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Periodic Report Summary 2 - PREVENTROP (New approach to treatment of the blinding disease Retinopathy of Prematurity (ROP))

Project Context and Objectives:
Retinopathy of prematurity (ROP) is a major cause of blindness in children in the developed and developing world, despite current treatment of late-stage ROP. As developing countries provide more neonatal intensive care, the incidence of ROP is increasing as more preterm children are saved. Approximately 40% of perinatal blindness can be attributed to ROP. The treatment of ROP, ablation of the avascular retina with laser photocoagulation or cryotherapy to cause involution of pathological vessels, has remained fundamentally unchanged for almost 50 years. These treatments are destructive and destroy the peripheral (non-vascularised) parts of the retina and may lead to a partial loss of peripheral or side vision.
PREVENTROP consortium consists of ten partners from five EU Member States (SE, DE, UK, NL and IT), Norway and USA. The overall objective of the PREVENTROP project is to develop a novel preventative intervention for the blinding disease ROP and other complications of prematurity. This work is based on the concept that replacement of critical factor(s), normally provided in utero and reduced due to the disruption of the maternal/fetal interaction, to the infant born prematurely will help prevent the complications of premature birth.
It has been shown experimentally and clinically that low levels of the growth factor Insulin-like growth factor 1 (IGF-I) in premature infants strongly correlate with ROP development, indicating that IGF-I is one of these critical factors. Our preliminary work suggests that replacement of IGF-I to normal levels found in utero will prevent ROP and other complications of premature birth
The PREVENTROP consortium proposes during the project period to conduct preclinical studies in mice model of ROP and rabbit pup models to refine the clinical approach. In addition we will conduct clinical studies: pharmacologic, pharmacodynamic, pharmacokinetic and toxicologic including phase II and phase III clinical trial of an EU designated orphan medicinal product IGF-I/IGFBP-3 complex to address treatment for ROP and other serious complications in premature infants.
ROP is a rare disease according to International Rare Diseases Research Consortium (IRDiRC) classification and the medicinal product Premiplex® has been granted orphan designation in Europe by EMA.
Primary Objectives in the proposed phase I-II study
• To determine the dose of rhIGF-I/rhIGFBP-3, administered by continuous intravenous infusion, required to reach and maintain over time a physiological range, defined as the in utero levels for corresponding gestational age in a normal population (30-100 µg/L), in premature infants.
• To determine serum levels of IGF-I and associated pharmacokinetic parameters after continuous intravenous infusion of rhIGF-I/rhIGFBP-3.
Secondary Objectives in the proposed phase I- II study
• Follow up of safety and efficacy parameters
Primary objective of the phase II- III study
• To compare the severity of retinopathy of prematurity among treated infants with untreated control patients, matched for GA at birth and gender.
Secondary objective of the phase II-III study
Development of a) bronchopulmonary dysplasia (BPD); b) necrotizing enterocolitis (NEC); c) metabolic state; d) body weight; e) length; f) head circumference; g) brain development; h) cognitive outcome and i) total number of days in neonatal intensive care prior to discharge.

• Conduct translational studies for the understanding of variation in infant response to treatment and will be undertaken in appropriate mouse model of retinopathy and preterm rabbit pup models and in in-vitro systems.

Project Results:
Resulting pharmacokinetic and safety data were published and reported to the Swedish Medical Product Agency (MPA), and formed the basis for continued study Phase II. In a continued Phase II study of infants born at 23-28 GW, infants received treatment until endogenous production of IGF-1 was considered sufficient (median duration 21 days) and matched individuals were evaluated as controls. Phase II study has expanded to a European multi-center study, which was finalized in 2015. The multi-center expansion required simplification of the infusion protocol; this was achieved by developing a population PK model which predicted that physiologic replacement could be achieved with a uniform dose.
Furthermore, the development of a new POC test which will only require a minimal amount of blood (5 microliter) and will generate the serum IGF-I levels in a minimal time (15 minutes) has almost been finalized. The POC test is an important clinical tool for a safe and secure monitoring regime. Parallel to the clinical studies intensified work securing drug manufacturing for the clinical phase III study has been successful. For instance, technology rights for drug manufacturing have been transferred from the company Insmed (USA) to one of the partners. Also Full scale GMP drug substance for the Phase 3 trial has been manufactured.
Two animal models one in mice for analysing the role of metabolism in ROP and one in rabbit for analysing the impact of IGF-I in brain injury has been successfully developed.

Potential Impact:
The project if successful, this will result in a clinical availability of a new orphan designated drug product, Premiplex®, improved care of preterm infants and a significant contribution towards the goal of the International Rare Disease Research Consortium (IRDiRC) by delivering one new therapy for the rare disease ROP.
The benefits of prevention, both as quality-of-life aspects for the individual and his/her family and, from an economic point-of-view, for the society, are superior to current destructive interventions aiming merely at stopping progress of the disease. Therefore, there is a huge unmet medical and economic need for a preventive intervention also from a cost-effectiveness point of view.
Based on analysis of data, and considering that visual impairment and blindness is a life-long handicap, we believe that an average cost of €1 million to the society per infant developing blinding ROP is a reasonable assumption. Recently, the annual cost of preterm birth throughout childhood in England and Wales was estimated to be £2.946 billion (US $4.567 billion) . The costs to society persist after childhood and through all adulthood when children are developmentally delayed and or blind.
There will be a major impact if it is possible to use the knowledge and methods within the field of all retinopathies as retinopathy today is a common cause of blindness in all age groups. As an example there are 15 million people in the United States and with age-related macular degeneration (AMD)—20% of those aged 65 to 74 years and 30% aged >74 years—and 1.6 million of those have neovascular (wet) AMD. In the working age population there are >20 million (>7% of the population) with diabetes, and 50% of patients with diabetes mellitus have diabetic retinopathy (DR) after 25 years. In children, retinopathy of prematurity (ROP) is a major cause of vision loss. Approximately 460,000 (11%) of infants per year in US are born prematurely, and there are ∼2000 infants per year with severe ROP.
We believe that multidisciplinary networks like PREVENROP collaboration provides the infrastructure that is necessary for performance of clinical trials and subsequent monitoring of newly authorized products.
The proposed project has a totally different approach to interventions for ROP than those currently applied. Instead of late stage treatment of sight threatening ROP, our research focuses on how to improve care during the first few weeks of life to promote growth of vascular and neural tissues in the retina thus avoiding the development of a large avascular zone and subsequent abnormal vessel growth.

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