Preeclampsia & eclampsia

Overview

Preeclampsia is a pregnancy-related disorder of the placenta and its blood vessels, which is characterised by sustained high blood pressure, protein in the urine, and/or organ complications after 20 weeks of gestation. Long-term risks to the mother include chronic high blood pressure, cardiovascular disease, and kidney issues, while for infants, it can lead to poor growth and prematurity, as well as an increased risk of cardiovascular, metabolic, immune, and endocrine problems. At its most advanced stage, complications can lead to eclampsia (seizures), which dramatically increases the risks of poor maternal and neonatal health outcomes. Preeclampsia and eclampsia are a leading cause of maternal death (16%), and stillbirth and early neonatal mortality (at least 10%) worldwide. Currently, screening, diagnosis, prevention and treatment of preeclampsia (and eclampsia) are limited, especially in LMICs where women are seven times more likely to develop pre-eclampsia than women in high-income countries.

Unmet needs

Better medicines and diagnostics are needed to prevent and treat this life-threatening condition. Currently, diagnosis relies on the appearance of clinical features and symptoms, making new diagnostic tests for early disease prediction essential. Biomarker-based diagnostics – such as the Mirvie test based on RNA signatures - show promise in early screening, especially crucial in low-resource settings where point-of-care screening options are essential for timely detection and treatment. New tools also need to be rapid, affordable, and user-friendly. Early detection is especially important given that preventive administration of low-dose aspirin must be implemented before 16 weeks’ gestation to be effective, which is often before any clinical symptoms appear. Effective treatment is also lacking with currently only one medicine – magnesium sulphate – and it works only for prevention and treatment of seizures associated with eclampsia. The only truly curative treatment for preeclampsia is early delivery or termination. Management, therefore, focuses on reducing symptoms, utilising off-label drugs such as blood pressure-reducing medications like labetalol and nifedipine, with variable efficacy and side effects. Safer symptomatic relief medications, and new or repurposed drugs or biologic therapies that target the underlying pathophysiology of the disease are needed. Novel candidates include those that work on inflammation pathways, such as sulfasalazine and celecoxib, vasoconstriction and vasodilation balancing drugs, such as nitric oxide donors and hydrogen sulphide-based therapies (e.g. sodium hydrosulphide).

Funding

Funding for preeclampsia and eclampsia (PE&E) totalled $178m in the five years from 2018 to 2023, with 2023’s total of $40m representing a 108% increase from 2022 and (narrowly) a record high. Funding fell sharply in 2022, but the $21m rebound in 2023 left total funding more than $20m above its 2018 level.

Historically, fluctuations in PE&E funding mostly reflected changes in the contributions from the US NIH, which was the largest single funder every year, with a strong focus on basic research, which continues to receive more funding than any other product area. Funding from the NIH rebounded to $21m in 2023, following a big drop in 2022. The cause of the record high in 2023, though, was a surge in funding from the Gates Foundation. It has gradually increased its PE&E funding from $0.6m in 2018 to more than $11m in 2023, with big increases for diagnostic and drug funding, including $2.1m to the Concept Foundation for the largest ever trial on the use of low-dose aspirin, aimed at determining optimal dosage.

While basic research continues to account for the largest single share of PE&E funding, a little under half of the long term rise, and just over half of the 2023 increase, went to diagnostics. Diagnostic R&D, at, $12m, now accounts for more than 30% of 2023 funding – up from a low of just 0.6% ($0.2m) in 2021.

This increase in overall Gates Foundation funding represents about half of the net growth in funding in 2023 and about half of the $20m in overall increase since 2018. The previous spike in PE&E funding, in 2019, resulted from $12m in (ultimately unsuccessful) biologics funding for a small pharmaceutical company. Despite some evidence of industry activity in the product pipeline, there has been no reported industry investment from survey participants since 2020.

Funding

Product landscape & pipeline

Similarly to other maternal health conditions, the pipeline for preeclampsia is characterised by a high number of repurposed medicines, highlighting a reliance on pre-existing marketed drugs with proven human safety to minimise risks of teratogenicity, and a lack of innovation in pregnancy related R&D. Most repurposed medicines have been marketed for decades for other conditions, reflecting the long time-lag taken for drugs to be tested in pregnancy to come to market, and the institutional reluctance to include pregnant individuals in clinical research altogether. However, there is some dynamism in the diagnostic R&D space for preeclampsia: considerable interest in biomarker research has yielded promising pathways, with the potential for earlier detection and screening, but also for an improved understanding of the general pathology, paving the way for new therapeutic approaches.

Seventy-five medicines are approved or adopted in clinical practice or under investigation for preeclampsia, including 43 drugs, 17 biologics and 15 dietary supplements.

Only eight products – seven drugs and one dietary supplement – have been adopted into clinical practice or incorporated into professional guidelines, and they are all repurposed products initially developed for other conditions. The WHO and clinical professional associations recommend the prophylactic use of low-dose aspirin before 20 weeks of gestation in women considered at risk, and magnesium sulphate as the first line prophylaxis and treatment of severe preeclampsia/eclampsia. Antihypertensive medications, such as nifedipine (first-line treatment when IV access is unfeasible), methyldopa, clonidine, labetalol and captopril are routinely used to lower blood pressure in preeclamptic women, despite captopril carrying registered risks during pregnancy. Calcium supplementation is also recommended by the WHO for the prevention of preeclampsia from 20 weeks of gestation.

There are 67 candidates in active development. Half of the drugs and biologics are in the discovery and preclinical phase (26 out of 53) but seven candidates have reached Phase III: two biologics, the probiotic lactobacilli tested for prophylaxis and antithrombin gamma investigated in patients with early-onset severe preeclampsia; and five drugs, pravastatin, investigated for both prophylaxis and treatment of symptomatic preeclampsia, the beta-blocker metoprolol, and three drugs that are not recommended during pregnancy but are investigated as postpartum preeclampsia antihypertensives: enalapril and the diuretics furosemide and hydrochlorothiazide. Dietary supplements under investigation are either preclinical (5) or in Phase II (3) or III (6), reflecting the lesser need for human safety studies (Phase I) in the dietary supplement regulatory landscape. Promising candidates in Phase III include the amino acid L-arginine, with documented preventative benefits, and several vitamins (A, D, E) for their impact on oxidative stress.

The R&D space for preeclampsia diagnostics appears rather active, with 88 diagnostic and screening tools marketed or in development. The ten marketed or adopted diagnostics include traditional mean arterial blood pressure measurement and five urine-based biomarker tests recommended by clinical guidelines. The latter includes uric acid, protein to creatinine ratio and its point of care version, Test-it, 24-hour urine protein excretion test, and the relatively more innovative Dip.io, allowing for smartphone-enabled home urinalysis of protein. Three serum biomarker tests are also approved or adopted in clinical practice: the sFlt-1/PlGF ratio ratio-based testing, the Lumella test (glycosylated fibronectin) and Proflo-u and EyeRa, two point-of-care tests to be used in combination for the detection of microRNA and protein-based biomarkers. Additionally, the Fetal Medicine Foundation algorithm is a multiparametric test which combines maternal characteristics, mean arterial blood pressure and uterine artery pulsatility index with serum levels of either placental growth factor  (PlGF), soluble Fms-like tyrosine kinase-1 (sFlt-1) or pregnancy-associated plasma protein A (PAPP-A) and has been included in the clinical guidelines of the International Federation of Gynaecology and Obstetrics (FIGO) and implemented in the UK through a dedicated app, Tommy’s Clinical Decision Tool.

The importance of biomarker testing within the approved diagnostics also characterises diagnostics in development, with 37 biomarker tests out of the 78 diagnostic candidates (47%), and an additional 346 biomarkers identified in omics studies with the potential to be developed into clinical tests. Multiparametric tests (18) are promising approaches reflecting the complexity of the pathology and with the potential to be developed as predictive screening tests and clinical decision support tools. One example is the Preeclampsia Predictor with Machine Learning (PEPrML) model developed at Columbia University based on preeclampsia predictive features such as blood pressure, uterine artery blood flow, placental analytes, endoglin, cholesterol, and Inhibin A. Almost all multiparametric tests involve at least one biomarker.

Imaging also plays a substantial role in new diagnostic development, with 12 ultrasound based-tests, two MRI-tests and a combined predictive model relying on both elastography and MRI measurements Other diagnostics tests in development include six additional blood pressure monitoring tools, impedance measurements, and the Nemo Fetal Monitoring System, which uses electrophysiological signals to monitor both maternal and fetal heart rate and is also in development for the detection of preterm labour.

While the diverse avenues explored for preeclampsia diagnosis, and particularly biomarker research, are promising, 88% of the candidates are still in early development. The large spectrum of symptoms and clinical features of preeclampsia makes diagnosis extremely challenging. Moreover, increasing awareness of the heterogeneity within preeclampsia cases suggests the existence of subtypes, such as the distinction between early-onset and late-onset preeclampsia, which might call for distinct screening approaches. Nevertheless, biomarker exploration has the potential to help inform these distinctions and improve both diagnostic and therapeutic capabilities in the future.

Preeclampsia and eclampsia pipeline