Short-Interfering RNA Infusion SLN360 Lowers Lp(a) in Cardiovascular-Risk Patients

Steve E. Nissen, MD

Short interfering RNA (siRNA) SLN360 was associated with a dose-dependent lowering of plasma lipoprotein(a) (Lp[a]) concentrations in patients without cardiovascular disease but increased Lp(a) levels that would indicate significantly high risk of cardiovascular disease, according to new phase 1 APOLLO trial data.

The findings, presented in a late-breaking session at the American College of Cardiology (ACC) 2022 Scientific Sessions in Washington, DC, this weekend, showed the investigative siRNA should be considered for further clinical investigation.

Led by Steve E. Nissen, MD, of the Cleveland Clinic Center for Clinical Research, investigators sought to assess any adverse events and tolerability associated with SLN360, designed to reduce the hepatic production of apolipoprotein(a) (apo[a]). They additionally observed treatment-associated changes in plasma Lp(a) concentrations in patients administered differing doses.

As they noted, Lp(a) concentration is a long-recognized genetically determined and independent risk factor for atherothrombotic cardiovascular disease—with previous research supporting a causal relationship between Lp(a) and patient risk of myocardial infarction, stroke, peripheral artery disease, and cardiovascular death.

“Patients with Lp(a) concentrations in the highest decile (approximately 350 nmol/L) have a lifetime risk of cardiovascular disease equivalent to those with familial hypercholesterolemia,” investigators wrote. “Elevated levels of Lp(a) also have been associated with aortic valve calcification, development and more rapid progression of aortic stenosis, and a higher rate of aortic valve replacement.”

While some available therapies have shown moderate impact on Lp(a) concentration lowering, including PCSK9 inhibitors, there are currently no drugs approved by the US Food and Drug Administration (FDA) for the direct treatment of elevated Lp(a). Recent research has focused on developing RNA-targeted therapies that could reduce hepatic production of apo(a) in order to reduce plasma concentrations of Lp(a)—including agents such as weekly infusion antisense oligonucleotide pelacarsen, which showed capability to reduce Lp(a) plasma concentration by up to 80%.

Nissen and colleagues assessed SLN360, an siRNA that targets the apo(a)-encoding LPA messenger RNA, binding and degrading it and theoretically reducing Lp(a) plasma concentration in treated patients. The team conducted APOLLO to determine the tolerability and associated Lp(a) concentrations in patients administered a single dose up to 150 days following administration.

The team conducted recruitment and analysis from 5 clinical research unit sites in the US, UK, and Australia. Eligible patients had Lp(a) concentrations of ≥150 nmol/L at screening and no clinically overt cardiovascular disease. The 32 participants in the phase 1 trial were randomized to either single-dose subcutaneous SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6) or 600 mg (n = 6), or placebo (n = 8).

Mean patient age was 50 years old, with 17 (53%) women. The team reported the following median baseline Lp(a) concentrations for each treatment arm:

• 30 mg SLN360: 171 nmol/L (IQR, 142 – 219)
• 100 mg SLN360: 217 nmol/L (IQR, 203 – 308)
• 300 mg SLN360: 285 nmol/L (IQR, 195 – 338)
• 600 mg SLN360: 231 nmol/L (IQR, 179 – 276)
• Placebo: 238 nmol/L (IQR, 203 – 308)

All 32 participants completed the trial. Investigators reported 2 serious adverse events in a single patient—including admission to the hospital for headaches following a COVId-19 vaccination, as well as later admission for complications of cholecystitis. Both were determined to be unrelated to SLN360.

Nissen and colleagues observed the following maximal median changes in Lp(a) for each treatment arm:

• 30 mg SLN360: -89 nmol/L (percent change, -46%)
• 100 mg SLN360: -185 nmol/L (-86%)
• 300 mg SLN360: -268 nmol/L (-96%)
• 600 mg SLN360: -227 nmol/L (-98%)
• Placebo: -20 nmol/L (-10%)

Indeed, the team stated that Lp(a) lowering was dose-dependent with single-dose SLN360, and persisted for 150 days post-administration. Low-grade injection site events were observed among patients, and an episode of 3-fold elevation in liver enzymes was observed in a patient who received 30 mg SLN360—temporarily associated with COVID-19 vaccination. However, all patients completed the trial, and further assessment will need to observe patients over a longer exposure time to better determine drug safety.

Nissen and colleagues concluded their assessment of the siRNA agent SLN360 supported further research into its efficacy and safety for lowering Lp(a) in elevated patients. If it were to reach its fullest potential of indicated use, it would currently be unmatched in available cardiovascular risk-reduction therapies.

“Plasma Lp(a) levels are genetically determined and are not influenced by lifestyle interventions, such as diet and exercise, that reduce low-density lipoprotein cholesterol and triglycerides or increase high-density lipoprotein cholesterol,” investigators wrote. “In the absence of an effective Lp(a)-lowering drug therapy, this risk factor has traditionally been considered essentially untreatable.”

The study, “Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels,” was published online in JAMA.