PCSK9 levels were significantly reduced in rat embryos with neural tube defects (NTDs) in the study, published in Scientific Reports. The main focus of the paper was to identify biomarkers that could be used for the prenatal detection of NTDs, because there are now no reliable methods to accurately detect NTDs at an early stage of pregnancy.
But the results also raise the possibility that blocking PCSK9 with the new PCSK9 inhibitors (evolocumab [Repatha] and alirocumab [Praluent]) 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, MD, a French cardiologist who is the co-chair of a very large ongoing outcomes trial with alirocumab, 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 this 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 PCSK9 drug makers, 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 NTDs 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, MD, of China's Shengjing Hospital, 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."
http://www.medpagetoday.com/Cardiology/CardioBrief/55506
The FDA, asked to comment about the paper, sent this 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 PCSK9 drug makers, 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 NTDs 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, MD, of China's Shengjing Hospital, 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."
http://www.medpagetoday.com/Cardiology/CardioBrief/55506
Dong An, Xiaowei Wei, Hui Li, Hui Gu, Tianchu Huang, Guifeng Zhao, Bo Liu, Weilin Wang, Lizhu Chen, Wei Ma, Henan Zhang, Songying Cao,Zhengwei Yuan. Identification of PCSK9 as a novel serum biomarker for the prenatal diagnosis of neural tube defects using iTRAQ quantitative proteomics. Scientific Reports 5, Article number: 17559 Published online:22 December 2015
ReplyDeleteAbstract
To identify candidate serum molecule biomarkers for the non-invasive early prenatal diagnosis of neural tube defects (NTDs), we employed an iTRAQ-based quantitative proteomic approach to analyze the proteomic changes in serum samples from embryonic day (E) 11 and E13 pregnant rats with spina bifida aperta (SBA) induced by all-trans retinoic acid. Among the 390 proteins identified, 40 proteins at E11 and 26 proteins at E13 displayed significant differential expression in the SBA groups. We confirmed 5 candidate proteins by ELISA. We observed the space-time expression changes of proprotein convertase subtilisin/kexin type 9 (PCSK9) at different stages of fetal development, including a marked decrease in the sera of NTD pregnancies and gradual increase in the sera of normal pregnancies with embryonic development. PCSK9 demonstrated the diagnostic efficacy of potential NTD biomarkers [with an area under the receiver operating characteristic curve of 0.763, 95% CI: 065–0.88]. Additionally, PCSK9 expression in the spinal cords and placentas of SBA rat fetuses was markedly decreased. PCSK9 could serve as a novel molecular biomarker for the non-invasive prenatal screening of NTDs and may be involved in the pathogenesis of NTDs at critical periods of fetal development.