Special Report
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Upcoming drugs for the treatment of preeclampsia in pregnant women Expert Rev. Clin. Pharmacol. 7(5), 599–603 (2014)
Sara Ornaghi*1,2 and Michael J Paidas2 1 Department of Obstetrics and Gynecology, University of Milano-Bicocca, via Pergolesi 33, Monza, MB, Italy 2 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Women and Children’s Center For Blood Disorders, Yale University School of Medicine, 333 Cedar Street, FMB 339B, New Haven, 06520-8063 CT, USA *Author for correspondence: Tel.: +1 203 737 1982 Fax: +1 203 737 2327 [email protected]
Preeclampsia is a pregnancy-specific multisystem disorder, complicating 2 – 8% of pregnancies, and represents a leading cause of maternal and perinatal morbidity and mortality. Recent investigations have elucidated the understanding of its underlying pathogenic mechanisms. However, despite these advances, therapeutic approaches are still severely limited. Ongoing lines of research indicate some potential novel therapeutic options, targeting the etiopathogenic pathways and, thus, offering hope for effective pharmacologic interventions to be available in the near future. In this editorial, we will give an updated overview of Preeclampsia pathogenesis and promising emerging therapeutic options. KEYWORDS: anti-digoxin antibody • endothelial dysfunction • ETA receptor antagonists • lipid apheresis • mesenchymal stem cells • nitric oxide modulators • Preeclampsia • recombinant human antithrombin • RLX030 • statins
Preeclampsia (PE) is a multisystem disorder complicating 2–8% of pregnancies and represents a significant cause of maternal and perinatal morbidity and mortality. The lack of effective pharmacologic therapeutic approaches, especially in preterm PE (PPE), is a serious health concern in clinical obstetrics. Indeed, contemporary management of PPE has remained essentially unchanged over the last few decades [1]. Advances in the understanding of PE pathogenesis and new lines of research indicate some potential novel therapeutic options [2]. Pathogenic mechanisms of PE
Suggested for the first time in 1989, the involvement of endothelial dysfunction in PE pathogenesis has subsequently received several validations. Aiming to identify its causative agents, the concept of a two-step disease has emerged [3]. The first step, asymptomatic, is characterized by an abnormal trophoblastic invasion, which leads to impaired uterine spiral arteries remodeling and resulting placental ischemia/reperfusion and oxidative injury, with trophoblastic debris release [4]. In addition, the hypoxic and oxidatively damaged placenta releases into circulation anti-angiogenic factors, namely soluble fms-like tyrosine kinase 1
informahealthcare.com
10.1586/17512433.2014.944501
(sFlt-1) and soluble endoglin (sEng) [5]. More precisely, placental ischemic and oxidative damage induces both a marked systemic inflammatory response in the mother, with Th1 pro-inflammatory cytokines secretion (tumor necrosis factor-alpha [TNF-a]; interleukin-6 [IL-6]), and coagulation activation [6], and a systemic endothelial dysfunction, by sFlt-1- and sEng-related sequestering of VEGF, placental growth factor (PlGF) and transforming growth factor-b (TGF-b). Indeed, VEGF, PlGF and TGF-b are pro-angiogenic molecules crucial for normal endothelial function via nitric oxide (NO) pathway. Of note, NO mediates vasodilation and inhibits platelet and inflammatory cell activation [5]. In addition, autoantibodies against the angiotensin II receptor (AT1-AAs) have been involved in endothelial dysfunction, due to their ability to induce TNF-a and antiangiogenic factors production [3]. The strong vasoconstrictor endothelin-1 (ET-1) has been suggested as the final molecule linking immune and circulating anti-angiogenic factors in determining systemic vasoconstriction and endothelial dysfunction [7]. This systemic involvement manifests as the clinical syndrome of PE (second step) and underlies most of the clinical and laboratoristic signs of the disease [8].
2014 Informa UK Ltd
ISSN 1751-2433
599
Special Report
Ornaghi & Paidas
Finally, a decreased placental expression of hemoxygenase-1 (HO-1) has been recently proposed to contribute to PE development. Indeed, HO-1 is an anti-inflammatory enzyme that inhibits sFlt-1 and sEng placental release, and it is considered crucial for proper vascular development of the placenta [9]. Of note, a decreased HO-1 mRNA expression has been identified both in 11-week chorionic villi of women who will develop PE and in preeclamptic placentas at term [10].
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Potential therapeutic options Therapeutic options currently under clinical evaluation Antithrombin
Antithrombin (AT) is a complex glycoprotein with strong effects on coagulation and inflammation. AT is the principal inhibitor of thrombin and factor Xa, thus countering the pro-thrombotic status of PE. Further, it is able to induce prostacyclin (PGI2) endothelial release. PGI2 inhibits leukocyte activation and TNF-a secretion and restores endothelial PGI2:TXA2 ratio. Decreased AT levels have been identified in PE [11]. Due to these pleiotropic properties, beneficial effects have been identified for plasmaderived AT administration in both animal models of PE and preliminary clinical trials. However, although promising, these preliminary studies present several limitations. Thus, the use of AT in this setting is still considered experimental and has not been widely embraced worldwide. In this setting, a high-quality randomized clinical trial investigating the role of recombinant human AT (rhAT; ATryn – rEVO Biologics, Framingham, MA, USA) in PPE has recently been started [12,13]. The PRESERVE-1 trial aims to assess the efficacy, expressed as increase in gestational age at delivery, safety and pharmacokinetics of rhAT in addition to expectant management for treatment of PPE. Lipid-regulating agents
In addition to the increased expression of anti-angiogenic molecules and pro-inflammatory and -coagulatory markers, abnormal circulating lipoprotein concentrations and lipid–protein composition have been suggested as pathogenic factors for endothelial dysfunction and placental acute atherosis in PE [14–16]. Indeed, placenta-mediated disorders, such as PE, bear similarity to the process of atherogenesis, and higher levels of lipoprotein a [Lp(a)] and low density lipoprotein (LDL) particles have been reported in preeclamptic patients [17]. Statins
The pleiotropic properties of statins (3-hydroxy-3-methyl-glutaryl-coenzyme A – HMG-CoA – reductase inhibitors) make them highly promising candidates for both treatment and prevention of PE. Indeed, using animal models, statins have been shown not only to lower circulating lipid levels but also to enhance endothelial function by increasing endothelial nitric oxide synthase and HO-1 placental expression. Antiinflammatory properties and long-term protective effects via controlling fetal programming have also been reported [18–20]. Currently, statins are US FDA category X drugs. However, both animal and clinical studies have not revealed an increase 600
in teratogenic outcomes after first-trimester exposure [21]. The ability of statins to restore the angiogenic balance is currently being tested in a ‘proof-of-concept’, randomized trial, the STaMP trial (EudraCT Number 2009-012968-13, start date March 2011). This is the first study evaluating pravastatin as therapy for severe early-onset PE, specifically looking at circulating anti-angiogenic factors. This study will also reveal the beneficial or adverse effects related to gestational exposure to pravastatin. In addition, a Eunice Kennedy Shriver National Institute of Child Health and Human Development-sponsored placebo-controlled Phase I study is currently ongoing in the USA, aiming to determine the pharmacokinetic parameters and to collect preliminary safety data for pravastatin when used as a prophylactic daily treatment in pregnant women at high risk of PE [22,23]. Data from this work will be used to set the foundation in establishing dosage and response information to be utilized in designing future clinical trials to evaluate pravastatin’s effectiveness to prevent PE in a high-risk population. Finally, since the well-known risk of future cardiovascular disease in women experiencing PE, a randomized, double-blind, placebocontrolled trial on the potential role of atorvastatin in improving vascular function in women with a history of PE has been recently initiated in UK [24]. Lipid apheresis
Heparin-mediated extracorporeal LDL precipitation apheresis has been in clinical use since 1985, and its main current indications are familial hypercholesterolemia, coronary heart disease and after heart transplantation [25]. It has been shown to effectively remove Lp(a), LDL, c-reactive protein, TNF-a, fibrinogen and other pro-coagulatory markers, adhesion molecules, ET-1 and homocysteine from the circulation. Therefore, a biological plausibility for beneficial effects of heparin-mediated extracorporeal LDL precipitation apheresis in PE can be recognized [26]. Indeed, simultaneous removal of pro-inflammatory and -coagulatory markers, adhesion molecules, vasopressive factors and atherogenic lipoproteins should be able to improve maternal endothelial function and to increase placental perfusion by reducing blood viscosity, thus leading to pregnancy prolongation. This hypothesis has been recently confirmed in a pilot study of nine preterm preeclamptic women [16]. An interventional trial, planning to include a larger cohort of cases, has recently started patient recruitment, aiming to assess the efficacy of lipid apheresis in prolonging preterm preeclamptic pregnancies [27]. Pregnant women with familial hypercholesterolemia have been also treated with a different type of apheresis, namely short-term extracorporeal adsorption pheresis, for over 30 years. This technique has been recently applied in a pilot study of Thadhani and colleagues, evaluating 5 women with very PPE and elevated circulating sFlt-1 levels [28]. Specifically, the Liposorber LA-15 system has been selected for this study because of its ability to efficiently and selectively remove sFlt-1 in vitro. A significant decrease in circulating sFlt-1 levels was observed with a single dextran sulfate cellulose apheresis treatment. Further, the authors recognized that multiple apheresis treatments Expert Rev. Clin. Pharmacol. 7(5), (2014)
Upcoming drugs for the treatment of preeclampsia in pregnant women
were able to reduce proteinuria and to stabilize blood pressure without apparent adverse events to mother and fetus, thus prolonging pregnancy of 2–3 weeks. To confirm these results, a multicenter, Phase Ib ‘proof-of-concept’ study has recently started patients’ enrollment [29].
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Serelaxin or RLX030 (recombinant human relaxin-2)
Relaxin is a vasodilatory hormone that helps the pregnant woman to cope with the additional cardiovascular demands of gestation. Immune neutralization or elimination of circulating relaxin in mid-term pregnant rats was shown to prevent systemic vasodilation. In vitro data suggest that relaxin’s effects are mediated by endothelial nitric oxide synthase and VEGF up-regulation [30]. Since this mechanism of action, a randomized clinical trial to assess relaxin safety, pharmacokinetics and efficacy in women with PE
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Upcoming drugs for the treatment of preeclampsia in pregnant women Expert Rev. Clin. Pharmacol. 7(5), 599–603 (2014)
Sara Ornaghi*1,2 and Michael J Paidas2 1 Department of Obstetrics and Gynecology, University of Milano-Bicocca, via Pergolesi 33, Monza, MB, Italy 2 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Women and Children’s Center For Blood Disorders, Yale University School of Medicine, 333 Cedar Street, FMB 339B, New Haven, 06520-8063 CT, USA *Author for correspondence: Tel.: +1 203 737 1982 Fax: +1 203 737 2327 [email protected]
Preeclampsia is a pregnancy-specific multisystem disorder, complicating 2 – 8% of pregnancies, and represents a leading cause of maternal and perinatal morbidity and mortality. Recent investigations have elucidated the understanding of its underlying pathogenic mechanisms. However, despite these advances, therapeutic approaches are still severely limited. Ongoing lines of research indicate some potential novel therapeutic options, targeting the etiopathogenic pathways and, thus, offering hope for effective pharmacologic interventions to be available in the near future. In this editorial, we will give an updated overview of Preeclampsia pathogenesis and promising emerging therapeutic options. KEYWORDS: anti-digoxin antibody • endothelial dysfunction • ETA receptor antagonists • lipid apheresis • mesenchymal stem cells • nitric oxide modulators • Preeclampsia • recombinant human antithrombin • RLX030 • statins
Preeclampsia (PE) is a multisystem disorder complicating 2–8% of pregnancies and represents a significant cause of maternal and perinatal morbidity and mortality. The lack of effective pharmacologic therapeutic approaches, especially in preterm PE (PPE), is a serious health concern in clinical obstetrics. Indeed, contemporary management of PPE has remained essentially unchanged over the last few decades [1]. Advances in the understanding of PE pathogenesis and new lines of research indicate some potential novel therapeutic options [2]. Pathogenic mechanisms of PE
Suggested for the first time in 1989, the involvement of endothelial dysfunction in PE pathogenesis has subsequently received several validations. Aiming to identify its causative agents, the concept of a two-step disease has emerged [3]. The first step, asymptomatic, is characterized by an abnormal trophoblastic invasion, which leads to impaired uterine spiral arteries remodeling and resulting placental ischemia/reperfusion and oxidative injury, with trophoblastic debris release [4]. In addition, the hypoxic and oxidatively damaged placenta releases into circulation anti-angiogenic factors, namely soluble fms-like tyrosine kinase 1
informahealthcare.com
10.1586/17512433.2014.944501
(sFlt-1) and soluble endoglin (sEng) [5]. More precisely, placental ischemic and oxidative damage induces both a marked systemic inflammatory response in the mother, with Th1 pro-inflammatory cytokines secretion (tumor necrosis factor-alpha [TNF-a]; interleukin-6 [IL-6]), and coagulation activation [6], and a systemic endothelial dysfunction, by sFlt-1- and sEng-related sequestering of VEGF, placental growth factor (PlGF) and transforming growth factor-b (TGF-b). Indeed, VEGF, PlGF and TGF-b are pro-angiogenic molecules crucial for normal endothelial function via nitric oxide (NO) pathway. Of note, NO mediates vasodilation and inhibits platelet and inflammatory cell activation [5]. In addition, autoantibodies against the angiotensin II receptor (AT1-AAs) have been involved in endothelial dysfunction, due to their ability to induce TNF-a and antiangiogenic factors production [3]. The strong vasoconstrictor endothelin-1 (ET-1) has been suggested as the final molecule linking immune and circulating anti-angiogenic factors in determining systemic vasoconstriction and endothelial dysfunction [7]. This systemic involvement manifests as the clinical syndrome of PE (second step) and underlies most of the clinical and laboratoristic signs of the disease [8].
2014 Informa UK Ltd
ISSN 1751-2433
599
Special Report
Ornaghi & Paidas
Finally, a decreased placental expression of hemoxygenase-1 (HO-1) has been recently proposed to contribute to PE development. Indeed, HO-1 is an anti-inflammatory enzyme that inhibits sFlt-1 and sEng placental release, and it is considered crucial for proper vascular development of the placenta [9]. Of note, a decreased HO-1 mRNA expression has been identified both in 11-week chorionic villi of women who will develop PE and in preeclamptic placentas at term [10].
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Potential therapeutic options Therapeutic options currently under clinical evaluation Antithrombin
Antithrombin (AT) is a complex glycoprotein with strong effects on coagulation and inflammation. AT is the principal inhibitor of thrombin and factor Xa, thus countering the pro-thrombotic status of PE. Further, it is able to induce prostacyclin (PGI2) endothelial release. PGI2 inhibits leukocyte activation and TNF-a secretion and restores endothelial PGI2:TXA2 ratio. Decreased AT levels have been identified in PE [11]. Due to these pleiotropic properties, beneficial effects have been identified for plasmaderived AT administration in both animal models of PE and preliminary clinical trials. However, although promising, these preliminary studies present several limitations. Thus, the use of AT in this setting is still considered experimental and has not been widely embraced worldwide. In this setting, a high-quality randomized clinical trial investigating the role of recombinant human AT (rhAT; ATryn – rEVO Biologics, Framingham, MA, USA) in PPE has recently been started [12,13]. The PRESERVE-1 trial aims to assess the efficacy, expressed as increase in gestational age at delivery, safety and pharmacokinetics of rhAT in addition to expectant management for treatment of PPE. Lipid-regulating agents
In addition to the increased expression of anti-angiogenic molecules and pro-inflammatory and -coagulatory markers, abnormal circulating lipoprotein concentrations and lipid–protein composition have been suggested as pathogenic factors for endothelial dysfunction and placental acute atherosis in PE [14–16]. Indeed, placenta-mediated disorders, such as PE, bear similarity to the process of atherogenesis, and higher levels of lipoprotein a [Lp(a)] and low density lipoprotein (LDL) particles have been reported in preeclamptic patients [17]. Statins
The pleiotropic properties of statins (3-hydroxy-3-methyl-glutaryl-coenzyme A – HMG-CoA – reductase inhibitors) make them highly promising candidates for both treatment and prevention of PE. Indeed, using animal models, statins have been shown not only to lower circulating lipid levels but also to enhance endothelial function by increasing endothelial nitric oxide synthase and HO-1 placental expression. Antiinflammatory properties and long-term protective effects via controlling fetal programming have also been reported [18–20]. Currently, statins are US FDA category X drugs. However, both animal and clinical studies have not revealed an increase 600
in teratogenic outcomes after first-trimester exposure [21]. The ability of statins to restore the angiogenic balance is currently being tested in a ‘proof-of-concept’, randomized trial, the STaMP trial (EudraCT Number 2009-012968-13, start date March 2011). This is the first study evaluating pravastatin as therapy for severe early-onset PE, specifically looking at circulating anti-angiogenic factors. This study will also reveal the beneficial or adverse effects related to gestational exposure to pravastatin. In addition, a Eunice Kennedy Shriver National Institute of Child Health and Human Development-sponsored placebo-controlled Phase I study is currently ongoing in the USA, aiming to determine the pharmacokinetic parameters and to collect preliminary safety data for pravastatin when used as a prophylactic daily treatment in pregnant women at high risk of PE [22,23]. Data from this work will be used to set the foundation in establishing dosage and response information to be utilized in designing future clinical trials to evaluate pravastatin’s effectiveness to prevent PE in a high-risk population. Finally, since the well-known risk of future cardiovascular disease in women experiencing PE, a randomized, double-blind, placebocontrolled trial on the potential role of atorvastatin in improving vascular function in women with a history of PE has been recently initiated in UK [24]. Lipid apheresis
Heparin-mediated extracorporeal LDL precipitation apheresis has been in clinical use since 1985, and its main current indications are familial hypercholesterolemia, coronary heart disease and after heart transplantation [25]. It has been shown to effectively remove Lp(a), LDL, c-reactive protein, TNF-a, fibrinogen and other pro-coagulatory markers, adhesion molecules, ET-1 and homocysteine from the circulation. Therefore, a biological plausibility for beneficial effects of heparin-mediated extracorporeal LDL precipitation apheresis in PE can be recognized [26]. Indeed, simultaneous removal of pro-inflammatory and -coagulatory markers, adhesion molecules, vasopressive factors and atherogenic lipoproteins should be able to improve maternal endothelial function and to increase placental perfusion by reducing blood viscosity, thus leading to pregnancy prolongation. This hypothesis has been recently confirmed in a pilot study of nine preterm preeclamptic women [16]. An interventional trial, planning to include a larger cohort of cases, has recently started patient recruitment, aiming to assess the efficacy of lipid apheresis in prolonging preterm preeclamptic pregnancies [27]. Pregnant women with familial hypercholesterolemia have been also treated with a different type of apheresis, namely short-term extracorporeal adsorption pheresis, for over 30 years. This technique has been recently applied in a pilot study of Thadhani and colleagues, evaluating 5 women with very PPE and elevated circulating sFlt-1 levels [28]. Specifically, the Liposorber LA-15 system has been selected for this study because of its ability to efficiently and selectively remove sFlt-1 in vitro. A significant decrease in circulating sFlt-1 levels was observed with a single dextran sulfate cellulose apheresis treatment. Further, the authors recognized that multiple apheresis treatments Expert Rev. Clin. Pharmacol. 7(5), (2014)
Upcoming drugs for the treatment of preeclampsia in pregnant women
were able to reduce proteinuria and to stabilize blood pressure without apparent adverse events to mother and fetus, thus prolonging pregnancy of 2–3 weeks. To confirm these results, a multicenter, Phase Ib ‘proof-of-concept’ study has recently started patients’ enrollment [29].
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 06/18/15 For personal use only.
Serelaxin or RLX030 (recombinant human relaxin-2)
Relaxin is a vasodilatory hormone that helps the pregnant woman to cope with the additional cardiovascular demands of gestation. Immune neutralization or elimination of circulating relaxin in mid-term pregnant rats was shown to prevent systemic vasodilation. In vitro data suggest that relaxin’s effects are mediated by endothelial nitric oxide synthase and VEGF up-regulation [30]. Since this mechanism of action, a randomized clinical trial to assess relaxin safety, pharmacokinetics and efficacy in women with PE
