Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles

Abstract

Background: The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs.

Methods: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass.

Results: The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols.

Conclusions: This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.

Keywords: Chloroquine; Drug development; Esomeprazole; Hypertension; L-Arginine; Maternal medicine; Metformin; Pregnancy; Sulfasalazine; Vitamin D.

Fig. 1

Details of the candidates in the R&D pipeline for pre-eclampsia. Summary of the 153 candidates in the R&D pipeline for the prevention and treatment of pre-eclampsia from 2000 to 2021. The proportion of candidates A in active development, and inactive (no publications since 2018), B in each phase of the development pipeline C classified as drugs, dietary supplements or biologicals and D classified as new chemical or biological entities or repurposed drugs

Fig. 2

Flowchart of assessment of candidates against the eligibility criteria

Fig. 3

Visual representation of target product profile matching for candidates to prevent pre-eclampsia. A traffic light system to visualise each candidate for pre-eclampsia prevention at A phase III, B phase II and C phase I clinical development. Candidates are classified as met preferred (dark green), met minimum (light green), partially met minimum (yellow) and did not meet the minimum (red) requirements in the target product profiles. When insufficient information is available for a specific variable, they have been classified as not yet known (grey). *Target country is classified as trials being conducted in HIC and LMIC (dark green), HIC only or LMIC only (both yellow) or country not stated (grey). **Stability has been classified as does not require cold chain (green), requires cold chain (red) or unsure (grey). #WHO EML is classified as the candidate is already on the WHO EML list (green) or the candidate is not on the WHO EML list (red). The final rank has been determined by quantification of the matching to the target product profiles (see Additional file 1: tables S3 and S4 for details of quantification coding), with efficacy and safety given a greater weight than other variables. HIC high-income country, LMIC low- or middle-income country, EML essential medicines list

Fig. 4

Visual representation of target product profile matching for candidates to treat pre-eclampsia. A traffic light system to visualise each candidate for pre-eclampsia treatment at A phase III, B phase II and C phase I clinical development. Candidates are classified as met preferred (dark green), met minimum (light green), partially met minimum (yellow) and did not meet the minimum (red) requirements in the target product profiles. When insufficient information is available for a specific variable, they have been classified as not yet known (grey). *Target country is classified as trials being conducted in HIC and LMIC (dark green), HIC only or LMIC only (both yellow) or country not stated (grey). **Stability has been classified as does not require cold chain (green), requires cold chain (red) or unsure (grey). #WHO is classified as candidate is already on the WHO EML list (green), or candidate is not on the WHO EML list (red). The final rank has been determined by quantification of the matching to the target product profiles (see Additional file 1: tables S3 and S4 for details of quantification coding), with efficacy and safety given a greater weight than other variables. HIC high-income country, LMIC low- or middle-income country, EML essential medicines list

Fig. 5

Details of the included preclinical candidates in the research and development pipeline for pre-eclampsia prevention and treatment. Summary of the preclinical candidates in the R&D pipeline for the prevention and treatment of pre-eclampsia from 2000 to 2021. The proportion of candidates A in active development, and inactive (no publications since 2018); B classified as drugs, dietary supplements or biologicals; and C classified as new chemical or biological entities or repurposed drugs