EMBARGOED UNTIL 8 AM EST, Sunday, April 3, 2022, Cleveland: Results of a new Phase 1 trial led by the Cleveland Clinic show that an experimental ‘gene silencing’ therapy reduced blood levels of lipoprotein (a), a key risk factor for heart disease, by up to 98 %.
The discoveries of the “APOLLO Trial: Magnitude and Duration of Effects of a Short-interfering RNA Targeting Lipoprotein(a): A Placebo-pressed Double-blind Dose-ranging Trial” was presented today during a last-minute scientific session at the American College of Cardiology 71st Annual Scientific Session and simultaneously published online in the Journal of the American Medical Association.
In the trial, participants who received higher doses of SLN360 – a therapeutic small interfering RNA (siRNA) that “silences” the gene responsible for producing lipoprotein (a) – saw their levels of lipoprotein (a) ) drop up to 96%-98%. Five months later, these participants’ lipoprotein(a) levels – also known as Lp(a) – remained 71-81% lower than baseline.
The results suggest that this siRNA therapy could be a promising treatment to help prevent premature heart disease in people with elevated Lp(a) levels, which is thought to affect 64 million people in the United States and 1.4 billion in people in the world. It is estimated that approximately 20-25% of the world’s population has an elevated Lp(a).
“These results demonstrated the safety and strong efficacy of this investigational treatment in reducing levels of Lp(a), a common but previously incurable genetically determined risk factor that leads to premature heart attack, stroke and aortic stenosis,” the study said. lead author Steven E. Nissen, MD, director of studies for the Heart, Vascular & Thoracic Institute at the Cleveland Clinic. “We hope that the further development of this therapy will also reduce the consequences of Lp(a) in the clinical setting through future studies.”
Lp(a) shares similarities with LDL, also known as the bad cholesterol. Lp(a) is made in the liver, where an additional protein called apolipoprotein(a) is attached to an LDL-like particle. Unlike other types of cholesterol particles, Lp(a) levels are 80-90% genetically determined. The structure of the Lp(a) particle causes plaque to build up in the arteries, which plays an important role in heart disease. A high Lp(a) greatly increases the risk of heart attacks and strokes.
Although there are effective therapies to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, there are currently no approved treatments to lower Lp(a). Since Lp(a) levels are determined by a person’s genes, lifestyle changes such as diet or exercise have no effect. In the current study, siRNA therapy reduces Lp(a) levels by “silencing” the gene responsible for Lp(a) production and blocking the creation of apolipoprotein(a) in the liver.
In the APOLLO trial, researchers recruited 32 people from five medical centers in three countries. All participants had Lp(a) levels above 150 nmol/L, with a median level of 224 nmol/L (75 nmol/L or less is considered normal). Eight participants received a placebo and the others received one of four doses of SLN360 via a single subcutaneous injection. The doses were 30 mg, 100 mg, 300 mg and 600 mg. Participants were closely observed for the first 24 hours after their injection and then assessed periodically for five months.
Participants receiving 300 mg and 600 mg of SLN360 showed a maximum reduction of 96% and 98% in Lp(a) levels, and a reduction of 71% and 81% at five months from baseline. Those who received a placebo saw no change in Lp(a) levels. The higher doses also reduced LDL cholesterol by about 20-25%. No major safety implications were reported and the most common side effect was temporary pain at the injection site. The study has been extended and researchers will continue to follow participants for a total of one year.
The APOLLO trial was funded by Silence Therapeutics plc (Nasdaq: SLN), London, UK. Dr. Nissen has consulted for numerous pharmaceutical companies and has overseen clinical trials for Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Esperion, Novartis, Novo Nordisk, Ordemanden, Takeda and Pfizer. However, it does not accept fees, consulting fees or other compensation from commercial entities.
The trial was coordinated by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) and sponsored by Silence Therapeutics plc (Nasdaq: SLN), London, UK.
About the Cleveland Clinic
Cleveland Clinic is a non-profit, multi-specialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision to provide exceptional patient care based on the principles of cooperation, compassion and innovation. The Cleveland Clinic has pioneered many medical breakthroughsincluding coronary bypass surgery and the first face transplant in the United States. US news and world report consistently names the Cleveland Clinic as one of the best hospitals in the nation in its annual “America’s Best Hospitals” survey. The Cleveland Clinic’s 72,500 employees worldwide include more than 5,050 salaried physicians and researchers, and 17,800 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,500-bed health system that includes a 173-acre main campus near downtown Cleveland, 21 hospitals, more than 220 ambulatory care facilities, including locations in northeast Ohio; southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2021, there were 10.2 million total outpatient visits, 304,000 hospital admissions and observations, and 259,000 surgical cases across the Cleveland Clinic health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. follow us on twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.
Editor’s note: Cleveland Clinic Press Office is available to provide broadcast-quality interviews and B-rolls on demand.
Journal of the American Medical Association
The title of the article
Single Increasing Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals with Elevated Plasma Lipoprotein(a) Levels
Publication date of articles
Warning: AAAS and EurekAlert! are not responsible for the accuracy of press releases posted on EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.