Short Interfering RNA Targeting Lipoprotein(a)
Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels.
Nissen SE, Wolski K, Balog C, et al.
JAMA. 2022 May 3;327(17):1679-1687. [Full text]
Summary by Avantika Banerjee
Lipoprotein (a), or Lp(a), is a cardiovascular risk factor that for which there are no approved treatments. It is genetically determined and largely unaffected by diet and lifestyle modification or statin therapy. Approximated 20% of the global population has an elevated Lp(a) > 60mg/dL.
Lp(a) produces a prothrombotic core LDL like particle called Apolipoprotein A (ApoA) that predisposes patients to atherosclerotic and atherothrombotic disease and is an independent risk factor for cardiovascular disease and aortic stenosis.
The LDA gene produces ApoA, the rate limiting step in the production of Lp(a). SLN-360 is a short 19 sequence interfering double stranded RNA that can be given subcutaneously and is conjugated to a N-acetyl-galactosamine (GalNAc). In a mechanism known as gene silencing, receptors in the liver uptake GalNAc and carry the short interfering RNA into hepatocytes where it splits into sense and antisense strands. The antisense strand combines with the mRNA produced from the LDA gene and degrades it, therefore inhibiting the translation to ApoA and ultimately the production of Lp(a). Described here is a phase 1 trial to assess the tolerability of SLN360 after a single dose.
Patient population and Design
This phase 1 trial is a single ascending dose study of SLN360 conducted at 5 clinical research sites located in the US, UK, and Australia. Participants were randomized in a single-blind fashion to placebo or a single subcutaneous dose of SLN360 of 30mg, 100mg, 300mg, or 600mg. The primary outcome was evaluation of safety and tolerability of the drug and the secondary outcome was the change in plasma concentration of Lp(a) at maximum follow up of 150 days.
The patient population was 32 adults over the age of 18 without history of atherosclerosis and with an elevated Lp(a) level >60mg/dL. Patients were required to have a Hgb A1C < 6.5% if without history of diabetes or < 8.5% if known to be a diabetic. Exclusion criteria were those with a history of severe hepatic cirrhosis, active HIV Hepatitis B or Hepatitis C infection, other liver disease predisposing to drug induced liver injury, elevated transaminases >1.5 the upper limit of normal, a platelet count below the lower limit of normal, a bilirubin greater than the upper level of normal if without Gilbert syndrome, or an eGFR < 60 mL/min/1.73 m2. Patients on medications that could influence levels of Lp(a) were confirmed to be on a stable dose for 8 weeks prior to enrollment. Patients who had received another investigational agent within 90 days of starting the trial or within 10 half lives of the drug (whichever period was longer) or were on other oligonucleotide therapy within 12 months of starting the trial were also excluded.
Results
Out of 32 participants, only one experienced a serious adverse event. This participant was admitted to the hospital for severe headache after receiving SARS-CoV-2 vaccination and later with complications of cholecystitis that were both deemed to be unrelated to the study. This participant was found to have elevated transaminases greater than 3 times the upper limit of normal which normalized by day 60 of the study. Other adverse events were generally mild and included low-grade injection site events and headache.
With regard to the secondary outcome, a dose dependent lowering of plasma Lp(a) was observed. The highest dose produced a 98% reduction in Lp(a) levels and the second highest dose produced a 95% reduction. The nadir was at 30 and 60 days, respectively. Levels gradually rose but, after 150 days of follow up, were 81% below baseline in the highest dose and 71% below baseline in the second highest dose.
Discussion
This innovative study using gene silencing RNA interferons (SLN360) to prevent the formation of LP(a), a prothrombotic genetic risk factor for atherosclerotic and atherothrombotic disease as well as aortic stenosis may be revolutionary in our approach to treating and preventing premature cardiovascular disease. There is a paucity of data on this topic and it is of great public interest. The New York Times published an article on Lp(a) in 2018 titled “A Heart Risk Factor Even Doctors Know Little About”; however this trial along with others is making headway in changing this fact. Testing for Lp(a) in patients with premature cardiovascular disease and close relatives may one day become the standard of care. The development and approval of targeted therapies to lower Lp(a) could have a major impact on cardiovascular health. But to novel mechanism of using interfering RNA has a potential for even more wide reaching clinical impact.
| F: Follow up | 150 days |
| R: Randomization | Yes |
| I: Intention to treat | NO |
| S: Similar at baseline | Yes |
| B: Blinding | Single blind |
| E: Equal treatment | Yes |
| S: Source (funding) | Silence Therapeutics PLC via Silence Therapeutics, Medspace contract research organization and C5Research in addition to support from the National Institute for Health Research Biomedical Research Centre at Imperial College London. |
