Add-on PCSK9 inhibitor cuts LDL-C by half, allows infrequent dosing in patients maxed out on statins

Injection with the novel, long-acting PCSK9 inhibitor recaticimab once every 3 months reduces LDL-cholesterol (LDL-C) levels by >50 percent compared with placebo in patients already maxed out on statins in the phase III REMAIN-2 trial.

Study investigator Dr Xin Du from Beijing Anzhen Hospital and Capital Medical University, China, who presented the results at AHA 2023, said the hope is to have more flexible dosing with recaticimab to improve patient compliance.

Two other PCSK9 inhibitors on the market – alirocumab and evolocumab – are dosed every 2–4 weeks. However, 40 percent of patients started on these drugs stop taking them within months of starting treatment, Du shared.

“Recaticimab is a new antibody that has a long half-life of 18.6–27.4 days compared with 11–17 days for alirocumab and evolocumab, so each treatment with recaticimab can be prolonged,” said Du. “It can get a very strong effect of LDL-C lowering even when given every 3 months.”

62 sites, 692 adults

The trial was conducted at 62 sites in China and involved 692 adults with nonfamilial or mixed hypercholesterolemia, who were not reaching their lipid targets despite taking statins and another lipid-lowering drug. [AHA 2023, abstract LBS.06]

After a run-in period that included lifestyle and diet interventions, patients were randomly assigned to one of three different doses of recaticimab: 150 mg/kg every 4 weeks, 300 mg/kg every 8 weeks, and 450 mg/kg every 12 weeks, or placebo. The study was conducted from June 2021 to March 2023.

By week 24, recaticimab was able to reduce LDL-C by 53.4 percent to 62.2 percent across all dosing regimens vs placebo, Du reported. The reductions were sustained out to 48 weeks at 48.4 to 64 percent.

While the number of placebo-treated patients reaching LDL goals remained in the low to mid-teens group, 86 to 95 percent of recaticimab-treated patients, depending on dose, achieved their LDL-C targets within 24 weeks. Similar benefits were seen in patients with or without atherosclerotic disease at baseline.

Other lipid parameters such as non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) also decreased significantly from baseline on the different doses of recaticimab. By contrast, there was no change seen in placebo-treated patients.

Common adverse events with a frequency of ≥5 percent in patients receiving recaticimab were upper respiratory tract infection, hyperuricaemia, urinary tract infection, increased blood creatine phosphokinase, COVID-19 infection, and increased alanine transferase and aspartate transferase.

Effective therapeutic option

“REMAIN-2 demonstrated the long-term efficacy and safety of add-on recaticimab as an effective therapeutic option, with an infrequent dosing interval, in patients with nonfamilial hypercholesterolaemia and mixed hyperlipidaemia, who were inadequately controlled on stable statin therapy,” Du said.

Longer-term studies of recaticimab are warranted to determine its ability produce durable LDL-C reduction in a cost-effective manner, said discussant Dr Stephen Nicholls, director of Victorian Heart Institute and professor at Monash University, 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.”

A separate study of recaticimab in heterozygous familial hypercholesterolaemia is ongoing, with results expected next year, added Du.