The Global Preclinical Research and Development Landscape for Pre-Eclampsia and Eclampsia Therapies.

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Jessica Postregna, Kate Mills, Fiona Bruinsma, Maya Goldstein, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7361131/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Surprisingly few medicines are available to prevent or manage pre-eclampsia, all of which are repurposed from non-pregnant populations and conditions. Analyses of clinical research and development (R&D) pipelines for pre-eclampsia medicines has identified high-potential candidates, however the preclinical pipeline has not been interrogated. We analysed and ranked the potential of 53 preclinical candidates for pre-eclampsia and eclampsia identified in a novel Maternal Health Pipeline spanning 2000 to 2021. Candidates were assessed across three domains – quality of preclinical evidence, product development stage and implementability. Each question in the prioritisation matrix was assigned a numerical value based on importance. The sum of these values was used to rank the potential of each candidate for future research. Among the 53 candidates analysed, 56.6% of which are novel medicines, 27 different binding targets were identified; the purported mechanism of action for 21 candidates was a reduction in sFlt-1. We identified eight high-potential candidates, three of which were novel, that should be prioritised for further development. Health sciences/Medical research/Drug development Health sciences/Medical research/Preclinical research Biological sciences/Physiology/Reproductive biology Figures Figure 1 Figure 2 Figure 3 Introduction Pre-eclampsia is the most common hypertensive disorder of pregnancy, affecting approximately 4 million women annually, worldwide. 1 As a leading cause of maternal and newborn mortality, pre-eclampsia is responsible for more than 60,000 maternal deaths, and approximately 440,000 stillbirths and newborn deaths annually. 1 – 4 Currently, there are few medicines that can prevent or treat this pregnancy complication - the only cure is delivering the baby and placenta. The lack of effective medicines for pre-eclampsia reflects a more generalised lack of investment in research and development (R&D) for maternal conditions. 1 More recently, the complex molecular mechanisms underlying pre-eclampsia have been elucidated, particularly the impact of elevated placental soluble fms-like tyrosine kinase 1 (sFlt-1). As an anti-angiogenic factor, rising sFlt-1 levels disrupt healthy blood vessel development and cause endothelial dysfunction. 5 , 6 Medicines currently recommended by the World Health Organization for pre-eclampsia include low-dose aspirin and calcium supplementation for prevention as well as antihypertensives and magnesium sulfate for treatment. However, they have limited efficacy in some women, and are still underused, particularly in low- and middle-income countries (LMICs). 7 – 9 This is driven by scarcity of health resources, variable access to healthcare services, and in the case of preventive low-dose aspirin, the need for risk screening early in pregnancy. 10 – 14 There have been no advances in new medicines for pre-eclampsia in the last 30 years that have reached clinical practice. 15 In 2021, through the Accelerating Innovation for Mothers (AIM) project, we mapped the R&D pipeline for pre-eclampsia and eclampsia medicines. 16 Between 2000 and 2021, 153 candidate medicines for pre-eclampsia and/or eclampsia were identified, across preclinical and clinical research stages. Previously, we analysed the 32 candidates undergoing clinical research against key criteria in published Target Product Profiles. 16 – 18 However, there is currently no defined methodology to assess and rank candidates at the preclinical stage. A critical question remains: which pre-eclampsia medicines from the preclinical R&D pipeline show the greatest potential? In the current study we aimed to develop a novel approach to ranking preclinical drug candidates and apply this to the preclinical R&D pipeline for drugs, supplements and biologics to prevent and treat pre-eclampsia and eclampsia. This approach assessed each candidate using three domains - quality of preclinical evidence, the product development stage and implementability. Our assessment has a particular focus on the needs and challenges of pregnant women, providers and healthcare services in LMICs. We also assessed pipeline diversity by mapping drug candidate binding targets and mechanisms of action. Methods Maternal Health Pipeline database Previously, as part of the AIM project, we conducted a landscape analysis, mapping the current and historic maternal medicines R&D pipeline. Drugs, dietary supplements and biologics investigated, either in preclinical or clinical settings, for five priority pregnancy-related conditions (pre-eclampsia, preterm birth/labour, postpartum haemorrhage, foetal growth restriction and fetal distress) were included. 19 The methodology to create the database is described elsewhere and the database is publicly available (available at: https://www.impactglobalhealth.org/data/maternal-health-pipeline) . 19,20 Briefly, initial candidate identification was sourced by systematically searching Adis Insight, Pharmaprojects, World Health Organization’s International Clinical Trials Registry Platform, PubMed, and relevant grant databases. 20 Preclinical and clinical data gathered was used to complete profiles for each candidate, which were then externally validated by independent clinical research specialists. 19 For this study, we used the October 2021 version of the Maternal Health Pipeline. Development of prioritisation matrix There are currently no tools to assess preclinical candidates. To address this gap, we developed a novel prioritisation matrix, drawing on several existing tools. Initially we outlined three overarching domains - evidence quality, product development and implementability. These three domains were chosen based on literature review, discussion with experts in the AIM project team, and diverse stakeholder feedback from other AIM activities. 16 , 17 , 21 , 22 These domains were then defined using different tools and instruments to advise selected questions. The first domain on quality of preclinical evidence was informed by the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool, and the Quality Assessment Tool For In Vitro Studies (QUIN) tool. 23 , 24 These tools are designed to assess the quality of preclinical studies for systematic reviews. We used common criteria from each tool, to assess both in vitro and in vivo studies using the same questions. For the second domain (product development) we used the established Technology Readiness Levels (TRL), a tool for assessing the maturity of products (Fig. 1 ). 25 – 31 TRLs 1 through 5 only are applicable to preclinical drug candidates. In this analysis we have also included TRL 3.5, which was defined as a candidate that had evidence of proof of concept in an appropriate pre-eclampsia model, compared to a TRL 3 which were still in the initial trailing phases of proof of concept in any model. The third domain on implementability was informed by selected criteria in the Target Product Profiles for medicines to prevent and treat pre-eclampsia, namely therapeutic indication, route of administration, cold chain requirements and developer type (pharmaceutical and/or academic). 16 , 17 , 32 A numerical value was assigned to each questions’ answer options. Assessment questions with greater importance in transitioning preclinical work into clinical trials, such as reliability of evidence and safety, were given greater weight. Next, all assessment questions were reviewed by the AIM research team comprised of experts in the maternal health field to ensure content validity. This prioritisation matrix was then piloted on 10 candidates from the Maternal Health Pipeline to further refine the questions according to information available for each candidate. The prioritisation matrix, containing the complete list of questions used to assess potential, is described in Supplementary Table 1. Preclinical Maternal Health Pipeline diversity The diversity of the pipeline was assessed by mapping the research trends over the time period 2000–2021, as well as the binding targets and mechanisms of action of candidates. Information on drug-specific binding sites was collected from information in the pipeline, supplemented with further literature searches. Analysis of preclinical candidates First, we considered all preclinical candidates in the R&D pipeline, and excluded those where: 1) no primary preclinical data were identified, and only a hypothesised role in prevention or treatment of pre-eclampsia was presented in the literature; 2) data was not publicly available or preclinical data was only available from published abstracts; or 3) preclinical evidence suggested significant adverse effects, such as fetal loss or reabsorption. The remaining candidates were included and analysed using the novel prioritisation matrix. Two reviewers scored each candidate independently based on the pre-defined criteria in the prioritisation matrix (Supplementary Table 1, Supplementary Data 1). Any differences were resolved via discussion or consulting a third reviewer. Product development and implementability were assessed overall for each candidate, whereas each preclinical study for a single candidate was assessed separately for quality of evidence. For candidates with more than one published study, the average score was calculated and adjusted for the total number of studies (Supplementary Table 1). Each candidate received a final score out of 90 with the following contributions: quality of evidence (58.9%; max total score of 53), product development (28.9%; max total score of 26) and implementability (12.2%; max total score of 11). Once the final score was assigned to each candidate, they were ranked as high, medium or low potential based on cut-off scores (Supplementary Table 1). Results Characteristics of the preclinical medicines pipeline for pre-eclampsia The Maternal Health Pipeline database included 65 preclinical candidate medicines for the prevention and treatment of pre-eclampsia and eclampsia. Following the exclusion of 12 candidates (Supplementary Table 2), 53 candidates were analysed. Of these, 31 (58.5%) were being actively investigated and 22 (41.5%) were inactive (i.e., no published activity since 2018; Table 1). In total, 27 (50.9%) candidates were classified as drugs, 13 (24.5%) as biologics and 13 (24.5%) as dietary supplements (Table 1). Thirty (56.6%) candidates were novel chemical/biological entities, while the remaining 23 (43.4%) candidates were repurposed (Table 1). Four (7.5%) targeted preterm pre-eclampsia, one (1.9%) targeted term pre-eclampsia, two (3.8%) targeted both preterm and term pre-eclampsia, while 46 (86.8%) were undefined (Table 1). Five (9.4%) candidates are being investigated for pre-eclampsia prevention, 26 (49.1%) candidates for pre-eclampsia treatment and one (1.9%) candidate for pre-eclampsia and eclampsia treatment (Table 1). Eleven (20.8%) candidates were being explored as both a prevention and treatment for pre-eclampsia and 10 (18.9%) candidates only investigated symptom management for pre-eclampsia (Table 1). Thirty-eight (71.7%) candidates were being investigated by academic institutes, six (11.3%) by pharmaceutical companies and nine (17.0%) candidates were being explored independently by both academic and pharmaceutical enterprises (Table 1). Preclinical studies for these candidates included in vitro (human placental cell) models and/or in vivo (animal) models. The most common models of pre-eclampsia were the N(ω)-nitro-L-arginine methyl ester pregnant rat model (16 candidates) and the reduced uteroplacental perfusion pressure (RUPP) pregnant rat model (11 candidates). However, 11.3% (6 candidates) were investigated only in pregnant, non-pre-eclamptic animal models. The number of preclinical candidate medicines increased over the 10-year period from 2011-2021 (Fig 2). Preclinical studies of herbal supplements and small molecule drugs were published across the 20-year period, though hydrogen sulfide donors emerged in later years. With the development of biologic technologies, pre-eclampsia-specific DNA, RNA and cell therapies have also been introduced into the R&D pipeline since 2012. Across the 53 candidates, 27 different binding targets were identified. The most common targets were sFlt-1 (six candidates, 11.3%), p38 mitogen-activated protein kinases (MAPK; three candidates, 5.7%), heme-oxygenase-1 (HO-1; three candidates, 5.7%), hypoxia‐inducible factor 1α (HIF‐1α; two candidates, 3.8%) and nuclear factor erythroid 2-related factor 2 (Nrf-2; two candidates, 3.8%) (Supplementary Table 3). All other candidates targeted one specific binding site (24 candidates, 45.3%). For 15 candidates (28.3%) no specific target binding site was identified (Fig 3, Supplementary Table 3). Despite differences in binding sites, many candidate medicines targeted similar mechanisms of action or signalling pathways (21 candidates; 39.6%). These pathways aimed to decrease levels of sFlt-1 or inhibit its release via target binding sites for epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR-1), coenzyme A reductase, HIF‐1α, p38 MAPK, HO-1, Nrf-2, nuclear factor kappa B (NF-κB) and nitric oxide to activate these signalling pathways. Potential of preclinical candidate medicines for pre-eclampsia Of the 53 candidates analysed, the majority were at either TRL 3 (24 candidates) or TRL 3.5 (23 candidates). Only three candidates each were at TRL 4 or TRL 5. Using the prioritisation matrix, eight candidates were ranked as high potential, 37 as medium potential and eight as low potential (Supplementary Data 1). The quality of evidence across preclinical studies, generally, had a moderate risk of bias where very few studies reported the use of randomisation or blinding during experimentation. For the majority of candidates, a mechanism of action was reported. The proposed mechanism of action was related to pre-eclampsia in 67.9% (36 candidates). However, only approximately half these candidates (28; 52.8%) reported evidence supporting the proposed mechanism of action from a pre-eclampsia model. Despite a safe human dose being established in 24 (45.3%) candidates, eight were using an unsafe human dose in preclinical experiments (liraglutide, moxonidine, saireito, scutellaria baicalensis root extract, tetramethylpyrazine, thymus schimperi, toki-shakuyaku-san and vinifera extract). 33-46 Overall, half of all candidate medicines (26; 49.1%) could be administered in oral formulations; the remaining were proposed to be administered as intraarterial, intravenous, subcutaneous, intraperitoneal or intramuscular injections. For two candidates an intended route of administration was not stated. Most candidates (32; 60.4%) would require cold chain transport and storage. High potential candidates Eight candidates were identified as high potential (Table 2) – MZe786, gefitinib, cyclosporin A, SynB1-ELP-p50i, mangiferin, rhPlGF, l-ergothioneine, and azathioprine. Five (62.5%) were investigated by academic institutions and one (12.5%) by a pharmaceutical company. The remaining two (25%) candidates are being explored by both, independently. Five high potential candidates were being investigated for pre-eclampsia treatment, one for pre-eclampsia prevention and two for both prevention and treatment. While most candidates utilise an oral route of administration (MZe786, gefitinib, cyclosporin A, mangiferin, l-ergothioneine, and azathioprine), some required subcutaneous (recombinant human placental growth factor (rhPlGF)) or intravenous injections (SynB1-ELP-p50i). Cold chain storage and transportation was required for four candidates (SynB1-ELP-p50i, mangiferin, rhPlGF, and l-ergothioneine). Gefitinib was the only high-potential candidate with a known safety concern in pregnancy. Alongside sFlt-1 inhibition, gefitinib also inhibits EGFR, which is involved in an essential signalling pathway for normal placental development. 47 As such, regulatory bodies like the Therapeutic Goods Administration have classified it as Category C (suspected of causing harmful effects on the human fetus or neonate without causing malformations) based on other animal studies; no human trials have measured its impact on fetal safety. 48,49 However, no adverse effects were observed in the gefitinib study included in the Maternal Health Pipeline. 50 MZe786, is a novel hydrogen sulfide-releasing aspirin that targets the HO-1 promoter, which is consequentially stimulated as a negative regulator of sFlt-1 (Table 2). 51 MZe786 is actively in development by MirZyme Therapeutics (United Kingdom), for the prevention of pre-eclampsia. Findings from two preclinical studies in two different animal models (RUPP mouse model and HO-1 haploid deficient pregnant mouse model in a high sFlt-1 environment) found that MZe786 was able to successfully prevent pre-eclampsia by reducing mean arterial pressure (MAP), glomerular damage, and levels of sFlt-1 alongside reducing fetal loss and fetal growth restriction. 51,52 Gefitinib is a repurposed drug originally developed to treat cancer. 19 It is being actively investigated in Australia for pre-eclampsia treatment by blocking EGFR. 50 One preclinical study reported a reduction in sFlt-1 following gefitinib treatment in both in vitro (preterm preeclamptic placental tissue and primary cytotrophoblasts, isolated from term normotensive placental tissue) and a pregnant mice model, without affecting pup or placental weight. 50 Gefitinib was administered using tail-vein injection, though it can also be taken orally. Cyclosporin A is an inhibitory repurposed drug that targets calcineurin to supress immune responses by blocking the activation and proliferation of cytotoxic T-cells. 19 Academic institutes in China are actively investigating it as a treatment for preeclampsia and eclampsia. One preclinical study involving administration of cyclosporin A to lipopolysaccharide-induced rats reported significantly reduced mean systolic blood pressure, proteinuria, serum IL-1β, tumour necrosis factor (TNF) -α, and IL-17 levels all while increasing fetal and placental weight. 53 Treatment with cyclosporin A also decreased the seizure severity and prolonged the latency to seizure. 53 Although this study was performed using a once-off intravenous infusion of cyclosporin A, in humans it can be taken orally. SynB1-ELP-p50i is a novel polypeptide delivery system specifically designed to inhibit the NF-κB signalling pathway and decrease TNF-α levels (Table 2). 19 Actively developed by Leflore Technologies (based in USA), SynB1-ELP-p50i is being investigated for pre-eclampsia treatment. Human umbilical vein endothelial cells that were stimulated with TNF-α showed that SynB1-ELP-p50i blocked the translocation of NF-κB into the nucleus. 54 When administered in a RUPP pregnant rat model, pre-eclampsia outcomes were improved by ameliorating placental ischemia-induced hypertension and reducing placental TNF with no signs of toxicity. 54 Mangiferin is a repurposed dietary supplement - a natural, non-steroidal polyphenol. 19 Academic researchers in China are actively investigating mangiferin for the prevention and treatment of pre-eclampsia. By targeting upregulation of Nrf-2 via Pl3K/Akt/mTOR signalling pathway, Mangiferin has high antioxidant, anti-inflammatory and anticancer effects. 55,56 Two preclinical studies have been conducted in two different models; the hyperuricemic rat and the phosphatidylserine/dioleoyl-phosphatidylcholine mouse. 55,56 Both studies found that mangiferin was able to reduce systolic blood pressure and increase nitric oxide secretion as well as attenuate sFlt-1 and rescue placental growth factor expression in the blood and placenta alongside the increased fetal weight in pre-eclamptic models. rhPlGF protein is a novel biological candidate that targets sFlt-1 which is being actively developed by Aggamin LLC (in the USA) and multiple international academic affiliates for pre-eclampsia treatment. 19 The first study in a RUPP pregnant rat model, found that intraperitoneal injections of rhPlGF reduced MAP, oxidative stress and sFlt-1 levels while increasing glomerular filtration. 57 The second study utilised uterine artery ligation in a non-human pregnant primate ( Papio hamadryas ) model, and reported that systolic blood pressure, proteinuria and uteroplacental ischemia were rescued in response to subcutaneous rhPlGF over a five-day period of injections. 58 An ex vivo study in plasma and placenta samples from normotensive and pre-eclamptic patients showed binding placental growth factor to excess sFlt-1 is a viable treatment for pre-eclampsia. 59 L-ergothioneine is an amino-acid and repurposed dietary supplement hypothesised to reduce mitochondrial reactive oxygen species production. 60,61 Although the specific binding partner in pre-eclampsia is not clear, l-ergothioneine is known to bind to Organic Cation Transporter 1 to facilitate antioxidant effects. 19,60 L-ergothioneine is being explored for the prevention and treatment of pre-eclampsia by multiple academic institutions. One preclinical study in the RUPP pregnant rat model reported that mitochondrial reactive oxygen species production mediates the mitochondrial dysfunction demonstrated in pre-eclampsia leading to oxidative damage and a poorly perfused placenta. 61 This study used l-ergothioneine to restore MAP and improve pre-eclampsia outcomes by significantly increasing pup weight while decreasing sFlt-1 levels. 61 Azathioprine is a repurposed drug that was being investigated by Scott and White Memorial Hospital in the USA but is currently inactive (Table 2). 19 While no mechanism of action specific to pre-eclampsia has been proposed, Azathioprine is known to have multiple binding partners including hypoxanthine-guanine phosphoribosyl transferase and thiopurine methyltransferase enzymes. 19 One study using a deoxycorticosterone acetate salt-low renin pregnant rat model reported oral azathioprine significantly attenuated hypertension, proteinuria and endothelial dysfunction in this model. 62 Medium and low potential candidates Of the 53 candidates, 37 were medium potential and eight were low potential candidates. Some medium potential candidates have evidence of efficacy and mechanism of action from preclinical studies and were at TRL 4 (GYY4137, sFlt-1-targeting small interfering RNA (siRNA) and tetramethylpyrazine; Supplementary Table 3) or TRL 5 (etanercept; Supplementary Table 3). 38,39,63-69 Despite having high TRLs, all of these medium potential candidates generally had invasive routes of administration involving intravenous, subcutaneous or intramuscular injections. Additionally, all four candidates require cold chain to be transported and stored stably (Supplementary Data 1). Full results for medium and low potential candidates are included as supplementary data (Supplementary Data 2). Discussion The preclinical R&D pipeline for pre-eclampsia medicines uncovers great innovation potential, especially when compared to the clinical pipeline, which is dominated by repurposed medicines. 16 50% of candidates in preclinical development were novel drugs which target a range of binding partners. Increasing innovation of novel candidates within the preclinical pipeline, such as molecular medicines (RNA/DNA or protein-based therapies), means that developing candidates are more targeted and specific to the complexity of pre-eclampsia and its associated complications. 70 However, 90% of all clinical drug development fails, largely because of reproducibility issues and difficultly translating preclinical evidence to human applications. 71 , 72 Due to this high rate of attrition, it is critical that multiple, diverse candidates continue to be developed so that even one medicine can reach the market. Despite the diversity of the pipeline initially appearing high, our analysis highlights that most candidates are targeting the same mechanism of action, namely a reduction in sFlt-1 signalling. Although the majority of global morbidity and mortality for pre-eclampsia occurs in LMICs, the development of high-potential candidate medicines remains concentrated in high-income countries. 2 Here, we have identified eight preclinical candidates with the strongest potential, warranting investment and advancement to next-stage clinical research. Few studies have analysed the global preclinical R&D medicines pipeline for pre-eclampsia, and none have systematically assessed the potential of candidates. A 2020 narrative review of proposed candidate medicines for the prevention and treatment of pre-eclampsia included some of the high-potential candidates included in this study, such as gefitinib and rhPlGF. 47 Due to the large number of articles identified using the descriptive review search strategy, the authors only focussed on studies published from 2015. 47 This means that inactive (though potentially promising) candidates with studies prior to 2015 are excluded. Published articles were assessed subjectively and prioritised drugs with in vivo preclinical data, to the exclusion of in vitro data. 47 Therefore, the review did not comprehensively assess all available preclinical data. In the current study, the process of assessing and ranking candidates against the prioritisation matrix provides a more objective, drug-agnostic method of ranking candidate potential. It has thus identified several high potential candidates that were not included in previous reviews, namely Mze786, cyclosporin A, SynB1-ELP-p50i, mangiferin, l-ergothioneine and azathioprine. Across the pipeline, the most common proposed mechanism of action was a reduction in sFlt-1 production or inhibition of its release, either directly or through surrogate targets including EGFR, VEGFR-1, coenzyme A reductase, HIF-1α, p38 MAPK, HO-1, Nrf-2, NF-κB and nitric oxide signalling pathways. 73 , 74 sFlt-1 is correlated with the severity of pre-eclampsia, and is increasingly used to facilitate diagnosis of pre-eclampsia, making it a promising target for therapeutic intervention. 75 Evidence from human trials show that removing excess sFlt-1, via therapeutic apheresis with a plasma-specific dextran sulfate column, can reduce circulating levels of this anti-angiogenic protein and safely prolong pregnancies in mothers with preterm pre-eclampsia. 76 , 77 However, sFlt-1 mediated pre-eclampsia is likely only a sub-set of the disease. Specifically, late-onset or term pre-eclampsia, which makes up most of the cases of pre-eclampsia globally, appears to not be mediated by angiogenic factors such as sFlt-1. 78 , 79 As the understanding of sub-categories of pre-eclampsia expands, so too should the preclinical drug targets being explored, to ensure innovation for all types of pre-eclampsia. Greater diversity in target mechanism of action would broaden the scope of possible successful therapies for pre-eclampsia/eclampsia. 1,14 One of the limitations of the current preclinical pipeline is the lack of diversity of animal models for pre-eclampsia. Our analysis identified that over a third of studies were using experimental models that were inappropriate for investigating the effect of candidates against pre-eclampsia. The RUPP rat model was commonly used for in vivo preclinical pre-eclampsia studies. The candidates tested using this model were often proposed to prevent or treat pre-eclampsia by reducing sFlt-1 signalling. However, this model does not mimic compromised placentation characteristic of sFlt-1 mediated preterm pre-eclampsia and so this model is better suited for studying term pre-eclampsia. 80 A 2022 review of available animal models for pre-eclampsia identified the Asb4 deletion mouse as useful for studying very early stages of pre-eclampsia and the Dahl salt-sensitive rat model appropriate for investigating superimposed pre-eclampsia. 81 However, neither model was used in any of the preclinical studies we analysed. Development of new animal models of pre-eclampsia, or improved tools such as physiological based pharmacokinetics, or organs on a chip, that closely mimic the aetiologies underlying either preterm or term pre-eclampsia will aid in the development of more targeted novel medicines for pre-eclampsia. 82 , 83 Strengths and limitations The prioritisation matrix provides a systematic method to assess potential of preclinical candidates from discovery to implementation. It provides a robust and systematic methodology, that can be applied and adapted to other pregnancy-related conditions, including those in the Maternal Health Pipeline. A limitation of the study revolves around data availability. The analysis relies heavily on publicly available information. Novel candidates in very early development typically lack data for implementability questions. This is indicative of the lack of end-to-end thinking in drug development for maternal medicines. 84 Repurposed candidates were more likely to score higher in this domain, which reflects the real-word situation where drugs already on the market for other conditions have more information available and move through to clinical trials more rapidly. 16 Candidates being developed by pharmaceutical companies are more likely to have associated commercial intellectual property rights meaning some information may not be publicly available. As this analysis is considered a living document the intention is to update it as more evidence is generated, and new candidates emerge. Conclusions We identified eight candidate medicines at preclinical stage with high potential for further development. The results from this study can be used to better direct research funding towards these promising candidates. Key limitations in the evidence base on preclinical science for pre-eclampsia medicines includes a lack of diversity in target mechanisms of action, and a lack of appropriate animal models for pre-eclampsia. To assist in finding pre-eclampsia specific medicines, further research into the aetiology of pre-eclampsia is also required. Despite many promising new candidates, R&D in pregnancy-related conditions remains fragile due to limited investment, hindering development of novel pre-eclampsia therapeutics. Greater commitment and coordination between industry, academic institutions and the maternal health field are needed to avoid attrition and develop new, better medicines for pre-eclampsia. Declarations Author contributions JP, KM, FB, AMcD, AA, AMG and JPV were involved in the conceptualisation of the project and the development of the methodology. MG, AT, LK and CV performed data collection and development of the pipeline database. JP and KM performed data collection and analysis of all data. JP and AM performed data visualisation. JP, KM, FB and AMcD were involved in the interpretation of the data. JP and AMcD wrote the original draft of the manuscript, and all authors contributed to writing and editing and had full access to the data. All authors read and approved the final manuscript. Acknowledgements The research was funded by The Gates Foundation (Grant INV-023749, INV-038938). J.P.V. is supported by an Australian National Health and Medical Research Council Emerging Leadership Investigator Grant. A.R.A.M. is supported by the Burnet Institute Lady Potter Emerging Leader Fellowship. Data availability The database generated and analysed during the current study (October 2021 version) is available at: https://www.impactglobalhealth.org/data/maternal-health-pipeline Materials and correspondence Correspondence and material requests should be address to Jessica Postregna ( [email protected] ; 85 Commercial Road, Melbourne VIC 3004, Australia). References Dimitriadis, E. et al. Pre-eclampsia. Nature Reviews Disease Primers 9 , 8 (2023). https://doi.org/10.1038/s41572-023-00417-6 Cresswell, J. A. et al. Global and regional causes of maternal deaths 2009–20: a WHO systematic analysis. The Lancet Global Health 13 , e626-e634 (2025). https://doi.org/https://doi.org/10.1016/S2214-109X(24)00560-6 Hug, L., Alexander, M., You, D. & Alkema, L. 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The absorption, distribution, metabolism and elimination characteristics of small interfering RNA therapeutics and the opportunity to predict disposition in pregnant women. Drug Metab Dispos 53 , 100018 (2025). https://doi.org/10.1124/dmd.123.001383 Ammerdorffer, A. et al. The drug drought in maternal health: an ongoing predicament. The Lancet Global Health 12 , e1174-e1183 (2024). https://doi.org/10.1016/S2214-109X(24)00144-X Tables Table 1: Summary characteristics of the preclinical Maternal Health Pipeline for pre-eclampsia. Pre-eclampsia prevention (n=5) Pre-eclampsia treatment (n=27) Pre-eclampsia prevention and treatment (n=11) Pre-eclampsia symptom management (n=10) TOTAL (n=53) STATUS Active 3(5.7%) 14(26.4%) 7(13.2%) 7(13.2%) 31(58.5%) Inactive 2(3.8%) 13(24.5%) 4(7.5%) 3(5.7%) 22(41.5%) CLASSIFICATION Drugs 3(5.7%) 19(35.9%) 3(5.7%) 2(3.8%) 27(50.9%) Dietary supplements 1(1.9%) 3(5.7%) 3(5.7%) 6(11.3%) 13(24.5%) Biologics 1(1.9%) 5(9.4%) 5(9.4%) 2(3.8%) 13(24.5%) ARCHETYPE Novel 4(7.5%) 15(28.3%) 7(13.2%) 4(7.5%) 30(56.6%) Repurposed 1(1.9%) 12(22.6%) 4(7.5%) 6(11.3%) 23(43.4%) ONSET Preterm pre-eclampsia 4(7.5%) 4(7.5%) Term pre-eclampsia 1(1.9%) 1(1.9%) Preterm and term pre-eclampsia 2(3.8%) 2(3.8%) Undefined 4(7.5%) 21(39.6%) 11(20.8%) 10(18.9%) 46(86.8%) INVESTIGATOR Academic 4(7.5%) 19(35.9%) 7(13.2%) 8(15.1%) 38(71.7%) Pharmaceutical 1(1.9%) 3(5.7%) 1(1.9%) 1(1.9%) 6(11.3%) Both 5(9.4%) 3(5.7%) 1(1.9%) 9(17.0%) Table 2. Summary of high potential preclinical candidate medicines for pre-eclampsia/eclampsia. Drug Candidate Development Status Archetype Target Investigator Therapeutic Indication Quality Product Development Implementability Final Score HIGH POTENTIAL CANDIDATES 1 MZe786 51,52 Active Novel HO1/Hmox1 promoter Pharmaceutical Prevention 34 20 9 63 2 Gefitinib 50 Active Repurposed EGFR inhibitor Academic Treatment 37 16 10 63 3 Cyclosporin A 53 Active Repurposed Calcineurin Academic Treatment 35 15 10 60 4 SynB1-ELP-p50i 54 Active Novel NF-κB Pharmaceutical/Academic Treatment 39 16 3 58 5 Mangiferin 55,56 Active Repurposed PI3K/Akt/mTOR signalling pathway Academic Prevention/ Treatment 31 19 7 57 6 rhPlGF 57-59 Active Novel sFlt-1 Pharmaceutical/Academic Treatment 30.33 21 4 55.33 7 L-ergothioneine 61 Active Repurposed Non-specific Academic Prevention/ Treatment 31 17 7 55 8 Azathioprine 62 Inactive Repurposed Non-specific Academic Treatment 27 18 10 55 Additional Declarations There is NO Competing Interest. 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06:59:28","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":76685,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/3ba97b737e3863384966a19f.png"},{"id":94864484,"identity":"01c6edb1-51d3-4e39-98aa-f3cb1dc2ade6","added_by":"auto","created_at":"2025-10-31 13:39:09","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90385,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/5acaa273ff4430eadaf6b2db.png"},{"id":94986245,"identity":"d53cee8b-a2ed-4760-a4dd-977c8edc4cbd","added_by":"auto","created_at":"2025-11-03 07:00:06","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":176488,"visible":true,"origin":"","legend":"","description":"","filename":"NCOMMS25634760structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/04fb061111785ee8666a7659.xml"},{"id":94986106,"identity":"63a16132-9fee-411a-8f00-f65dc014189a","added_by":"auto","created_at":"2025-11-03 06:59:47","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":190079,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/3ee83b51e8f6eef8c2b530dc.html"},{"id":94864481,"identity":"0de4daed-058e-4422-8379-4751e867581d","added_by":"auto","created_at":"2025-10-31 13:39:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":205058,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression of Technology Readiness Levels (TRLs). \u003c/strong\u003eTRLs are used to measure the maturity of the development of a product. The levels extend from TRL 1, basic research principles observed, to TRL 9, a proven technology already in place or ready for launch. Generally, preclinical drug candidates are between TRL 3 and TRL 5.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/6f309435e5d1b9f4dbe8ce9c.png"},{"id":94864491,"identity":"9194425c-b35c-4d67-a6f1-d0b3f0463eee","added_by":"auto","created_at":"2025-10-31 13:39:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":279641,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTimeline of preclinical candidate medicines for pre-eclampsia.\u003c/strong\u003e Each candidate appears in order of the publication date of the first preclinical study investigating its use for pre-eclampsia from 2000 to 2021. Asterisks denote a novel candidate, and a circle represents a candidate that is currently in actively development Candidate medicines are colour coordinated based on drug classification.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/0296aa012a2820e44ce812e3.png"},{"id":94864487,"identity":"ddfe7108-59d6-4dc9-a483-6d8947c923df","added_by":"auto","created_at":"2025-10-31 13:39:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":318337,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBullseye diagram of preclinical candidates for pre-eclampsia. \u003c/strong\u003eEach ring represents a different technology readiness level (TRL) where the outermost ring is a TRL 3 and the innermost a TRL 5. The diagram is split into the different target binding sites for each drug candidate. The developer of each drug candidate is divided into academic (red), pharmaceutical (yellow) or academic/pharmaceutical (blue) enterprises. Asterisks denote a binding target related to the sFlt-1 signalling pathway.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/e7fc7ddabb848bfc9cb9d367.png"},{"id":95000615,"identity":"e7fb821f-2814-4ee1-9003-592457db24cb","added_by":"auto","created_at":"2025-11-03 08:59:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1921887,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/83c69795-8fcd-40cb-9255-fc34810af0f0.pdf"},{"id":94985335,"identity":"72440a33-02eb-4115-a643-f928935cebf0","added_by":"auto","created_at":"2025-11-03 06:57:58","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":65687,"visible":true,"origin":"","legend":"Supplementary Data 1","description":"","filename":"PostregnaSupplementaryData1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/790ebd53d509e7570b29c69a.xlsx"},{"id":94864489,"identity":"08e013fe-8b06-4126-8d0e-67d693edec5a","added_by":"auto","created_at":"2025-10-31 13:39:09","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":634326,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"PostregnaSupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7361131/v1/dd6d47c2827d0e52c3fcf724.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"The Global Preclinical Research and Development Landscape for Pre-Eclampsia and Eclampsia Therapies.","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePre-eclampsia is the most common hypertensive disorder of pregnancy, affecting approximately 4\u0026nbsp;million women annually, worldwide.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e As a leading cause of maternal and newborn mortality, pre-eclampsia is responsible for more than 60,000 maternal deaths, and approximately 440,000 stillbirths and newborn deaths annually.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Currently, there are few medicines that can prevent or treat this pregnancy complication - the only cure is delivering the baby and placenta. The lack of effective medicines for pre-eclampsia reflects a more generalised lack of investment in research and development (R\u0026amp;D) for maternal conditions.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e More recently, the complex molecular mechanisms underlying pre-eclampsia have been elucidated, particularly the impact of elevated placental soluble fms-like tyrosine kinase 1 (sFlt-1). As an anti-angiogenic factor, rising sFlt-1 levels disrupt healthy blood vessel development and cause endothelial dysfunction.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eMedicines currently recommended by the World Health Organization for pre-eclampsia include low-dose aspirin and calcium supplementation for prevention as well as antihypertensives and magnesium sulfate for treatment. However, they have limited efficacy in some women, and are still underused, particularly in low- and middle-income countries (LMICs).\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e This is driven by scarcity of health resources, variable access to healthcare services, and in the case of preventive low-dose aspirin, the need for risk screening early in pregnancy.\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e There have been no advances in new medicines for pre-eclampsia in the last 30 years that have reached clinical practice.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn 2021, through the Accelerating Innovation for Mothers (AIM) project, we mapped the R\u0026amp;D pipeline for pre-eclampsia and eclampsia medicines.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Between 2000 and 2021, 153 candidate medicines for pre-eclampsia and/or eclampsia were identified, across preclinical and clinical research stages. Previously, we analysed the 32 candidates undergoing clinical research against key criteria in published Target Product Profiles.\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e However, there is currently no defined methodology to assess and rank candidates at the preclinical stage. A critical question remains: which pre-eclampsia medicines from the preclinical R\u0026amp;D pipeline show the greatest potential?\u003c/p\u003e\u003cp\u003eIn the current study we aimed to develop a novel approach to ranking preclinical drug candidates and apply this to the preclinical R\u0026amp;D pipeline for drugs, supplements and biologics to prevent and treat pre-eclampsia and eclampsia. This approach assessed each candidate using three domains - quality of preclinical evidence, the product development stage and implementability. Our assessment has a particular focus on the needs and challenges of pregnant women, providers and healthcare services in LMICs. We also assessed pipeline diversity by mapping drug candidate binding targets and mechanisms of action.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMaternal Health Pipeline database\u003c/h2\u003e\u003cp\u003ePreviously, as part of the AIM project, we conducted a landscape analysis, mapping the current and historic maternal medicines R\u0026amp;D pipeline. Drugs, dietary supplements and biologics investigated, either in preclinical or clinical settings, for five priority pregnancy-related conditions (pre-eclampsia, preterm birth/labour, postpartum haemorrhage, foetal growth restriction and fetal distress) were included.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The methodology to create the database is described elsewhere and the database is publicly available (available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.impactglobalhealth.org/data/maternal-health-pipeline)\u003c/span\u003e\u003cspan address=\"https://www.impactglobalhealth.org/data/maternal-health-pipeline)\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003csup\u003e19,20\u003c/sup\u003e Briefly, initial candidate identification was sourced by systematically searching Adis Insight, Pharmaprojects, World Health Organization\u0026rsquo;s International Clinical Trials Registry Platform, PubMed, and relevant grant databases.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Preclinical and clinical data gathered was used to complete profiles for each candidate, which were then externally validated by independent clinical research specialists.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e For this study, we used the October 2021 version of the Maternal Health Pipeline.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDevelopment of prioritisation matrix\u003c/h3\u003e\n\u003cp\u003eThere are currently no tools to assess preclinical candidates. To address this gap, we developed a novel prioritisation matrix, drawing on several existing tools. Initially we outlined three overarching domains - evidence quality, product development and implementability. These three domains were chosen based on literature review, discussion with experts in the AIM project team, and diverse stakeholder feedback from other AIM activities.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThese domains were then defined using different tools and instruments to advise selected questions. The first domain on quality of preclinical evidence was informed by the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool, and the Quality Assessment Tool For In Vitro Studies (QUIN) tool.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e These tools are designed to assess the quality of preclinical studies for systematic reviews. We used common criteria from each tool, to assess both \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e studies using the same questions. For the second domain (product development) we used the established Technology Readiness Levels (TRL), a tool for assessing the maturity of products (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003csup\u003e\u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29 CR30\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e TRLs 1 through 5 only are applicable to preclinical drug candidates. In this analysis we have also included TRL 3.5, which was defined as a candidate that had evidence of proof of concept in an appropriate pre-eclampsia model, compared to a TRL 3 which were still in the initial trailing phases of proof of concept in any model. The third domain on implementability was informed by selected criteria in the Target Product Profiles for medicines to prevent and treat pre-eclampsia, namely therapeutic indication, route of administration, cold chain requirements and developer type (pharmaceutical and/or academic).\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e A numerical value was assigned to each questions\u0026rsquo; answer options. Assessment questions with greater importance in transitioning preclinical work into clinical trials, such as reliability of evidence and safety, were given greater weight.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext, all assessment questions were reviewed by the AIM research team comprised of experts in the maternal health field to ensure content validity. This prioritisation matrix was then piloted on 10 candidates from the Maternal Health Pipeline to further refine the questions according to information available for each candidate. The prioritisation matrix, containing the complete list of questions used to assess potential, is described in Supplementary Table\u0026nbsp;1.\u003c/p\u003e\n\u003ch3\u003ePreclinical Maternal Health Pipeline diversity\u003c/h3\u003e\n\u003cp\u003eThe diversity of the pipeline was assessed by mapping the research trends over the time period 2000\u0026ndash;2021, as well as the binding targets and mechanisms of action of candidates. Information on drug-specific binding sites was collected from information in the pipeline, supplemented with further literature searches.\u003c/p\u003e\n\u003ch3\u003eAnalysis of preclinical candidates\u003c/h3\u003e\n\u003cp\u003eFirst, we considered all preclinical candidates in the R\u0026amp;D pipeline, and excluded those where: 1) no primary preclinical data were identified, and only a hypothesised role in prevention or treatment of pre-eclampsia was presented in the literature; 2) data was not publicly available or preclinical data was only available from published abstracts; or 3) preclinical evidence suggested significant adverse effects, such as fetal loss or reabsorption.\u003c/p\u003e\u003cp\u003eThe remaining candidates were included and analysed using the novel prioritisation matrix. Two reviewers scored each candidate independently based on the pre-defined criteria in the prioritisation matrix (Supplementary Table\u0026nbsp;1, Supplementary Data 1). Any differences were resolved via discussion or consulting a third reviewer. Product development and implementability were assessed overall for each candidate, whereas each preclinical study for a single candidate was assessed separately for quality of evidence. For candidates with more than one published study, the average score was calculated and adjusted for the total number of studies (Supplementary Table\u0026nbsp;1). Each candidate received a final score out of 90 with the following contributions: quality of evidence (58.9%; max total score of 53), product development (28.9%; max total score of 26) and implementability (12.2%; max total score of 11). Once the final score was assigned to each candidate, they were ranked as high, medium or low potential based on cut-off scores (Supplementary Table\u0026nbsp;1).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCharacteristics of the preclinical medicines pipeline for pre-eclampsia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Maternal Health Pipeline database included 65 preclinical candidate medicines for the prevention and treatment of pre-eclampsia and eclampsia. Following the exclusion of 12 candidates (Supplementary Table 2), 53 candidates were analysed. Of these, 31 (58.5%) were being actively investigated and 22 (41.5%) were inactive (i.e., no published activity since 2018; Table 1). In total, 27 (50.9%) candidates were classified as drugs, 13 (24.5%) as biologics and 13 (24.5%) as dietary supplements (Table 1). Thirty (56.6%) candidates were novel chemical/biological entities, while the remaining 23 (43.4%) candidates were repurposed (Table 1). Four (7.5%) targeted preterm pre-eclampsia, one (1.9%) targeted term pre-eclampsia, two (3.8%) targeted both preterm and term pre-eclampsia, while 46 (86.8%) were undefined (Table 1). Five (9.4%) candidates are being investigated for pre-eclampsia prevention, 26 (49.1%) candidates for pre-eclampsia treatment and one (1.9%) candidate for pre-eclampsia and eclampsia treatment (Table 1). Eleven (20.8%) candidates were being explored as both a prevention and treatment for pre-eclampsia and 10 (18.9%) candidates only investigated symptom management for pre-eclampsia (Table 1). Thirty-eight (71.7%) candidates were being investigated by academic institutes, six (11.3%) by pharmaceutical companies and nine (17.0%) candidates were being explored independently by both academic and pharmaceutical enterprises (Table 1). Preclinical studies for these candidates included \u003cem\u003ein vitro\u003c/em\u003e (human placental cell) models and/or \u003cem\u003ein vivo\u003c/em\u003e (animal) models. The most common models of pre-eclampsia were the N(\u0026omega;)-nitro-L-arginine methyl ester pregnant rat model (16 candidates) and the reduced uteroplacental perfusion pressure (RUPP) pregnant rat model (11 candidates). However, 11.3% (6 candidates) were investigated only in pregnant, non-pre-eclamptic animal models.\u003c/p\u003e\n\u003cp\u003eThe number of preclinical candidate medicines increased over the 10-year period from 2011-2021 (Fig 2). Preclinical studies of herbal supplements and small molecule drugs were published across the 20-year period, though hydrogen sulfide donors emerged in later years. With the development of biologic technologies, pre-eclampsia-specific DNA, RNA and cell therapies have also been introduced into the R\u0026amp;D pipeline since 2012.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcross the 53 candidates, 27 different binding targets were identified. The most common targets were sFlt-1 (six candidates, 11.3%), p38 mitogen-activated protein kinases (MAPK; three candidates, 5.7%), heme-oxygenase-1 (HO-1; three candidates, 5.7%), hypoxia‐inducible factor 1\u0026alpha; (HIF‐1\u0026alpha;; two candidates, 3.8%) and nuclear factor erythroid 2-related factor 2 (Nrf-2; two candidates, 3.8%) (Supplementary Table 3). All other candidates targeted one specific binding site (24 candidates, 45.3%). For 15 candidates (28.3%) no specific target binding site was identified (Fig 3, Supplementary Table 3). Despite differences in binding sites, many candidate medicines targeted similar mechanisms of action or signalling pathways (21 candidates; 39.6%). These pathways aimed to decrease levels of sFlt-1 or inhibit its release via target binding sites for epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR-1), coenzyme A reductase, HIF‐1\u0026alpha;, p38 MAPK, HO-1, Nrf-2, nuclear factor kappa B (NF-\u0026kappa;B) and nitric oxide to activate these signalling pathways.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePotential of preclinical candidate medicines for pre-eclampsia\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 53 candidates analysed, the majority were at either TRL 3 (24 candidates) or TRL 3.5 (23 candidates). Only three candidates each were at TRL 4 or TRL 5. Using the prioritisation matrix, eight candidates were ranked as high potential, 37 as medium potential and eight as low potential (Supplementary Data 1). The quality of evidence across preclinical studies, generally, had a moderate risk of bias where very few studies reported the use of randomisation or blinding during experimentation. For the majority of candidates, a mechanism of action was reported. The proposed mechanism of action was related to pre-eclampsia in 67.9% (36 candidates). However, only approximately half these candidates (28; 52.8%) reported evidence supporting the proposed mechanism of action from a pre-eclampsia model. Despite a safe human dose being established in 24 (45.3%) candidates, eight were using an unsafe human dose in preclinical experiments (liraglutide, moxonidine, saireito, \u003cem\u003escutellaria baicalensis\u003c/em\u003e root extract, tetramethylpyrazine, thymus schimperi, toki-shakuyaku-san and \u003cem\u003evinifera\u003c/em\u003e extract).\u003csup\u003e33-46\u003c/sup\u003e Overall, half of all candidate medicines (26; 49.1%) could be administered in oral formulations; the remaining were proposed to be administered as intraarterial, intravenous, subcutaneous, intraperitoneal or intramuscular injections. For two candidates an intended route of administration was not stated. Most candidates (32; 60.4%) would require cold chain transport and storage. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh potential candidates\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEight candidates were identified as high potential (Table 2) \u0026ndash; MZe786, gefitinib, cyclosporin A, SynB1-ELP-p50i, mangiferin, rhPlGF, l-ergothioneine, and azathioprine. Five (62.5%) were investigated by academic institutions and one (12.5%) by a pharmaceutical company. The remaining two (25%) candidates are being explored by both, independently. Five high potential candidates were being investigated for pre-eclampsia treatment, one for pre-eclampsia prevention and two for both prevention and treatment. While most candidates utilise an oral route of administration (MZe786, gefitinib, cyclosporin A, mangiferin, l-ergothioneine, and azathioprine), some required subcutaneous (recombinant human placental growth factor (rhPlGF)) or intravenous injections (SynB1-ELP-p50i). Cold chain storage and transportation was required for four candidates (SynB1-ELP-p50i, mangiferin, rhPlGF, and l-ergothioneine). Gefitinib was the only high-potential candidate with a known safety concern in pregnancy. Alongside sFlt-1 inhibition, gefitinib also inhibits EGFR, which is involved in an essential signalling pathway for normal placental development.\u003csup\u003e47\u003c/sup\u003e As such, regulatory bodies like the Therapeutic Goods Administration have classified it as Category C (suspected of causing harmful effects on the human fetus or neonate without causing malformations) based on other animal studies; no human trials have measured its impact on fetal safety.\u003csup\u003e48,49\u003c/sup\u003e However, no adverse effects were observed in the gefitinib study included in the Maternal Health Pipeline.\u003csup\u003e50\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eMZe786, is a novel hydrogen sulfide-releasing aspirin that targets the HO-1 promoter, which is consequentially stimulated as a negative regulator of sFlt-1 (Table 2).\u003csup\u003e51\u003c/sup\u003e MZe786 is actively in development by MirZyme Therapeutics (United Kingdom), for the prevention of pre-eclampsia. Findings from two preclinical studies in two different animal models (RUPP mouse model and HO-1 haploid deficient pregnant mouse model in a high sFlt-1 environment) found that MZe786 was able to successfully prevent pre-eclampsia by reducing mean arterial pressure (MAP), glomerular damage, and levels of sFlt-1 alongside reducing fetal loss and fetal growth restriction.\u003csup\u003e51,52\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eGefitinib is a repurposed drug originally developed to treat cancer.\u003csup\u003e19\u003c/sup\u003e It is being actively investigated in Australia for pre-eclampsia treatment by blocking EGFR.\u003csup\u003e50\u003c/sup\u003e One preclinical study reported a reduction in sFlt-1 following gefitinib treatment in both \u003cem\u003ein vitro\u003c/em\u003e (preterm preeclamptic placental tissue and primary cytotrophoblasts, isolated from term normotensive placental tissue) and a pregnant mice model, without affecting pup or placental weight.\u003csup\u003e50\u003c/sup\u003e Gefitinib was administered using tail-vein injection, though it can also be taken orally.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCyclosporin A is an inhibitory repurposed drug that targets calcineurin to supress immune responses by blocking the activation and proliferation of cytotoxic T-cells.\u003csup\u003e19\u003c/sup\u003e Academic institutes in China are actively investigating it as a treatment for preeclampsia and eclampsia. One preclinical study involving administration of cyclosporin A to lipopolysaccharide-induced rats reported significantly reduced mean systolic blood pressure, proteinuria, serum IL-1\u0026beta;, tumour necrosis factor (TNF) -\u0026alpha;, and IL-17 levels all while increasing fetal and placental weight.\u003csup\u003e53\u003c/sup\u003e Treatment with cyclosporin A also decreased the seizure severity and prolonged the latency to seizure.\u003csup\u003e53\u003c/sup\u003e Although this study was performed using a once-off intravenous infusion of cyclosporin A, in humans it can be taken orally.\u003c/p\u003e\n\u003cp\u003eSynB1-ELP-p50i is a novel polypeptide delivery system specifically designed to inhibit the NF-\u0026kappa;B signalling pathway and decrease TNF-\u0026alpha; levels (Table 2).\u003csup\u003e19\u003c/sup\u003e Actively developed by Leflore Technologies (based in USA), SynB1-ELP-p50i is being investigated for pre-eclampsia treatment. Human umbilical vein endothelial cells that were stimulated with TNF-\u0026alpha; showed that SynB1-ELP-p50i blocked the translocation of NF-\u0026kappa;B into the nucleus.\u003csup\u003e54\u003c/sup\u003e When administered in a RUPP pregnant rat model, pre-eclampsia outcomes were improved by ameliorating placental ischemia-induced hypertension and reducing placental TNF with no signs of toxicity.\u003csup\u003e54\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMangiferin is a repurposed dietary supplement - a natural, non-steroidal polyphenol.\u003csup\u003e19\u003c/sup\u003e Academic researchers in China are actively investigating mangiferin for the prevention and treatment of pre-eclampsia. By targeting upregulation of Nrf-2 via Pl3K/Akt/mTOR signalling pathway, Mangiferin has high antioxidant, anti-inflammatory and anticancer effects.\u003csup\u003e55,56\u003c/sup\u003e Two preclinical studies have been conducted in two different models; the hyperuricemic rat and the phosphatidylserine/dioleoyl-phosphatidylcholine mouse.\u003csup\u003e55,56\u003c/sup\u003e Both studies found that mangiferin was able to reduce systolic blood pressure and increase nitric oxide secretion as well as attenuate sFlt-1 and rescue placental growth factor expression in the blood and placenta alongside the increased fetal weight in pre-eclamptic models.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003erhPlGF protein is a novel biological candidate that targets sFlt-1 which is being actively developed by Aggamin LLC (in the USA) and multiple international academic affiliates for pre-eclampsia treatment.\u003csup\u003e19\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eThe first study in a RUPP pregnant rat model, found that intraperitoneal injections of rhPlGF reduced MAP, oxidative stress and sFlt-1 levels while increasing glomerular filtration.\u003csup\u003e57\u003c/sup\u003e The second study utilised uterine artery ligation in a non-human pregnant primate (\u003cem\u003ePapio hamadryas\u003c/em\u003e) model, and reported that systolic blood pressure, proteinuria and uteroplacental ischemia were rescued in response to subcutaneous rhPlGF over a five-day period of injections.\u003csup\u003e58\u003c/sup\u003e An \u003cem\u003eex vivo\u003c/em\u003e study in plasma and placenta samples from normotensive and pre-eclamptic patients showed binding placental growth factor to excess sFlt-1 is a viable treatment for pre-eclampsia.\u003csup\u003e59\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eL-ergothioneine is an amino-acid and repurposed dietary supplement hypothesised to reduce mitochondrial reactive oxygen species production.\u003csup\u003e60,61\u003c/sup\u003e Although the specific binding partner in pre-eclampsia is not clear, l-ergothioneine is known to bind to Organic Cation Transporter 1 to facilitate antioxidant effects.\u003csup\u003e19,60\u003c/sup\u003e L-ergothioneine is being explored for the prevention and treatment of pre-eclampsia by multiple academic institutions. One preclinical study in the RUPP pregnant rat model reported that mitochondrial reactive oxygen species production mediates the mitochondrial dysfunction demonstrated in pre-eclampsia leading to oxidative damage and a poorly perfused placenta.\u003csup\u003e61\u003c/sup\u003e This study used l-ergothioneine to restore MAP and improve pre-eclampsia outcomes by significantly increasing pup weight while decreasing sFlt-1 levels.\u003csup\u003e61\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAzathioprine is a repurposed drug that was being investigated by Scott and White Memorial Hospital in the USA but is currently inactive (Table 2).\u003csup\u003e19\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eWhile no mechanism of action specific to pre-eclampsia has been proposed, Azathioprine is known to have multiple binding partners including hypoxanthine-guanine phosphoribosyl transferase and thiopurine methyltransferase\u0026nbsp;enzymes.\u003csup\u003e19\u003c/sup\u003e One study using a deoxycorticosterone acetate salt-low renin pregnant rat model reported oral azathioprine significantly attenuated hypertension, proteinuria and endothelial dysfunction in this model.\u003csup\u003e62\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMedium and low potential candidates\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 53 candidates, 37 were medium potential and eight were low potential candidates. Some medium potential candidates have evidence of efficacy and mechanism of action from preclinical studies and were at TRL 4 (GYY4137, sFlt-1-targeting small interfering RNA (siRNA) and tetramethylpyrazine; Supplementary Table 3) or TRL 5 (etanercept; Supplementary Table 3).\u003csup\u003e38,39,63-69\u003c/sup\u003e Despite having high TRLs, all of these medium potential candidates generally had invasive routes of administration involving intravenous, subcutaneous or intramuscular injections. Additionally, all four candidates require cold chain to be transported and stored stably (Supplementary Data 1). Full results for medium and low potential candidates are included as supplementary data (Supplementary Data 2).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe preclinical R\u0026amp;D pipeline for pre-eclampsia medicines uncovers great innovation potential, especially when compared to the clinical pipeline, which is dominated by repurposed medicines.\u003csup\u003e16\u003c/sup\u003e 50% of candidates in preclinical development were novel drugs which target a range of binding partners. Increasing innovation of novel candidates within the preclinical pipeline, such as molecular medicines (RNA/DNA or protein-based therapies), means that developing candidates are more targeted and specific to the complexity of pre-eclampsia and its associated complications.\u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e However, 90% of all clinical drug development fails, largely because of reproducibility issues and difficultly translating preclinical evidence to human applications.\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e,\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e Due to this high rate of attrition, it is critical that multiple, diverse candidates continue to be developed so that even one medicine can reach the market. Despite the diversity of the pipeline initially appearing high, our analysis highlights that most candidates are targeting the same mechanism of action, namely a reduction in sFlt-1 signalling. Although the majority of global morbidity and mortality for pre-eclampsia occurs in LMICs, the development of high-potential candidate medicines remains concentrated in high-income countries.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Here, we have identified eight preclinical candidates with the strongest potential, warranting investment and advancement to next-stage clinical research.\u003c/p\u003e\u003cp\u003eFew studies have analysed the global preclinical R\u0026amp;D medicines pipeline for pre-eclampsia, and none have systematically assessed the potential of candidates. A 2020 narrative review of proposed candidate medicines for the prevention and treatment of pre-eclampsia included some of the high-potential candidates included in this study, such as gefitinib and rhPlGF.\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e Due to the large number of articles identified using the descriptive review search strategy, the authors only focussed on studies published from 2015.\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e This means that inactive (though potentially promising) candidates with studies prior to 2015 are excluded. Published articles were assessed subjectively and prioritised drugs with \u003cem\u003ein vivo\u003c/em\u003e preclinical data, to the exclusion of \u003cem\u003ein vitro\u003c/em\u003e data.\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e Therefore, the review did not comprehensively assess all available preclinical data. In the current study, the process of assessing and ranking candidates against the prioritisation matrix provides a more objective, drug-agnostic method of ranking candidate potential. It has thus identified several high potential candidates that were not included in previous reviews, namely Mze786, cyclosporin A, SynB1-ELP-p50i, mangiferin, l-ergothioneine and azathioprine.\u003c/p\u003e\u003cp\u003eAcross the pipeline, the most common proposed mechanism of action was a reduction in sFlt-1 production or inhibition of its release, either directly or through surrogate targets including EGFR, VEGFR-1, coenzyme A reductase, HIF-1α, p38 MAPK, HO-1, Nrf-2, NF-κB and nitric oxide signalling pathways.\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e sFlt-1 is correlated with the severity of pre-eclampsia, and is increasingly used to facilitate diagnosis of pre-eclampsia, making it a promising target for therapeutic intervention.\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e Evidence from human trials show that removing excess sFlt-1, via therapeutic apheresis with a plasma-specific dextran sulfate column, can reduce circulating levels of this anti-angiogenic protein and safely prolong pregnancies in mothers with preterm pre-eclampsia.\u003csup\u003e\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e,\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u003c/sup\u003e However, sFlt-1 mediated pre-eclampsia is likely only a sub-set of the disease. Specifically, late-onset or term pre-eclampsia, which makes up most of the cases of pre-eclampsia globally, appears to not be mediated by angiogenic factors such as sFlt-1.\u003csup\u003e\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e,\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e As the understanding of sub-categories of pre-eclampsia expands, so too should the preclinical drug targets being explored, to ensure innovation for all types of pre-eclampsia. Greater diversity in target mechanism of action would broaden the scope of possible successful therapies for pre-eclampsia/eclampsia.\u003csup\u003e1,14\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOne of the limitations of the current preclinical pipeline is the lack of diversity of animal models for pre-eclampsia. Our analysis identified that over a third of studies were using experimental models that were inappropriate for investigating the effect of candidates against pre-eclampsia. The RUPP rat model was commonly used for \u003cem\u003ein vivo\u003c/em\u003e preclinical pre-eclampsia studies. The candidates tested using this model were often proposed to prevent or treat pre-eclampsia by reducing sFlt-1 signalling. However, this model does not mimic compromised placentation characteristic of sFlt-1 mediated preterm pre-eclampsia and so this model is better suited for studying term pre-eclampsia.\u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u003c/sup\u003e A 2022 review of available animal models for pre-eclampsia identified the Asb4 deletion mouse as useful for studying very early stages of pre-eclampsia and the Dahl salt-sensitive rat model appropriate for investigating superimposed pre-eclampsia.\u003csup\u003e\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u003c/sup\u003e However, neither model was used in any of the preclinical studies we analysed. Development of new animal models of pre-eclampsia, or improved tools such as physiological based pharmacokinetics, or organs on a chip, that closely mimic the aetiologies underlying either preterm or term pre-eclampsia will aid in the development of more targeted novel medicines for pre-eclampsia.\u003csup\u003e\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e,\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and limitations\u003c/h2\u003e\u003cp\u003eThe prioritisation matrix provides a systematic method to assess potential of preclinical candidates from discovery to implementation. It provides a robust and systematic methodology, that can be applied and adapted to other pregnancy-related conditions, including those in the Maternal Health Pipeline. A limitation of the study revolves around data availability. The analysis relies heavily on publicly available information. Novel candidates in very early development typically lack data for implementability questions. This is indicative of the lack of end-to-end thinking in drug development for maternal medicines.\u003csup\u003e\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u003c/sup\u003e Repurposed candidates were more likely to score higher in this domain, which reflects the real-word situation where drugs already on the market for other conditions have more information available and move through to clinical trials more rapidly.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Candidates being developed by pharmaceutical companies are more likely to have associated commercial intellectual property rights meaning some information may not be publicly available. As this analysis is considered a living document the intention is to update it as more evidence is generated, and new candidates emerge.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe identified eight candidate medicines at preclinical stage with high potential for further development. The results from this study can be used to better direct research funding towards these promising candidates. Key limitations in the evidence base on preclinical science for pre-eclampsia medicines includes a lack of diversity in target mechanisms of action, and a lack of appropriate animal models for pre-eclampsia. To assist in finding pre-eclampsia specific medicines, further research into the aetiology of pre-eclampsia is also required. Despite many promising new candidates, R\u0026amp;D in pregnancy-related conditions remains fragile due to limited investment, hindering development of novel pre-eclampsia therapeutics. Greater commitment and coordination between industry, academic institutions and the maternal health field are needed to avoid attrition and develop new, better medicines for pre-eclampsia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJP, KM, FB, AMcD, AA, AMG and JPV were involved in the conceptualisation of the project and the development of the methodology. MG, AT, LK and CV performed data collection and development of the pipeline database. JP and KM performed data collection and analysis of all data. JP and AM performed data visualisation. JP, KM, FB and AMcD were involved in the interpretation of the data. JP and AMcD wrote the original draft of the manuscript, and all authors contributed to writing and editing and had full access to the data. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research was funded by The Gates Foundation (Grant INV-023749, INV-038938). J.P.V. is supported by an Australian National Health and Medical Research Council Emerging Leadership Investigator Grant. A.R.A.M. is supported by the Burnet Institute Lady Potter Emerging Leader Fellowship.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe database generated and analysed during the current study (October 2021 version) is available at: https://www.impactglobalhealth.org/data/maternal-health-pipeline\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and correspondence\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence and material requests should be address to Jessica Postregna ([email protected]; 85 Commercial Road, Melbourne VIC 3004, Australia).\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDimitriadis, E.\u003cem\u003e et al.\u003c/em\u003e Pre-eclampsia. \u003cem\u003eNature Reviews Disease Primers\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 8 (2023). https://doi.org/10.1038/s41572-023-00417-6\u003c/li\u003e\n\u003cli\u003eCresswell, J. 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W.\u003cem\u003e et al.\u003c/em\u003e Tumor necrosis factor alpha (TNF-\u0026alpha;) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia. \u003cem\u003eHypertens Pregnancy\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 399-404 (2020). https://doi.org/10.1080/10641955.2020.1793999\u003c/li\u003e\n\u003cli\u003eHanisch, M. \u0026amp; Rake, B. Repurposing without purpose? Early innovation responses to the COVID-19 crisis: Evidence from clinical trials. \u003cem\u003eR\u0026amp;D Management\u003c/em\u003e \u003cstrong\u003e51\u003c/strong\u003e, 393-409 (2021). https://doi.org/https://doi.org/10.1111/radm.12461\u003c/li\u003e\n\u003cli\u003eSun, D., Gao, W., Hu, H. \u0026amp; Zhou, S. Why 90% of clinical drug development fails and how to improve it? \u003cem\u003eActa Pharmaceutica Sinica B\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 3049-3062 (2022). https://doi.org/https://doi.org/10.1016/j.apsb.2022.02.002\u003c/li\u003e\n\u003cli\u003eSeyhan, A. A. Lost in translation: the valley of death across preclinical and clinical divide \u0026ndash; identification of problems and overcoming obstacles. \u003cem\u003eTranslational Medicine Communications\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 18 (2019). https://doi.org/10.1186/s41231-019-0050-7\u003c/li\u003e\n\u003cli\u003eBurton, G. J., Redman, C. W., Roberts, J. M. \u0026amp; Moffett, A. Pre-eclampsia: pathophysiology and clinical implications. \u003cem\u003eBMJ\u003c/em\u003e \u003cstrong\u003e366\u003c/strong\u003e, l2381 (2019). https://doi.org/10.1136/bmj.l2381\u003c/li\u003e\n\u003cli\u003eStaff, A. C. The two-stage placental model of preeclampsia: An update. \u003cem\u003eJournal of Reproductive Immunology\u003c/em\u003e \u003cstrong\u003e134-135\u003c/strong\u003e, 1-10 (2019). https://doi.org/https://doi.org/10.1016/j.jri.2019.07.004\u003c/li\u003e\n\u003cli\u003eVerlohren, S.\u003cem\u003e et al.\u003c/em\u003e Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia. \u003cem\u003ePregnancy Hypertension\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 42-50 (2022). https://doi.org/https://doi.org/10.1016/j.preghy.2021.12.003\u003c/li\u003e\n\u003cli\u003eThadhani, R.\u003cem\u003e et al.\u003c/em\u003e Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. \u003cem\u003eCirculation\u003c/em\u003e \u003cstrong\u003e124\u003c/strong\u003e, 940-950 (2011). https://doi.org/10.1161/circulationaha.111.034793\u003c/li\u003e\n\u003cli\u003eThadhani, R.\u003cem\u003e et al.\u003c/em\u003e Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia. \u003cem\u003eJ Am Soc Nephrol\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 903-913 (2016). https://doi.org/10.1681/asn.2015020157\u003c/li\u003e\n\u003cli\u003eLevine Richard, J.\u003cem\u003e et al.\u003c/em\u003e Circulating Angiogenic Factors and the Risk of Preeclampsia. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e \u003cstrong\u003e350\u003c/strong\u003e, 672-683 https://doi.org/10.1056/NEJMoa031884\u003c/li\u003e\n\u003cli\u003eVerlohren, S. \u0026amp; Dr\u0026ouml;ge, L. A. The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia. \u003cem\u003eAm J Obstet Gynecol\u003c/em\u003e \u003cstrong\u003e226\u003c/strong\u003e, S1048-s1058 (2022). https://doi.org/10.1016/j.ajog.2020.09.046\u003c/li\u003e\n\u003cli\u003eYang, Y.\u003cem\u003e et al.\u003c/em\u003e The Potent Antioxidant MitoQ Protects Against Preeclampsia During Late Gestation but Increases the Risk of Preeclampsia When Administered in Early Pregnancy. \u003cem\u003eAntioxid Redox Signal\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 118-136 (2021). https://doi.org/10.1089/ars.2019.7891\u003c/li\u003e\n\u003cli\u003eBakrania, B. A., George, E. M. \u0026amp; Granger, J. P. Animal models of preeclampsia: investigating pathophysiology and therapeutic targets. \u003cem\u003eAm J Obstet Gynecol\u003c/em\u003e \u003cstrong\u003e226\u003c/strong\u003e, S973-s987 (2022). https://doi.org/10.1016/j.ajog.2020.10.025\u003c/li\u003e\n\u003cli\u003eHarrison, A. M. \u0026amp; Bailey-Hytholt, C. M. Recent progress in 2D, 3D, and on-a-chip models of the placenta. \u003cem\u003eCells Tissues Organs\u003c/em\u003e, 1-50 (2025). https://doi.org/10.1159/000547560\u003c/li\u003e\n\u003cli\u003eAmaeze, O., Isoherranen, N. \u0026amp; Shum, S. The absorption, distribution, metabolism and elimination characteristics of small interfering RNA therapeutics and the opportunity to predict disposition in pregnant women. \u003cem\u003eDrug Metab Dispos\u003c/em\u003e \u003cstrong\u003e53\u003c/strong\u003e, 100018 (2025). https://doi.org/10.1124/dmd.123.001383\u003c/li\u003e\n\u003cli\u003eAmmerdorffer, A.\u003cem\u003e et al.\u003c/em\u003e The drug drought in maternal health: an ongoing predicament. \u003cem\u003eThe Lancet Global Health\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, e1174-e1183 (2024). https://doi.org/10.1016/S2214-109X(24)00144-X\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Summary characteristics of the preclinical Maternal Health Pipeline for pre-eclampsia.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-eclampsia prevention (n=5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-eclampsia treatment (n=27)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-eclampsia prevention and treatment (n=11)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-eclampsia symptom management (n=10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=53)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 601px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTATUS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eActive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e14(26.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e7(13.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e7(13.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e31(58.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInactive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2(3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e13(24.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e4(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22(41.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 601px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCLASSIFICATION\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrugs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e19(35.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e2(3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e27(50.9%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDietary supplements\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e6(11.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13(24.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiologics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e5(9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e5(9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e2(3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13(24.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 601px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eARCHETYPE\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNovel\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e15(28.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e7(13.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e4(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e30(56.6%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRepurposed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e12(22.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e4(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e6(11.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e23(43.4%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 601px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eONSET\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreterm pre-eclampsia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4(7.5%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTerm pre-eclampsia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1(1.9%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreterm and term pre-eclampsia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e2(3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2(3.8%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUndefined\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e21(39.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e11(20.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e10(18.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e46(86.8%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 601px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eINVESTIGATOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcademic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4(7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e19(35.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e7(13.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e8(15.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e38(71.7%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePharmaceutical\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6(11.3%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBoth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cul\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e5(9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e3(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9(17.0%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Summary of high potential preclinical candidate medicines for pre-eclampsia/eclampsia.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"1058\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug Candidate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDevelopment Status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArchetype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTarget\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInvestigator\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTherapeutic Indication\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQuality\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProduct Development\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImplementability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFinal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eScore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"11\" valign=\"top\" style=\"width: 1058px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHIGH POTENTIAL CANDIDATES\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMZe786\u003csup\u003e51,52\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHO1/Hmox1\u0026nbsp;\u003c/p\u003e\n \u003cp\u003epromoter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ePharmaceutical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePrevention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eGefitinib\u003csup\u003e50\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eRepurposed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eEGFR inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eAcademic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eTreatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eCyclosporin A\u003csup\u003e53\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eRepurposed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eCalcineurin\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eAcademic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eTreatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eSynB1-ELP-p50i\u003csup\u003e54\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNF-\u0026kappa;B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ePharmaceutical/Academic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eTreatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eMangiferin\u003csup\u003e55,56\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eRepurposed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003ePI3K/Akt/mTOR\u0026nbsp;signalling pathway\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eAcademic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePrevention/\u003c/p\u003e\n \u003cp\u003eTreatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003erhPlGF\u003csup\u003e57-59\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esFlt-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ePharmaceutical/Academic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n 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\u003cp\u003eNon-specific\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eAcademic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePrevention/ Treatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eAzathioprine\u003csup\u003e62\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eInactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eRepurposed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eNon-specific\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eAcademic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eTreatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7361131/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7361131/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSurprisingly few medicines are available to prevent or manage pre-eclampsia, all of which are repurposed from non-pregnant populations and conditions. Analyses of clinical research and development (R\u0026amp;D) pipelines for pre-eclampsia medicines has identified high-potential candidates, however the preclinical pipeline has not been interrogated. We analysed and ranked the potential of 53 preclinical candidates for pre-eclampsia and eclampsia identified in a novel Maternal Health Pipeline spanning 2000 to 2021. Candidates were assessed across three domains \u0026ndash; quality of preclinical evidence, product development stage and implementability. Each question in the prioritisation matrix was assigned a numerical value based on importance. The sum of these values was used to rank the potential of each candidate for future research. Among the 53 candidates analysed, 56.6% of which are novel medicines, 27 different binding targets were identified; the purported mechanism of action for 21 candidates was a reduction in sFlt-1. We identified eight high-potential candidates, three of which were novel, that should be prioritised for further development.\u003c/p\u003e","manuscriptTitle":"The Global Preclinical Research and Development Landscape for Pre-Eclampsia and Eclampsia Therapies.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-31 13:39:04","doi":"10.21203/rs.3.rs-7361131/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1f722db1-feac-4188-894c-3d707437a1fc","owner":[],"postedDate":"October 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":53495172,"name":"Health sciences/Medical research/Drug development"},{"id":53495173,"name":"Health sciences/Medical research/Preclinical research"},{"id":53495174,"name":"Biological sciences/Physiology/Reproductive biology"}],"tags":[],"updatedAt":"2025-10-31T13:39:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-31 13:39:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7361131","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7361131","identity":"rs-7361131","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}