Anna David Reader in Obstetrics and Maternal Fetal Medicine The EVERREST Project: Developing a maternal gene therapy for severe early onset fetal growth restriction Anna David Reader in Obstetrics and Maternal Fetal Medicine 27/02/2019

Fetal Growth Restriction Failure to achieve your growth potential in utero 8% pregnancies Contributes to 50% of stillbirths Mostly due to placental insufficiency No treatment 27/02/2019

Placental insufficiency Trophoblast invades the spiral arteries converting them into high flow, low resistance vessels In FGR there is less trophoblast invasion, reduced uterine artery perfusion Moffett-King A, 2002 Non-pregnant FGR Pregnant 27/02/2019

Utero-placental perfusion Placental insufficiency Uteroplacental blood flow is proportional to fetal size (Konje et al. 2003) Uterine blood flow (ml/min) Gestational Age (Weeks) FGR = fetal growth restriction AGA = appropriately grown for gestation Sheep pregnancy

Neonatal outcomes in fetal growth restriction Between 23 and 26 weeks of gestation, an increase in birthweight of 100g reduces the risk of dying by 40%. total survival Increasing the gestational age by 1 week will reduce costs by 30% over the preterm range % survival without disability median survival gained per day in utero is 2% (range 1.1–2.6) between 24 and 27 weeks of gestation. Baschat et al 2007 Gestational age at birth

The cost of severe Fetal Growth Restriction The cost of caring for babies to discharge £39,483 / €45,397, this is 50% higher than babies born weighing over 1000g Increasing the gestational age at birth by 1 week will reduce costs by 30% over the early preterm range 27/02/2019

Hypothesis behind the EVERREST treatment Delivery of adenovirus vector containing VEGF gene to maternal uterine artery Local over-expression of VEGF Normal and FGR sheep ✔ Normal and FGR guinea pigs ✔ Increase fetal growth in severe FGR Increase uterine blood flow Normal sheep ✔ Alter uterine artery vascular tone & angiogenesis Normal and FGR sheep ✔ Normal and FGR guinea pigs ✔ FGR sheep ✔ FGR guinea pigs ✔ 27/02/2019

ethical & regulatory approval Phase I/IIa safety/efficacy study scientific advice original idea ethical & regulatory approval Phase I/IIa safety/efficacy study 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 bioethics 27/02/2019

EVERREST Does vascular endothelial growth factor gene therapy safely improve outcome in severe early-onset fetal growth restriction? Bioethics study - completed Reproductive toxicology - ongoing Prospective observational study - ongoing First-in-woman phase I/IIa safety/efficacy study – late 2016

First-in-woman trial Prospective study on untreated patients 2013-2018 collecting data on affected pregnancies Clinical trial 2015-2018 Inclusion criteria: Severe early onset FGR >22 weeks and <26 weeks of gestation Uteroplacental insufficiency Exclude other causes of FGR Vector instilled into uterine artery for 5 minutes using interventional radiology Primary outcome is safety Secondary efficacy and exploratory outcomes

EVERREST Prospective Study Putting together a: Clinical database and Biobank of samples from pregnancies affected by severe early onset Fetal Growth Restriction to Provide detailed information on adverse events to inform the clinical trial Develop methods to provide prognostic information at the time of diagnosis 27/02/2019

What the prospective study involves Collecting information about the woman 27/02/2019

What the prospective study involves Collecting samples Maternal blood ( 30ml) Maternal blood ( 30ml) Cord blood Placenta & umbilical cord Myometrial & placental bed biopsy (Caesarean only)

What the prospective study involves Collecting information about the fetus/baby Maternal blood ( 30ml) Maternal blood ( 30ml) Cord blood Placenta & umbilical cord Myometrial & placental bed biopsy (Caesarean only) As per routine clinical care 27/02/2019

EFW <3rd centile & <600g How you can help Live singleton fetus 20+0 – 26+6 EFW <3rd centile & <600g Refer to UCLH FMU For more details / any questions: Ask the team: phone, email Look at the website 27/02/2019

Summary Severe early onset fetal growth restriction has high mortality and morbidity, and a high cost An effective treatment is needed Maternal VEGF growth factor gene therapy improves fetal growth in pre-clinical studies EVERREST prospective study is carefully collecting data on outcomes of severe early onset FGR EVERREST clinical trial will study safety and efficacy of maternal VEGF growth factor gene therapy 27/02/2019

www.everrest-fp7.eu PI: Anna David Twitter @FP7EVERREST a.david@ucl.ac.uk Twitter @FP7EVERREST