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Boost Brittle Bones Before Birth

Periodic Reporting for period 3 - BOOSTB4 (Boost Brittle Bones Before Birth)

Reporting period: 2019-01-01 to 2020-06-30

The Boost Brittle Bones Before Birth (BOOSTB4) project is focused on the shared ambition of a group of leading European clinicians, researchers and industrial stakeholders to translate fetal mesenchymal stem cell (MSC) transplantation into the clinic as a therapy for severe inherited diseases.

What is the problem/issue being addressed?
Osteogenesis Imperfecta (OI) is a debilitating inherited disorder with prenatal onset leading to osteopenia (low bone density) and bone brittleness. Affected children and adults suffer from multiple bone fractures, requiring hospitalisation and surgery, and often leading to irreversible deformities. They also suffer from short stature and chronic pain.

Why is it important for society?
The BOOSTB4 project is focused on translating fetal MSC transplantation into the clinic as a therapy for OI. During the project we will investigate the safety and efficacy of this innovation. Successful clinical demonstration of the BOOSTB4 therapy in OI will pave the way for the treatment of many developmental disorders. Decreasing the severity of such congenital diseases will result in life-long benefits for the affected individuals and their families from birth onwards.

What are the overall objectives?
The overall objective of BOOSTB4 is to develop a treatment using stem cells for severe types of OI. The objectives of the project can be summarised in three categories; Clinical, Ethical and Health Economics.

Clinical Objectives
To measure the safety and efficacy of postnatal or pre- and postnatal allogeneic fetal MSC infusion (n=30) as therapy for severe types of OI.

Primary objective:
The primary objective is to assess safety and tolerability in the child, woman and her fetus after postnatal or prenatal infusion of fetal MSC.

Secondary objective:
The secondary objective is to assess the effect of four doses of fetal MSC on:
1. Fracture frequency
2. Time (days) to first fracture after the last dose
3. Number of fractures at birth (prenatal treatment group only)
4. Bone mineral density (BMD)
5. Growth (cm and kg)
6. Clinical status of OI
7. Biochemical bone turnover

Exploratory objectives:
1. To study the Quality of Life
2. To study the extent of donor cell engraftment in tissue samples obtained from subjects infused with allogeneic human fetal MSC
3. To study paracrine effects of infusions of allogeneic human fetal MSC
4. To study the effect of infusions of allogeneic human fetal MSC on endogenous immune cells
5. To study non-invasive prenatal diagnosis of OI

Ethical objectives
To evaluate the acceptability of fetal MSC treatment, both from the patient and family perspective, as well as from health professionals in the area and from an ethical perspective through:
• Exploring the views and experiences of 15 parents whose child is undergoing fetal MSC transplantation either postnatally or pre- and postnatally and of 15 health professionals who are involved in referring or providing the treatment to understand motivations, expectations and quality of life impact
• To examine current ethical standards and risks associated with prenatal stem cell transplantation

Health Economics Objectives
• To determine if fetal MSC transplantation as a treatment for OI is cost effective.
• To monitor the resource needed for individuals with severe types of OI and compare to those consumed by matched historical controls.
• To develop a cost analysis model for transplantation of fetal MSC to OI patients.
The BOOSTB4 consortium has sought approval for the clinical trial from national regulatory authorities. This has involved scientific advisory meetings with the authorities, developing the clinical trial protocol and related documents, finalising manufacture methods of the fetal MSC and, after initially making applications through the Voluntary Harmonization Procedure, amending trial set-up and manufacturing according to regulatory authorities' requirements.

Further work has been undertaken harmonising necessary procedures and manuals at each clinical site as well as composing agreements, biobanks and risk assessments. The consortium is also developing a method for non-invasive prenatal diagnosis of OI and has started to investigate the biosignature of the fetal MSC.

The trial is approved and open in Sweden where two patients have already received MSC and a further three are in early discussions about becoming trial participants. In the United Kingdom there are ongoing negotiations of the final required agreements before the trial can open. Submission to the Competent Authority has been made in the Netherlands and we expect a response in September 2020. The clinical trial application has been rejected by the competent authority in Germany but documents are being prepared to enable recruitment of patients to the non-treatment control arm of the trial.

The consortium agreed we should capitalise on the unique possibility presented by the BOOSTB4 trial to provide detailed health economics data on the total cost of OI and the cost for treatment with MSC. For data collection we have already designed forms to record child and maternal resource use and we have started to capture the data now.

Lastly, the acceptability of prenatal and postnatal fetal stem cell treatment for OI from the perspective of patient and families, health professionals and patient advocates has been evaluated. The work shows that key stakeholders support the application of stem cell therapy for OI. The current ethical standards and recommendations have been summarized and assessed, and two systematic reviews have been performed.
The MSC treatment proposed here has the potential to reduce fracture rates by half in patients receiving treatment. The ambition of the BOOSTB4 consortium is to complete our MSC therapy on a large enough cohort to evaluate accurately the potential of this treatment strategy in children with OI.
There is currently no cure for OI and the only current pharmaceutical treatments are palliative and fail to sufficiently reduce fracture frequency and does not address the underlying bone brittleness and collagen defect. An individual born with OI is affected throughout their lifetime and the costs of managing the disease are extremely high. Typically, care for these patients requires a large, multidisciplinary team including a neuro paediatrician, physiotherapist, occupational therapist, orthopaedic surgeon, orthopaedic technician, radiologist, geneticist, nurse and dentist. We estimate, conservatively, that the cost of each fracture event in a patient with OI is approximately €15,000. Our early stage indicative costing suggests costs of €10,000 per treatment (four doses) with MSC therapy. The annual cost savings associated with treatment of patients with the severest forms of OI across the EU, based on a reduction in fracture incidence alone, would be more than €60 million 10 years after introduction of MSC therapy, assuming that each patient has 10 fractures each year, and that this number is reduced to 5 following MSC treatment. If extended to the wider group of patients with OI, these cost savings would increase.

Demonstration of safety and efficacy and the translation of this new technology into clinical practice will likely lead to increased research efforts to apply this technology to other genetic diseases. The results of the BOOSTB4 study will therefore have a large impact on the future treatment of these disorders with MSC.
MSC colony