PCSK9 may play an important role in neural tube development (NTD), a new study in rats suggests. The study, published in Scientific Reports, found that PCSK9 levels were significantly reduced in rat embryos with NTDs. The main focus of the paper was to identify biomarkers that could be used for the prenatal detection of NTDs, since there are now no reliable methods to accurately detect NTD at an early stage of pregnancy.
But the results also raise the possibility that blocking PCSK9 with the new PCSK9 inhibitors (Repatha, Amgen, and Praluent, Sanofi) could increase the risk of birth defects in fertile women taking the drugs. The connection is still far from certain and remains the subject of ongoing research.
Experts say the findings may be enough to warrant cautious use of the new drugs in women of childbearing age. The FDA labels for the drugs do not exclude fertile women from taking the drugs, but the labels do warn that “there are no available data on use of” the drugs “in pregnant women to inform a drug-associated risk.” The label advises physicians to “consider the benefits and risks” and “possible risks to the fetus before prescribing” the drugs to pregnant women, but does not make a statement about use of the drug in fertile women.
Philippe Gabriel Steg, a French cardiologist who is the co-chair of a very large ongoing outcomes trial with Praluent, said in an email message that he “would definitely recommend caution in women of childbearing potential, and if there is a good indication for use (e.g. familial hypercholesterolemia) make absolutely sure that highly effective contraception is used as a precondition to prescription.”
The FDA, asked to comment about the paper, sent the following statement:
“We are aware of the… paper and will review the findings. We will take them, and all other relevant information, into account when making regulatory decisions concerning PCSK9 inhibitors.”
Representatives from both Amgen and Sanofi declined to comment on the details of the study. Both companies pointed out that in studies that are required for new drugs no signal for birth defects was observed in animals taking PCSK9 inhibitors. A Sanofi representative said that as part of the company’s ongoing post marketing studies, “a pregnancy exposure registry is planned because no data are available on use of Praluent in pregnant women to inform a drug-associated risk.”
In the new study researchers in China found that PCSK9 is expressed during neurogenesis and that animals with NTD had significantly lower levels of PCSK9. However, they also noted that there have been no observable effects on the development of the nervous system in PCSK9 knockout mice. The researchers also measured PCSK9 levels in women during pregnancy. PCSK9 levels were consistently lower in NTD pregnancies, while PCSK9 levels increased in women during the course of pregnancy.
The senior author of the paper, Zhengwei Yuan, said in an email message that the mechanism is “still not clear” for the decreased levels of PCSK9 in NTD animal models and maternal serum. “Now we are planning to study the effect of PCSK9 inhibitors on pregnant animal models,” he said. In the meantime, he said, he was concerned about the use of PCSK9 inhibitors in fertile women.
Statins are by far the most frequently used class of drugs to lower cholesterol levels. The use of statins during pregnancy is contraindicated, though the evidence linking statins to birth defects is far from definitive. For now, the biggest potential risk, for statins and for PCSK9 inhibitors alike, is in premenopausal women with unplanned pregnancies.
Marilyn Mann, a patient advocate for families with familial hypercholesterolemia, offered the following caution: “Given that evolocumab and alirocumab are newly approved drugs, the safety information on these drugs, including with respect to use during pregnancy, is very limited. As with statins, women who are able to become pregnant should be advised to use reliable birth control and to discontinue use of the drug several months before attempting to become pregnant.”