Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - EVERREST (Does vascular endothelial growth factor gene therapy safely improve outcome in severe early-onset fetal growth restriction?)

Project Context and Objectives:
Severe, early onset fetal growth restriction (FGR) affects 11,000 babies annually in the EU. In most cases, reduced uterine blood flow restricts substrate delivery to the fetus causing growth to slow or cease. There are no therapies that improve fetal growth in utero. Current management of FGR involves very preterm delivery of the fetus (before 28 weeks of gestation), before death occurs in utero, with the aim of minimising irreversible organ damage, particularly to the brain. This adds additional risks to the baby from extremely preterm birth, with its own attendant short and long-term complications; affected neonates suffer intracranial haemorrhage, chronic lung disease, cerebral palsy, with heart disease and diabetes as adults. Furthermore FGR may be detected while the fetal weight is far below 500g, a situation considered by many to be non-viable. From cohort studies and local data, we estimate that the cumulative stillbirth/morbidity/neonatal mortality rate in pregnancies affected by severe early onset FGR is between 75-80%.

Recent improvements in the care of premature growth restricted neonates means that more neonates survive delivery, but at great cost. Survival studies suggest, however, that even modest increases in birthweight (e.g from 500 to 600g) and gestation at delivery (e.g from 26 to 27 weeks) are associated with significant improvements in mortality and morbidity. Improving uterine blood flow is key and Vascular Endothelial Growth Factor (VEGF) is important to achieve this. In preclinical animal models, EVERREST consortium partners have shown that local VEGF gene transfer to the uteroplacental circulation using adenovirus vectors increases uterine blood flow, attenuates constriction of uterine arteries and increases angiogenesis; these changes result in improved growth of severely growth restricted fetuses.

The aim of the EVERREST project is to translate these findings from bench to bedside by developing the first clinically applicable evidence based therapy that could improve perinatal outcome in severe early onset FGR. The project has three key objectives:
1) To complete a reproductive toxicology programme in rabbits to include analysis of the biodistribution of the adenoviral vector after injection into the maternal uterine artery and intense examination for any possible exposure of the fetuses to the vector, or any effects on their prenatal or postnatal development.
2) To review the literature on gene therapy, experimental treatment of pregnant women and fetal medicine research to clarify the ethical, legal and regulatory issues relevant to the conduct of the EVERREST clinical trial, and to evaluate the ethical and social acceptability of the EVERREST trial and intervention in couples affected by severe early onset FGR and a wide range of stakeholder groups across the EVERREST partner member states.
3) To perform an uncontrolled, open-label, dose finding Phase I/II (to mother and baby) study in 15 and up to 27 pregnancies affected by severe early onset FGR, at four centres of excellence in the EU, of VEGF in an adenoviral vector, delivered to the maternal uterine artery using minimally invasive techniques to show (a) safety and tolerability, and (b) efficacy by improving the reduction in uterine blood flow by 50%, when compared to historical data from untreated pregnancies affected by severe early onset FGR. Exploratory end-points of fetal growth and gestational age at delivery, and a composite outcome for fetal and neonatal mortality and serious morbidity will also be studied and compared with historical cohort data.

Project Results:
The EVERREST consortium has made good progress towards each of its objectives during the second period of the project:

Pre-clinical toxicology
During the second period of the project, the reproductive toxicology study conducted to Good Laboratory Practice standards began using the specific VEGF-D adenovirus vector developed by partner FinVector (Objective 1). The study is being done by a CRO with experience in conducting reproductive toxicology studies to GLP. We anticipate it will report in August 2016. This study will be used to assess the safety of the Investigational Product and ultimately to establish the doses to be used in the clinical study.

Bioethics Study
For Objective 2, during Period 1 of the project a literature review of the ethical, legal, regulatory and policy literature on experimental therapy in pregnant women and the evaluation of the acceptability of this technology to affected women, and to society was carried out. Neither the findings of the literature review, nor the semi-structured interviews with stakeholders and women who had had previous pregnancies, identified any fundamental or insurmountable objections to a trial of maternal gene therapy for severe early onset FGR.

An article outlining the work conducted and its findings has been accepted for publication (February 2016) in Ultrasound in Obstetrics and Gynecology, the journal of the International Society of Ultrasound in Obstetrics and Gynecology.

Clinical study design (Prospective study)
The EVERREST Prospective Study is now running at all four sites, recruiting women who have babies with an estimated fetal weight less than the 3rd centile between 20 and 26+6 weeks of pregnancy in the UK, Spain and Sweden. This forms part of Objective 3, providing “historical data from untreated pregnancies affected by severe early onset FGR”. The detailed clinical database and biobank of samples which we are collecting as part of this study, including neurodevelopmental follow up for 2 years for surviving babies and children, will help us assess the safety of the gene therapy during the clinical trial. So far we have recruited 60 women to the prospective observational study: 45 at UCLH, 6 in Barcelona, 5 in Hamburg, and 4 in Lund, and some born babies are reaching their first birthdays.

Clinical vector manufacture
The vector for use in the clinical trial has been manufactured by partner FinVector to GMP specifications and is now being stored. Once the results of the reproductive toxicology study are known, the vector will be vialled to the correct doses for the clinical trial and then tested for quality before release for the clinical trial. A stability testing programme will also be initiated.

Ethical and Regulatory Approval
In Q1 2015 Magnus, on behalf of the EVERREST project, was awarded Orphan Drug status for the Ad.VEGF-DΔNΔC programme. This represents a significant success for the programme both in terms of scientific validation from the EMA and commercial opportunity that this status brings. The EMA’s Public Summary of Opinion on our designation can be read here:

Phase I/IIa Clinical Trial Protocol
Development of the EVERREST Clinical Trial protocol for Objective 3 has been a multinational and multi-disciplinary exercise. There has been regular input from the various disciplines within the EVERREST consortium. The protocol will be finalised once the results of the reproductive toxicology study are available. Following receipt of these results, a review version of the protocol will be prepared. This will undergo evaluation, and if necessary amendment, by the Consortium, Independent Ethics Committee, Data Safety Monitoring Board, UCL Protocol Review Committee, and Trial Steering Committee, before the final version is approved and submitted for ethical and regulatory approval.

Potential Impact:
The EVERREST consortium has established that there are no fundamental ethical objections to a clinical trial of maternal uterine artery administration of VEGF in an adenoviral vector to women with pregnancies affected by severe early onset FGR. The publication in the journal Ultrasound in Obstetrics and Gynecology outlines these findings.

The consortium identified the need for an internationally recognised set of definitions and grading criteria for pregnancy-related adverse events (AEs) reported during clinical trials. Furthermore, the terms for many fetal AEs were not included in the Medical Dictionary for Regulatory Activities (MedDRA). To address this issue, the EVERREST International AE Consensus Group met in May 2015. Through review of the current literature, national and international guidelines, expert discussion, and a process of iterative review, draft sets of maternal and fetal adverse event severity grading criteria were developed. Through discussion with MedDRA some AE terms used in the criteria have been refined to fit into the structure of the dictionary, and several new fetal AE terms have been accepted.

The clinical trial will aim to demonstrate the safety and tolerability of VEGF in an adenoviral vector in women with pregnancies affected by severe early onset FGR, and will aim to gain initial insights into the efficacy of the product. These data will enable further development of the therapy through clinical trials to demonstrate efficacy, and support regulatory approval and commercial launch. Our aspiration for this therapy, should we find that it is safe and effective, is for it to become the standard of care in the EU within the next 15-20 years.

The prospective study collecting data and samples from women who experience severe early onset FGR will be the first database of its kind and will be a rich source of data to explore short and long term maternal and neonatal morbidities of this condition. It may also generate novel biomarkers that could be used to predict prognosis of severe early onset FGR. We are already investigating specific markers of prognosis at diagnosis of severe early onset FGR that may be useful for clinical management and counselling of affected women.

Recent improvements in the perinatal and neonatal care of premature growth restricted babies have increased survival, but survivors need neonatal intensive care which is stressful for the baby, and costly for parents and society. The immediate clinical impact of improving fetal growth in pregnancies complicated by severe early onset FGR will be a reduction in stillbirths and neonatal mortality and morbidity.
- Neonatal mortality is dependent on gestational age at delivery and birthweight for gestational age. Survival studies suggest that even modest increases in birthweight (eg 500 to 600g) and gestation at delivery (eg 26 to 27 weeks) are associated with improvements in mortality and morbidity.
- The complications of prematurity after severe FGR are dependent on gestational age at birth: major morbidity reduces progressively as gestational age advances from 56.6% at 24 weeks to 10.5% at 32 weeks. Significant improvements in neonatal morbidity are likely to result from quite modest increases in gestational age at delivery.
- Preschool children born preterm and at very low birth weight perform more poorly than their peers in physical, emotional, and/or social functioning. Again, increasing gestational age at delivery should lead to improved outcomes.
- Reductions in chronic lung disease of prematurity and improvements in cardiovascular performance, through improved blood vessel development and avoidance of childhood hypertension have the potential to lead to better physical outcomes for those affected by severe early onset FGR as adults.
This represents a significant long term impact on healthy ageing and participation in society, and economic potential for the individuals treated.

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