Short interfering RNA therapy dramatically lowers Lp(a) in phase 1 trial
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WASHINGTON — In the phase 1 APOLLO study, a short interfering RNA therapy lowered lipoprotein(a) by a maximum of more than 90% in certain doses, researchers reported at the American College of Cardiology Scientific Session.
The agent, SLN360 (Silence Therapeutics), is one of several in development to reduce Lp(a), elevated levels of which are a major CVD risk factor and are not effectively treated by existing therapies.
“There are no approved therapies for treating lipoprotein(a); it represents the frontier in the treatment of lipids,” 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, who presented the data, told Healio. “There are three in development, all with different approaches. There is very strong evidence from Mendelian randomization studies and epidemiological studies that Lp(a) is a very powerful risk factor for both atherosclerotic CVD and aortic stenosis. It has not been treatable; everything we have tried has minimal effects. It is a pure genetic risk factor. The LPA gene makes messenger RNA, which then makes apolipoprotein A, which then forms lipoprotein(a) particles. The only way to approach the disease is to silence the gene. This agent is a small piece of double-stranded RNA that is connected to a sugar called N-acetylgalactosamine (GalNAc). The liver takes up the GalNAc and removes it, leaving interfering RNA in the hepatocytes, where it combines with messenger RNA and degrades it, which means it blocks production of apolipoprotein A and ultimately lipoprotein(a).”
The researchers randomly assigned 32 adults with Lp(a) plasma concentrations of at least 150 nmol/L (mean age, 50 years; 53% women) to a single dose of placebo or SLN360 at one of the following doses: 30 mg, 100 mg, 300 mg or 600 mg. Participants had follow-up visits at 7, 14, 30, 45, 60, 90 and 150 days after dosage.
The main purpose of the study was to assess safety and tolerability. One participant reported two serious adverse events, neither of which were deemed to be related to the study drug.
“You can’t really establish safety with 32 patients, so there is considerable work left to be done before this therapy will start large phase 3 trials, but nonetheless, we see the results as promising,” Nissen told Healio.
Reductions in Lp(a)
The maximal median changes in Lp(a) were –20 nmol/L (interquartile range [IQR], –61 to 3) in the placebo group, –89 nmol/L (IQR, –119 to –61) in the 30 mg group, –185 nmol/L (IQR, –226 to –163) in the 100 mg group, –268 nmol/L (IQR, –292 to –189) in the 300 mg group and –227 nmol/L (IQR, –270 to –174) in the 600 mg group, according to the researchers.
Nissen said the maximal median percentage changes in Lp(a) were as follows:
- placebo group, –10% (IQR, –16 to 1);
- 30 mg group, –46% (IQR, –64 to –40);
- 100 mg group, –86% (IQR, –92 to –82);
- 300 mg group, –96% (IQR, –98 to –89); and
- 600 mg group, –98% (IQR, –98 to –97).
The 96% reduction observed in the 300 mg group occurred on the day 45 visit and the 98% reduction observed in the 600 mg group occurred on the day 60 visit, and at 150 days, the 300 mg group had a 71% reduction, and the 600 mg group had an 81% reduction, Nissen said during a presentation.
“Considering that this is a disease for which we have no treatments, it is clearly a step forward,” Nissen told Healio. “This approach may offer some hope for patients whom we have been unable to treat. Some patients have an MI as early as in their 40s or premature aortic stenosis. All we have been able to tell them is we can modify their other risk factors and hope for the best. I am looking forward to the day when we have a very specific treatment.”
SLN360 also produced a dose-dependent reduction in LDL and total cholesterol, with a maximal 26% reduction in LDL and 18% reduction in total cholesterol conferred by the 600 mg dose, according to the researchers.
In addition, Nissen said, the maximal reductions in apolipoprotein B were 21% in the 300 mg group, observed on day 45, and 24% in the 600 mg group, observed on day 60.
A multi-dose trial is now underway and development is “moving stepwise really quickly toward the later-phase trials,” Nissen told Healio.
The study was simultaneously published in JAMA.
CV outcome trials needed
In a related editorial in JAMA, Brian A. Ference, MD, MPhil, MSc, FACC, FESC, director of research (professor) in translational therapeutics and executive director of the Center for Naturally Randomized Trials at the University of Cambridge, U.K., wrote: “Because of the uncertainty about the magnitude of Lp(a) lowering needed to reduce the risk of cardiovascular events, it is important to continue to evaluate the safety and efficacy of the small interfering RNA in the study reported by Nissen and colleagues as well as a similar small interfering RNA in development. A series of cardiovascular outcome trials evaluating multiple different antisense oligonucleotide and small interfering RNA therapies will provide the most robust estimate of the clinical benefit of lowering Lp(a) and help identify which individuals are likely to benefit most from lowering Lp(a).”
References:
- Ference BN. JAMA. 2022;doi:10.1001/jama.2022.5333.
- Nissen SE, et al. JAMA. 2022;doi:10.1001/jama.2022.5050.
Perspective
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Dipti Itchhaporia, MD, FACC, FESC
Lp(a) is involved with atherosclerosis, and we really have not had any treatment for it. This agent was tried in several different dosages to see if it was safe and if it impacted Lp(a). The small study of 32 patients showed it was safe and effective. Obviously, we will need more data, but the results are exciting because this is an area for which we have no treatment.
Perspective
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James A. Underberg, MD, MS, PLLC, FACPM, FASPC, FNLA, FSVM, FACP
This agent is a short interfering RNA as opposed to pelacarsen (Amgen/Ionis), which is an antisense oligonucleotide. This small trial was really a dose-finding and safety one. In that context, there were three exciting developments from it.
No. 1, there were reductions in Lp(a) greater than 80%, and in some cases, greater than 90% depending on the dose. That is pretty amazing. There are some interesting data from genomic analyses suggesting that if you don’t lower Lp(a) about 80% or more, you may not see an outcome benefit, so you want to demonstrate that type of reduction.
No. 2, the agent seemed to be well tolerated and did not have any significant side effects. The researchers seem comfortable that for the one patient who suffered an adverse event, it was not drug-related. The caveat is that it is a small trial.
No. 3, as is the case with other small inhibitors of RNA such as inclisiran (Leqvio, Novartis), there was a durable effect. Patients had suppression of Lp(a) levels by day 30, and at the highest doses, that persisted out all the way to near day 90. That is pretty amazing from an adherence perspective. Maybe patients will only need two injections per year, as is the case with inclisiran. We don’t yet know what the frequency of dosing will be, but those initial curves are encouraging in that this is a medication that does not have to be given frequently. All of those points indicate this is an exciting option to move forward with for Lp(a) lowering.
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Nissen SE, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, D.C. (hybrid meeting).
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