Treatment with zerlasilan resulted in a sustained decrease in lipoproteins (a) [Lp(a)] Expanded data from the APOLLO Phase 1 trial showed decreased concentrations over 1 year in adults with elevated Lp(a).
“Zerasilan produces long-term Lp(a) reduction. This study was designed to determine how long it is effective and what doses are appropriate.” said Dr. Stephen E. Nissen of the Cleveland Clinic in Cleveland, Ohio. Heart.org | Medscape Cardiology. “This sets the stage for further development, which will ultimately be a Phase 3 clinical trial.”
The new data was published online on April 8th. Japan Automobile Manufacturers Association.
Zerlasiran (Silence Therapeutics) is a short interfering RNA (siRNA) agent, or “gene silencing” therapy. binds to and temporarily blocks its action. LPA This gene encodes apolipoprotein (a), the major rate-limiting component in the synthesis of Lp(a) particles in the liver.
APOLLO studied 32 healthy adults without atherosclerotic cardiovascular disease (ASCVD) but with elevated Lp(a) and 36 patients with ASCVD and Lp(a) levels ≥150 nmol/L. It was a single escalating, multiple-dose study that enrolled patients.
Participants received either a single subcutaneous dose of placebo (Zelasilan 300 mg or 600 mg) or a placebo (Zerlasilan 200 mg twice 4 weeks apart or 300 mg or 450 mg twice 8 weeks apart). patients were randomly assigned to one of the treatment groups.
Results of the single escalating dose portion of the study in healthy adults. Japan Automobile Manufacturers Association As previously reported by 2022, zerlasiran (formerly known as SLN360) was shown to be well tolerated and reduce Lp(a) by up to 98%. Heart.org | Medscape Cardiology.
new Japan Automobile Manufacturers Association This paper reports results from a 365-day extended follow-up of healthy participants who received two doses of the highest dose of zerlasiran and a 201-day follow-up of ASCVD patients who received two doses.
Zerrasiran was safe and well-tolerated, with no serious adverse events. Mild to moderate injection site reactions were observed primarily during the first 24 hours after drug administration. An increase in C-reactive protein was seen at 24 hours but was no longer present at 7 days.
The reduction in Lp(a) concentrations had the greatest effect after two doses of 300 mg, but there was little difference between the 300 mg and 450 mg doses.
Median changes from baseline in serum Lp(a) concentrations 365 days after a single dose of placebo, 300 mg, and 600 mg were +14%, -30%, and -29%, respectively.
Maximum median changes from baseline after two doses of placebo 200 mg, 300 mg, and 450 mg were +7%, -97%, -98%, -99%, and 0.3%, -60%, 90% It decreased to After 201 days, they were 89% and 89%, respectively.
“What we learned is that this drug has a long duration of action and we found the right dose,” Nissen said.
“We found that there was little difference between the 300 mg dose and the 450 mg dose. This is important because we always want to use the lowest dose that is effective for a drug. And now we can “We know that you can. If you take maybe 300 mg every 12 weeks, which is only four times a year, you can reduce Lp(a) by more than 90 percent,” Nissen said.
Fourth on the market?
Last month, the company announced positive 36-week results from ALPACAR-360, an ongoing Phase 2 trial of zerlasiran in adults with baseline Lp(a) levels of 125 nmol/L or higher and at high risk of ASCVD events. Reported topline data.
Nissen noted that 20% of the world's population has elevated Lp(a) levels, which is the “main cause” of early-onset ASCVD worldwide.
“Zelasilan is one of several new treatments being developed for elevated Lp(a), a historically untreatable disease. This is a very exciting area,” Nissen said. Ta. Heart.org | Medscape Cardiology.
When asked for comment, Robert S. Rosenson, M.D., professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said the data on zerlasiran “are similar to what we've seen with other siRNA inhibitors.” We are in agreement.” Complete inhibition of Lp(a). ”
“RNA inhibitors are long-lasting and truly represent the future of Lp(a) treatment,” Rosenson said. Heart.org | Medscape Cardiology.
He said two other RNA-based drugs that target Lp(a) (peracarsen and olpasilan) are already in Phase 3 trials, and a third (lepodisiran) is expected to enter Phase 3 trials this summer. He pointed out that Zerrasiran “could be the fourth to be introduced to the market.” . ”
The study was sponsored by Silence Therapeutics PLC and coordinated by Silence Therapeutics, Medpace (a contract research organization), and Cleveland Clinic Center for Clinical Research (C5Research). A complete list of author disclosures is available in the original article. Mr. Rosenson had no relevant disclosures.