New PCSK9 Inhibitor Allows 3-Month Treatment Intervals

PHILADELPHIA – An investigational PCSK9 inhibitor that can be injected every 1-3 months as add-on therapy for patients with stubbornly high low-density lipoprotein (LDL) cholesterol has demonstrated cholesterol lowering for up to a year, in a clinical trial.

The results are from the phase 3 Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolemia and Mixed Hyperlipidemia (REMAIN-2) trial.

"It's a new antibody that has a long half-life so each treatment can be prolonged," investigator Xin Du, MD, professor of cardiology at Beijing Anzhen Hospital and the Capital Medical University, said in an interview. "Previous drugs like alirocumab and evolocumab have to be given every 2 weeks or every 4 weeks, and this new drug can be given even every 12 weeks, so it can get a very strong effect of LDL cholesterol lowering even when given every 3 months."

Recaticimab has demonstrated a half-life of 18.6 to 27.4 days vs. 11 to 17 days for alirocumab and evolocumab, she said.

"Currently a high proportion of patients prescribed the PCSK9 inhibitors withdraw from therapy," Dr. Du said. "After 36 months, only half of them are still on that therapy."

Dr. Du presented the trial results at the annual scientific sessions of the American Heart Association.

Trial design and results

REMAIN-2 randomly assigned 692 patients to one of three recaticimab dosing arms vs. placebo: 150 mg/kg every 4 weeks; 300 mg/kg every 8 weeks; and 450 mg/kg every 12 weeks. The study was conducted from June 2021 to March 2023. The average age of the participants was 56 years and 64% were men. A high percentage of patients, 87% to 93.5%, completed the study across all groups. All participants had high LDL-C levels despite statin therapy: ≥ 70 mg/dL for those with cardiovascular disease and ≥ 100 mg/dL for those without.

Recaticimab enhanced LDL-C reduction by 53.4% to 62% vs. placebo at 24 weeks with a similar effect across all dosing regimens, Dr. Du said. That level of reduction was sustained out to 48 weeks, she said, at 48.4% to 64%.

At week 24, 86% to 94.5% of all patients across the three dosing arms achieved their LDL-C goal. The treatment had a positive impact on other lipid levels as well, Dr. Du said. Levels of non-HDL-C declined 55% to 47%. Apolipoprotein B (ApoB) levels fell 53% to 42% and lipoprotein (a), or Lp(a) readings declined 39.5% to 29%. The placebo arms had no change or small increases in non-HDL-C and ApoB levels and modest reductions in Lp(a).

The trial demonstrated acceptable safety and tolerability of recaticimab, Dr. Du said. At 48 weeks, the rates of injection site reactions were 3.9% in the treatment arms vs. 1.3% in the placebo arms. Common adverse events with a frequency ≥ 5% in patients receiving recaticimab were upper respiratory tract infection, hyperuricemia, urinary tract infection, increased blood creatine phosphokinase – a marker of damage to the heart – COVID-19 infection, and increased alanine transferase and aspartate transferase, both of which are markers of liver damage.

Larger, longer studies needed

Longer-term studies of recaticimab are still needed to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Stephen Nicholls, MD, director of Victorian Heart Institute and professor at Monash University in Australia. "It is important to note that these are still relatively short studies and the short treatment period cannot exclude the formation of neutralizing antibodies that have undermined development of other humanized antibodies," he told attendees.

The every-12-week dosing, Dr. Nicholls said in an interview, "provides a dosing regimen that may be palatable to many patients."

Besides the potential for the development of antibodies, Dr. Nicholls foresaw potential challenges with recaticimab. "The reality will lie in longer-term data," he said. "If they can achieve durable lipid lowering without such neutralizing antibodies that would be very good."

Dr. Nicholls added, "There's a lot going on in the PCSK9 inhibitor space and the challenge for any new therapeutic, including this one, is where will it fit in given the space is getting crowded. So, data is important and clinical uptake will be equally important."

Dr. Du disclosed relationships with Sanofi, AstraZeneca and Bayer. Dr. Nicholls disclosed relationships with AstraZeneca, Akcea, Amarin, Amgen, Anthera, Boehringer Ingelheim, Cerenis, CSL Behring, Eli Lilly, Esperion, Novartis, LipoScience, The Medicines Company, Merck, New Amsterdam Pharma, Omthera, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Takeda, Vaxxinity, and Seqirus.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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Cite this: New PCSK9 Inhibitor Allows 3-Month Treatment Intervals - Medscape - Nov 29, 2023.