Short-chain interfering RNA therapy dramatically lowers Lp (a) in Phase 1 trials

In the Washington-Phase 1 APOLLO study, short-term interfering RNA therapy reduced lipoprotein (a) by up to 90% or more at certain doses, researchers reported in a scientific session at the American College of Cardiology. ..

Agent SLN360 (Silence Therapeutics) is one of several drugs under development to reduce Lp (a), and elevated levels are a major CVD risk factor and are effective with existing therapies. Not treated.

Stephen E. Nissen

“There is There is no approved treatment for treating lipoproteins (a)It’s a kind of last frontier. ” Cardiology today Editorial committee Stephen E. Nissen, MD, MACC, Sydell and Arnold Miller Family Heart, Chief Academic Officer of the Vascular & Thoracic Institute, and the Lewis and Patricia Dickey Chair of Cardiovascular Medicine at the Cleveland Clinic, who presented the data, told Healio. “There are three under development, all taking different approaches. From Mendel’s randomized and epidemiological studies, Lp (a) is a very strong risk for both atherosclerosis and aortic stenosis. There is very strong evidence that it is a factor. It was not treatable. We all [have tried] The impact, if any, is minimal. It is a pure genetic risk factor. The LPA The gene makes messenger RNA, which in turn makes apolipoprotein A, which in turn forms lipoprotein (a) particles. The only way to get close to the disease is to silence the gene. This agent is a small fragment of double-stranded RNA attached to. A sugar called N-acetylgalactosamine (GalNAc)). The liver takes up GalNAc and cuts it. Currently, there is interfering RNA in the hepatocytes of the liver, where it binds to and degrades messenger RNA. That is, no apolipoprotein A or lipoprotein (a) is produced. “

Researchers randomly assigned 32 adults (mean age 50 years, 53% female) with Lp (a) plasma levels of at least 150 nmol / L to a single dose of placebo or SLN360: 30 mg. , 100 mg, 300 mg or 600 mg. Participants made follow-up visits on days 7, 14, 30, 45, 60, 90, and 150 days after dosing.

The main purpose of this study was to assess safety and tolerability. One participant reported two serious adverse events, neither of which was considered to be related to the study drug.

“Since safety cannot actually be established in 32 patients, there is still a lot of work to be done before this enters into a large phase 3 trial, but we still believe the results are promising. “Masu,” Nissen told Healio.

Decrease in Lp (a)

The maximum median change in Lp (a) was –20 nmol / L (interquartile range) [IQR]–61 ~ 3) Placebo group, –89 nmol / L (IQR, –119 ~ –61) 30 mg group, –185 nmol / L (IQR, –226 ~ –163) 100 mg group, 300 according to researchers –268 nmol / L (IQR, –292 to –189) in the mg group and –227 nmol / L (IQR, –270 to –174) in the 600 mg group.

Nissen stated that the median maximum rate of change in Lp (a) is:

• 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-–89);
• 600 mg group, –98% (IQR, –98-–97).

The 96% reduction observed in the 300 mg group occurred on the 45th day visit and the 98% reduction observed in the 600 mg group occurred on the 60th day visit and 300 mg at 150 days. The group showed a 71% decrease. In his presentation, Nissen said there was an 81% reduction in the 600 mg group.

“Given that this is an untreated illness, it’s clearly a step forward,” Nissen told Healio. “This may give some hope to patients we couldn’t treat. They may have MI as early as 40s or early aortic stenosis. We have them. All I was able to tell was that they could fix their other risk factors and expect the best. I look forward to the day of receiving very special treatment. ”

According to researchers, SLN360 also resulted in a dose-dependent reduction in LDL and total cholesterol, with a dose of 600 mg reducing LDL by up to 26% and total cholesterol by 18%.

In addition, according to Nissen, the largest reduction in apolipoprotein B was 21% in the 300 mg group observed on day 45 and 24% in the 600 mg group observed on day 60.

Multiple-dose trials are currently underway and development is “very rapid and step-by-step towards late-stage trials,” Nissen told Healio.

The study was published at the same time JAMA..

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Brian A. Ferrence

In a related editorial JAMA, Brian A. Ferrence, MD, MPhil, MSc, FACC, FESC, The Research Director (Professor) of Translational Therapy at the University of Cambridge, UK and the Executive Director of the Center for Natural Randomized Controls said: At the event, it is important to continue to evaluate the safety and efficacy of small interfering RNAs, as well as similar small interfering RNAs under development, in a study reported by Nissen and his colleagues. A series of cardiovascular outcome trials evaluating multiple different antisense oligonucleotides and small interfering RNA therapies provided the most reliable estimates of the clinical benefit of lowering Lp (a), which individuals received Lp ( It helps identify what is most likely to benefit from reducing a).

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Dipti Itchhaporia, MD, FACC, FESC

Lp (a) is involved in atherosclerosis and has never been treated. This drug was tested at several different doses to see if it was safe and if it affected Lp (a). A small study of 32 patients showed that it was safe and effective. Obviously, we need more data, but the results are exciting because this is an area where we are not being treated.

Dipti Itchhaporia, MD, FACC, FESC

Eric & Sheila Samson Donated Cardiovascular Health Chair

Disease Management Manager

Jeffrey M. Carlton Heart and Vascular Institute

Hoag Memorial Hospital, Newport Beach, California

Medical Assistant Clinical Professor

University of California, Irvine

President of the American College of Cardiology

Cardiology today Editorial committee

Disclosure: Itchhaporia has not reported disclosure of relevant financial information.

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