Boost Brittle Bones Before Birth

Project Information

BOOSTB4

Grant agreement ID: 681045

DOI 10.3030/681045

Closed project

EC signature date 11 September 2015

Start date 1 January 2016

End date 31 December 2022

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost € 8 378 755,75

EU contribution € 6 608 754,50

Coordinated by

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 5 - BOOSTB4 (Boost Brittle Bones Before Birth)

Reporting period: 2022-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

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 Osteogenesis Imperfecta (OI).

What is the problem being addressed?
OI is a debilitating inherited disorder with prenatal onset leading to osteopenia (low bone density), bone brittleness, short stature and chronic pain. Affected children and adults suffer from multiple fractures, requiring hospitalisation and surgery, and often leading to irreversible deformities. Current therapies are only partly effective at treating the disease, and pre-clinical and initial clinical data show that MSCs could be used to treat OI. The BOOSTB4 project therefore aims to develop fetal MSC transplantation as a therapy for OI.

Why is it important for society?
Individuals with OI suffer from life-long repeat fractures, pain, disability and reduced quality of life. There is no cure for OI and almost no treatment options exist, therefore the implications of a successful therapy for these individuals are vast. Persons with OI are affected throughout their lifetime; the costs of managing the disease and caring for patients, borne by healthcare providers and society, are extremely high. Typically, care for these patients requires a large multidisciplinary team. The care includes direct medical costs, direct non-medical costs, and indirect costs/production loss associated with OI.
Successful clinical demonstration of MSC therapy in OI will pave the way for the treatment of many inherited diseases where no or few therapy options are available, especially for children. Decreasing the severity of such congenital diseases will result in life-long benefits for the affected individuals and their families from birth onwards, as well as reducing the above mentioned costs.

What are the overall objectives?
The overall objective of BOOSTB4 is to develop a treatment using MSCs for severe types of OI. The main core of the BOOSTB4 project is the open label phase I/II trial that evaluates the safety and efficacy of postnatal (n=15) or pre- and postnatal (n=5) administration of multiple doses of first trimester human allogeneic fetal liver MSCs as a treatment of severe OI type III/IV. The primary endpoint of the trial is safety and tolerability of intravenous administration of MSCs to the infant, fetus and pregnant woman. Efficacy is evaluated as secondary endpoints and includes fracture frequency, time to fracture, number of fractures at birth, growth, bone mineral density and biochemical bone turnover in blood. Paracrine effects, influence on recipient immune cells, donor cell engraftment and Quality of Life are evaluated as exploratory endpoints. Ethical standards and risks, experience, impact and perception of the therapy, non-invasive prenatal diagnosis and health economics are also investigated in the project.


Conclusions of the action
The BOOSTB4 consortium has successfully developed a promising therapy for OI. This includes a method for non-invasive prenatal diagnosis of OI, a biosignature of fetal MSCs and response after therapy, manufacturing of MSCs for clinical use, and investigation of the safety of pre-and/or postnatal intravenous administration of fetal MSCs to young children with OI. To date, after 70 doses of same-donor MSCs, no significant short-term complications have been recorded.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The BOOSTB4 consortium started with scientific advisory meetings with regulatory authorities. Then our consortium led investigations into the perception of the therapy , as well as the ethical standards and risks, showed that key stakeholders support the application of stem cell therapy for OI. Further work was undertaken to develop the clinical trial protocol and finalise manufacture methods of the fetal MSCs, as well as establish their biosignature.

The trial was approved in Sweden, the United Kingdom and the Netherlands, but was only opened in Sweden (EudraCT-number: 2015-00369-60, ClinicalTrial.gov ID: NCT03706482). Eighteen children with clinical and molecular diagnosis of OI type III or severe type IV have been included from 7 countries. Each child has received 4 doses of MSCs at 4-month intervals:
1) Postnatal group: The 1st dose was administered before 18 months of age (n=15).
2) Prenatal group: The 1st dose was administered prenatally and 3 doses postnatally (n=3).
The participants underwent in-patient monitoring for 48 (dose 1–2) or 24 (dose 3–4) hours after each dose. No significant short-term adverse reactions have been identified in the infant, fetus or pregnant woman. The primary follow-up at 6 and 12 months after the last dose is currently being performed, thereafter the subjects (including the mother) will be followed yearly. Historical controls have been recruited from the Netherlands, United Kingdom, Sweden and Germany. The biological responses after each dose have been evaluated and show that the immune system of the participants is not triggered after the allogenic transplantation. Efficacy will be evaluated in Q4 2023. The developed method for non-invasive prenatal diagnosis of OI is now accredited and in clinical practice.

The project captured detailed resource data on the total cost of OI and the cost for treatment with MSCs and has developed a cost analysis model for transplantation of fetal MSCs to OI patients. The project has investigated the views and experiences of parents whose child underwent fetal MSC transplantation, either postnatally or pre- and postnatally, and of health professionals who were involved in referring or providing the treatment to understand motivations, expectations and quality of life impact. BOOST Pharma was founded as an exploitation vehicle for the project’s results, and an Orphan Drug Designation has been submitted and approved in the EU and US for treatment of OI with fetal MSCs.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Demonstration of safety, and potentially also efficacy, with the subsequent translation of this new technology into clinical practice will likely lead to increased research efforts to apply this technology to other genetic diseases. Understanding key stakeholder’s views and the costs associated with current treatment of OI, as well as the therapy with MSCs, will aid in the development of therapies in general, but of cell therapies for rare diseases in particular. The results of the BOOSTB4 project will therefore have a large impact on the future treatment of many disorders with MSCs, especially in young children.

BOOSTB4 graphical abstract