking presentation at the 2022 American College of Cardiology Conference today, Steven Nissen (Cleveland Clinic) and his team presented the results of the Phase I “A Single Ascending Dose Study of an siRNA Targeting Lipoprotein(a)” (APOLLO) Trial.

The APOLLO study (NCT04606602) was a single ascending dose study conducted across 5 centers in the US, UK, and Australia. Adult patients without known ASCVD and an Lp(a) level ≥150nmol/L were eligible. Some relevant exclusion criteria included BMI <18 or >45, cirrhosis, or use of other drug therapies which may alter Lp(a).

A total of 32 patients were randomized; 8 participants were assigned to each drug dose cohort (30mg, 100mg, 300mg, and 600mg); 2 patients per each SL360 drug dose cohort were assigned to placebo. All patients received 24 hours monitoring post dose administration and were followed for 150 days. The average age was 49.6; 47% were male. The median Lp(a) was 224nmol/L.  The primary outcome was effect on Lp(a) concentration at 150 days from baseline. A dose-dependent lowering of Lp(a) was observed, with a 70% reduction at 150days with 300mg and 81% reduction with 600mg. This reduction was even more profound at day 60 in the 600mg group, with up to 98% reduction in Lp(a) at that timepoint. Secondary outcomes included effects on LDL-C, apoB, oxidized LDL, inflammatory markers, plasminogen, and pharmacokinetics. LDL-C was modestly lowered at both 300 and 600mg doses (21% maximally at 45 days in the 300mg group, and 26% at 90 days in the 600mg group). Apo-B had a similar degree of reduction (21% and 24% respectively). From a safety perspective, only 2 adverse events occurred, none of which were judged to be secondary to the medication itself; otherwise, only transient injection site reactions occurred.

When discussing the implications of the study in a press interview with the ACC, Dr. Nissen stated: “Lipoprotein(a) is the last frontier in lipids…multiple therapies are moving forward and showing very strong efficacy at reducing levels of lipoprotein(a). We hope they will also be shown to reduce the consequences of elevated lipoprotein(a) in ongoing studies.”

The full manuscript is available in JAMA now.