Extended Zerlasiran Data Show Sustained Lp(a) Reduction

Treatment with zerlasiran produced sustained reductions in lipoprotein(a) [Lp(a)] concentrations out to 1 year in adults with elevated Lp(a), extended data from the APOLLO phase 1 trial showed.

“Zerlasiran produces a prolonged reduction in Lp(a). This study was designed to determine how long it would work and what’s the right dose,” Steven E. Nissen, MD, Cleveland Clinic, Cleveland, Ohio, told theheart.org | Medscape Cardiology. “This sets the stage for further development in what is now going to be ultimately a phase 3 trial.”

The new data were published online on April 8 in JAMA.

Zerlasiran (Silence Therapeutics) is a short interfering RNA (siRNA) agent, or “gene silencing” therapy. It binds to and temporarily blocks the action of the LPA gene, which encodes for apolipoprotein(a), a dominant and rate-limiting component in the hepatic synthesis of the Lp(a) particle.

APOLLO was a single ascending and multiple-dose trial that enrolled 32 healthy adults without atherosclerotic cardiovascular disease (ASCVD) but with elevated Lp(a) and 36 patients with ASCVD and Lp(a) concentrations ≥ 150 nmol/L.

Participants were randomized to receive either a single subcutaneous dose of placebo, zerlasiran 300 mg or 600 mg, or two doses of placebo, zerlasiran 200 mg at a 4-week interval or 300 mg or 450 mg at an 8-week interval.

Results from the single ascending dose portion of the trial in the healthy adults, published in JAMA in 2022, showed that zerlasiran (formerly SLN360) was well tolerated and lowered Lp(a) by up to 98%, as reported previously by theheart.org | Medscape Cardiology.

The new JAMA publication reports findings from the extended 365-day follow-up of healthy participants who received the two highest doses of zerlasiran and 201 days of follow-up for patients with ASCVD administered two doses.

Zerlasiran 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. Elevations in C-reactive protein were seen at 24 hours but were no longer present at 7 days.

Reductions in Lp(a) concentrations showed maximal effects after two doses of 300 mg, with little differentiation between the 300-mg and 450-mg doses.

The median change from baseline in serum Lp(a) concentrations 365 days after single doses for placebo, 300 mg, and 600 mg was +14%, −30%, and −29%, respectively.

The maximal median change from baseline after two doses of placebo, 200 mg, 300 mg, and 450 mg was +7%, −97%, −98%, and −99%, attenuating to 0.3%, −60%, 90%, and 89%, respectively, after 201 days.

“What we learned is that the drug has a prolonged duration of action, and we found the right dose,” Nissen said.

“It turns out that there was almost no difference between the 300-mg and the 450-mg doses. That’s important because you always want to use the lowest dose of a drug that will do the job. And we now know that we can give 300 mg, probably every 12 weeks — that’s just four times a year — and produce 90+ percent reduction in Lp(a),” Nissen said.

Fourth to Market?

Last month, the company reported positive topline 36-week data from ALPACAR-360, the ongoing phase 2 study of zerlasiran in adults with baseline Lp(a) levels ≥ 125 nmol/L at high risk for ASCVD events.

Nissen noted that 20% of the global population have elevated Lp(a) levels, and it’s a “major cause” for premature ASCVD globally.

“Zerlasiran is one of several new therapies in development for elevated Lp(a), which has historically been an untreatable disorder. This is a very exciting field,” Nissen told theheart.org | Medscape Cardiology.

Reached for comment, Robert S. Rosenson, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said the data on zerlasiran are “in line with what we see with other siRNA inhibitors where you’re getting complete inhibition of Lp(a).”

“RNA inhibitors have a long durability and really are the future of Lp(a) treatment,” Rosenson told theheart.org | Medscape Cardiology.

He noted that two other RNA-based drugs targeting Lp(a) are already in phase 3 testing (pelacarsen and olpasiran), and a third (lepodisiran) will go into phase 3 testing this summer — so zerlasiran “could be fourth to the market.”

The trial was funded by Silence Therapeutics PLC and coordinated by Silence Therapeutics, Medpace (a contract research organization), and the Cleveland Clinic Center for Clinical Research (C5Research). A complete list of author disclosures is available with the original article. Rosenson had no relevant disclosures.