New Monoclonal Antibody to PCSK9 Impresses With LDL-Cholesterol Reductions

March 27, 2012

March 26, 2012 (Washington, DC) — Yet more research presented this week shows impressive reductions in LDL-cholesterol levels in patients treated with the investigational human monoclonal antibody specific to proprotein convertase subtilisin/kexin 9 (PCSK9). Among a group of patients treated with atorvastatin who still had elevated cholesterol levels, treatment with the new compound reduced LDL cholesterol by more than 70% from baseline, report investigators.

"I'm enthusiastic for this new product because it might be the next big step," said lead investigator Dr James McKenney (National Clinical Research, Richmond, VA). "If it pans out--and we have a long way to go in research--the data presented today say it is quite powerful, at least as, if not more than, a statin itself, and it takes us to another level of treatment potential."

Presenting the results of the study to the media following the late-breaking clinical-trials session at the American College of Cardiology (ACC) 2012 Scientific Sessions, McKenney said that while statins have provided remarkable reductions in LDL cholesterol leading to the prevention of coronary heart disease, "some patients are left behind." Some patients, he said, are statin intolerant, while others, such as those with familial hypercholesterolemia, have trouble getting to treatment goals.

Dr Rick Nishimura (Mayo Clinic, Rochester, MN), the moderator during the press conference, called the new compound, known currently as SAR236553/REGN727 (Regeneron Pharmaceuticals/Sanofi), or REGN727 for short, a potential "game changer" but stressed that these are early days, indeed.

"For anything to be effective, you have to look at clinical outcomes," Nishimura told heartwire . "We've had a lot of things in the past that lower cholesterol and that everybody has been very excited about. When you actually look to see whether it prevents heart attacks in thousands of patients, that's where the rubber really hits the road. All this new stuff that's being presented, we're very excited about, but it's happened time and time again where new drugs come out to lower cholesterol, and you test them in a randomized trial for hard outcomes, and they might not be effective."

PCSK9 and Its Monoclonal Antibody

PCSK9 is a serine protease synthesized in the liver. Upon entering the circulation, it binds to hepatic LDL receptors, leading to their breakdown. As a result, the liver loses some of its capacity to remove LDL cholesterol from circulation, which results in an increase in LDL-cholesterol levels. Researchers have previously shown that gain-of-function mutations in the Pcsk9 gene were linked to hypercholesterolemia and that loss-of-function mutations are associated with low LDL-cholesterol levels and a low prevalence of coronary heart disease events.

Three phase 1 studies published last week showed that the monoclonal antibody specific to PCSK9 significantly reduced LDL-cholesterol levels in a group of healthy volunteers and in statin-treated subjects with familial and nonfamilial forms of hypercholesterolemia. Yesterday, Dr Eli Roth (University of Cincinnati College of Medicine, OH) presented data showing that the addition of REGN727 on top of atorvastatin 80 mg reduced LDL-cholesterol levels by 73%.

In this latest dose-ranging investigation, McKenney and colleagues conducted a 12-week study in 182 patients taking atorvastatin 10 mg, 20 mg, and 40 mg who had LDL-cholesterol levels >100 mg/dL. Patients were treated with a subcutaneous injection of REGN727 50 mg, 100 mg, and 150 mg every two weeks, and two other groups of patients were treated with an subcutaneous injection of REGN727 200 mg and 300 mg once every four weeks (with an alternating placebo injection at two weeks).

From baseline, the addition of REGN727 resulted in a significant reduction in LDL cholesterol. The treatment benefit ranged from a 39.6% reduction with the 50-mg dose to a 72.4% reduction in LDL cholesterol with the 150-mg dose of REGN727. The biweekly injection appeared to be more potent for reductions in LDL cholesterol than the subcutaneous dose administered every four weeks. At week 12, 100% of patients treated with the 150-mg injection of REGN727 achieved LDL-cholesterol levels <70 mg/dL.

Changes in LDL Cholesterol From Baseline to Week 12

Intervention Baseline LDL cholesterol (mg/dL) Mean change in LDL-C (%)
Placebo 130.2 -5.1
REGN727 50 mg, every 2 wk 123.2 -39.6
REGN727 100 mg, every 2 wk 127.0 -64.2
REGN727 150 mg, every 2 wk 123.9 -72.4
REGN727 200 mg, every 4 wk 128.2 -43.2
REGN727 300 mg, every 4 wk 131.6 -47.7

p<0.0001 for the percent change in LDL cholesterol with every dose of REGN727

During the morning press conference, McKenney was enthusiastic about the findings, telling the media that the results, especially in patients already treated with statin therapy, wowed him and others. "It's so impressive, considering that the statin we used should have already produced a 40% to 50% reduction," he said. "On top of this, we're getting another 40% to 70% reduction. So if the drug pans out and if it continues to show this kind of efficacy, especially it shows safety, then maybe we have another era in the treatment of lipid disorders, and more important, in the treatment of heart disease in this country."

Regarding safety, McKenney reported that treatment-emergency serious adverse events occurred in three patients treated with REGN727 and in one patient treated with placebo. Treatment-related adverse events that led to the discontinuation of therapy occurred in one patient treated with the 100-mg dose, one patient treated with the 150-mg dose, three patients treated with the 200-mg dose, and one patient treated with the 300-mg dose. One patient, upon biopsy, was diagnosed with leukocytoclastic vasculitis, a significant medical event deemed related to REGN727.

Speaking with heartwire about the results, Dr Steven Nissen (Cleveland Clinic, OH) was excited about the findings but measured. "I think it's really promising, and yes, it's injectable, but it means that we can get virtually anybody to their LDL-cholesterol targets. I think the drugs are likely to turn out to be safe, and we already are seeing that they're very effective. There are a lot of people not at goal who are going to benefit. There are a lot of people who are statin intolerant who are going to benefit. It's a very promising class, but it's early. We need phase 3 data. The studies presented at this meeting are phase 1 and phase 2 studies."

Nissen said that because REGN727 works through the LDL receptor, which is how statins work, he expects the drug to turn out to be safe. Second, there are genetic models supporting the role of PCSK9. Dr Helen Hobbs (University of Texas Southwestern Medical Center, Dallas), he noted, showed that patients with genetic deficiencies in Pcsk9 were healthy and had a significantly lowered risk of developing coronary heart disease. "So the genetic model for inhibiting Pcsk9 is people who have a genetic defect, and they do very, very well," said Nissen. "That makes you very comfortable."

On the whole, Nissen said the very low LDL-cholesterol levels achieved with REGN727 aren't a cause for concern, given that analyses of SATURN, ASTEROID, and JUPITER, among others, showed that very low levels of cholesterol appear to be safe. "The real question, though, is, is it beneficial?" he said.

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