Promising Phase 1 Results For New Monoclonal Antibody to PCSK9

Promising results from very early studies with an experimental new cholesterol-lowering drug, a monoclonal antibody to PCSK9, have been published in the New England Journal of Medicine. Evan Stein and colleagues report the results of two single-dose studies in which the drug, REGN727, was administered intravenously and subcutaneously to healthy subjects. In a third, randomized, placebo-controlled, dose-ranging trial, REGN727 was administered subcutaneously on days 1, 29, and 43 in adults with and without familial hypercholesterolemia (FH).

REGN727 was well tolerated and no subjects stopped taking the drug due to adverse events. Five patients had brief elevations in creatine kinase over three times the upper limit of normal. The drug had a powerful LDL-lowering effect: in the dose-ranging study in subjects already receiving atorvastatin

  • the 50 mg dose caused a 39% reduction of LDL cholesterol to 77.5 mg/dl,
  • the 100 mg dose caused a 53% reduction of LDL cholesterol to 61.3 mg/dl, and
  • the 150 mg dose caused a  61% reduction of LDL cholesterol to 53.8 mg/dl.

In an accompanying editorial, Stephen Young and Loren Fong write that “at this point, the status of PCSK9 therapeutics appears to be full speed ahead.” But they also express caution, noting that much work remains to be done:

In the end, evidence of long-term safety, along with data showing protection from coronary disease, will be needed to define the role of these agents in clinical practice. High-risk patients who have not reached their recommended cholesterol target and patients who cannot tolerate statins could benefit greatly. Patient selection will undoubtedly be influenced by cost–benefit considerations.

Monty Krieger, a well-known lipid researcher at MIT, told CardioBrief:

There are individuals who cannot tolerate statins, yet appear to be at increased risk for CHD because of elevated LDL cholesterol levels. Effective, alternative methods to treat these individuals to lower LDL cholesterol are clearly desirable and PCSK9 is one of the most attractive targets for such an approach. The report by Stein et all in NEJM confirms the importance of PCSK9-based approaches for LDL cholesterol lowering. It is encouraging that the highest dose administered three times over a 43 day period lowered LDL cholesterol significantly over a period extending beyond the last injection (days 8-85). One hopes that a safe, small molecule pharmaceutical approach directed at PCSK9 can be developed to achieve robust LDL cholesterol lowering without the issues associated with injecting antibodies.

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