DM199 for Pregnancy Complications

Preeclampsia and fetal growth restriction are leading causes of maternal and fetal morbidity. Both result from poor placental function. Preeclampsia is further characterized by inflammation and oxidative stress, leading to maternal endothelial dysfunction and hypertension. Hence, a drug that improves maternal vascular function including vasodilatation (and blood pressure reduction) may be a treatment for both conditions. Tissue kallikrein(KLK1) is an endogenous enzyme that cleaves kininogen to produce active kinins, mainly bradykinin. Bradykinin is a potent natural vasodilator with pro-angiogenic and possible anti-oxidant and potentially anti-inflammatory effects. Specifically, bradykinin binds and activates the bradykinin 2 receptor located on blood vessel endothelium. Activation of these receptors increases nitric oxide and prostacyclin production, resulting in relaxation of the smooth muscle of blood vessels and consequently vasodilation. Bradykinin 2 receptor activation may also have other beneficial actions such as upregulating antioxidant defenses. DM199 is a pharmaceutical formulation comprised of recombinant tissue kallikrein. It is a protein that is identical to KLK1,except for two amnio acids. Given the beneficial actions of KLK1, DM199 could be a therapeutic to treat preeclampsia. Furthermore, its vasodilatory properties might enhance blood perfusion to the placenta. If so, it could have merit in treating fetal growth restriction. Preclinical studies, animal toxicology studies and clinical trials (non-pregnant population) have shown DM199 to be safe and well tolerated. DM199 is a protein meaning it is unlikely to cross the placenta and reach the fetus. These properties make DM199 an ideal candidate to evaluate as a possible treatment of preeclampsia and possibly fetal growth restriction. This protocol describes an unblinded study to determine an effective and safe dose of DM199 for women with preeclampsia and/or fetal growth restriction.Preeclampsia is an unwelcome complication affecting 5-7% of all pregnancies.2 It is one of the two leading causes of maternal death during pregnancy. For every maternal death related to preeclampsia, another 50 to 100 women suffer severe health injuries.3 Around the world, there are estimated to be around 1.6 million cases of preeclampsia with severe features every year.

Preeclampsia is a pregnancy specific disorder that presents with hypertension and multi-organ injury in the second half of pregnancy. A hallmark of preeclampsia is severe maternal vascular dysfunction, where damage to the mother's blood vessels leads to hypertension and injury to many vital organs. The mother is at risk of developing seizures (eclampsia), cerebral injury like infarctions or intracranial haemorrhage, renal injury or failure, hepatic rupture and pulmonary edema. She may also develop haematological complications which include haemolysis, elevated liver enzymes and low platelet (HELLP) syndrome and disseminated intravascular coagulation. This puts her at a high risk of haemorrhage. Preeclampsia can also cause a placental abruption, where the placenta prematurely separates from the uterine wall due to bleeding resulting in catastrophic consequences for both the mother and unborn child.

Preeclampsia is both a placental and maternal disease. In early pregnancy the placenta fails to properly implant in the inner lining of the uterus. This may result in co-existing fetal growth restriction where the fetus fails to reach its genetically pre-determined growth potential. Fetuses with fetal growth restriction are at increased risk of adverse perinatal outcomes including stillbirth.

Preeclampsia is common Preeclampsia complicates about 5% of all pregnancies and is estimated to cause at least 42,000 maternal deaths every year.4,5 Worldwide, it is estimated that over 90% of deaths caused by preeclampsia occur in low and middle-income countries. Globally, preeclampsia disproportionately affects minority populations and those living in low and low middle-income countries. In South Africa, hypertensive disorders of pregnancy are responsible for 14% of all maternal deaths.8 Preeclampsia has no treatment apart from delivery There are certain medications given to women with preeclampsia: drugs to reduce hypertension or an infusion of magnesium sulphate to reduce the risk of eclampsia. However, these medications only control the late end-organ consequences of preeclampsia. Critically, there are no drugs that slow the underlying disease progression (such as improve placental health or quench the blood vessel injury).

Because there are no drugs to treat preeclampsia, delivery is the only definitive treatment. Birth of the fetus arrests the disease because the placenta is removed - the source of the anti-angiogenic factors responsible for the vascular and end-organ damage. Even after delivery, it may take weeks for a woman to recover from the acute end-organ complications of preeclampsia.