Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MCDS-Therapy (Repurposing of carbamazepine for treatment of skeletal dysplasia)

Teaser

Metaphyseal chondrodysplasia, type Schmid (MCDS) is an autosomal dominant skeletal dysplasia results from mutations in collagen X and affects

Summary

Metaphyseal chondrodysplasia, type Schmid (MCDS) is an autosomal dominant skeletal dysplasia results from mutations in collagen X and affects <1/100,000 of the population. It presents in early childhood and has debilitating effects during the whole of life. These include short stature, bowing and malalignment of the long bones with resulting chronic pain. Moreover, abnormal gait, pain and decreased functional capacity and mobility that can then lead to those with MCDS being overweight/obesity with associated co-morbidity. The disease is incurable and MCDS patients rely on the long-term use of analgesia and also undergo numerous orthopaedic surgical interventions to correct knee and hip deformities. We have previously shown that MCDS results from cell stress induced through the accumulation of mutant misfolded collagen X. Cell stress can be alleviated and bone growth restored in mice models of MCDS through the administration of carbamazepine (cbz).

The overarching objective of MCDS-Therapy is therefore to advance the repurposing of carbamazepine (CBZ) to deliver the first non-surgical therapeutic intervention for metaphyseal chondrodysplasia, type Schmid. As part of this project a comprehensive health economic assessment of the socio-economic burden of MCDS and the potential benefit of pharmacological intervention will also be delivered, whilst the identification of novel biomarkers will form an important foundation for determining clinical efficacy.

The MCDS-Therapy project is important for society being fully aligned with the European “SC1-PM-08-2017: New therapies for rare diseases” which calls for projects with concrete benefits for patients living with rare diseases. MCDS-Therapy will therefore provide proof-of-principle that targeting cell-stress is an innovative and cost-effective approach for providing new therapies for a group of phenotypically and genetically distinct rare diseases that share this common disease mechanism. This is likely to have high societal impact and significant advance the delivery of new therapies for orphan diseases.

Work performed

The MCDS Therapy trial of carbamazepine in the treatment of children is now underway. Regulatory and sponsor approval has been obtained in the UK and recruitment of patients at Newcastle and Guys and St. Thomas is close to completion (WP1). Plans are underway for the recruitment of patients in the sites in the rest of Europe and Australia beginning in 2020 with appropriate regulatory approvals being sought (WP2).

Defining clinical end points for rare disease clinical trials is a challenge, which is particularly apparent for rare bone disease in which improved bone growth may not be apparent during the course of drug treatment. Identifying soluble biomarkers is therefore a priority and is the focus of WP3. To this end a preliminary MCDS biomarker candidate signature was identified using relevant serum samples from mouse models of MCDS. Furthermore, the scioDiscover assay was updated in terms of protein target coverage to better reflect the MCDS disease pathology and protocols were optimised to less sample while maintaining the reproducibility and sensitivity levels. This is important for the analysis of serum samples from children with MCDS.

A comprehensive health economic assessment of the socio-economic burden of MCDS and potential benefit of pharmacological intervention is important. As a first step in informing the final budget impact and cost-effectiveness analyses a conceptual model of patient care and disease progression was developed (WP4). Pre-defined questions were put to local clinicians regarding current management of patients with MCDS. This initial conceptual model forms the basis for the budget impact and cost-effectiveness models. Understanding how patients are currently treated and how cbz could potentially impact these care pathways allowed us to define the parameter requirements for the final models.

Long-term use of cbz for MCDS will likely require market aurthorisation. UNEW has approached the European Medicines Agency for advice on market authorisation and were supplied with the relevant documents and forms. These have now formed the Marketing Authorization dossier for MCDS-Therapy (WP5).

Dissemination to all stakeholders is a key objective in MCDS-Therapy and in the first 18 month of the MCDS-Therapy project WP6 has had three major points of focus (WP6):
1. The development of communication infrastructure and online presence.
2. Working with the clinical team to secure ethical approvals for dissemination activities.
3. Introducing the MCDS-Therapy project to the rare disease world at conferences and events.
We have successfully developed a simple bold brand and launched our websites, which forms the online home for the collaboration. We have developed social media channels and newsletter as a simple way for people to keep up to date with the progress of the trial. We have spoken about the MCDS-Therapy project at over 22 major events, helping to highlight the role of drug repurposing in rare disease, and the potential for academic consortia to deliver clinical research from bench to bedside.

A large multidisciplinary project such as MCDS-Therapy requires a robust management framework (WP7) and this is now in place after 18 months of activities. Procedures for the efficient coordination and management of MCDS-Therapy, such as the management boards, are now established and functioning efficiently.

Following review of the MCDS-Therapy project by the European Commission a number of additional ethical requirements were requested. These have all been completed and submitted as deliverable reports (WP8).

Final results

In the first 18 months MCDS-Therapy has progressed beyond the state-of-the-art by recruiting children with MCDS into the first investigator-led drug repurposing clinical trial for a rare bone disease. Significant progress has been made in understanding the regulatory requirements that are necessary for a clinical single sponsor in a multicentre multinational clinical trial and is in line with EU directive 536/2014. In addition, MCDS-Therapy has identified the first potential biomarker signature for MCDS, indeed no biomarker signature currently exists for any rare bone disease (or cell-stress related rare disease). MCDS-Therapy has initiated a comprehensive health economic assessment of the socio-economic burden of MCDS and the potential benefit of pharmacological intervention. This has rarely been undertaken for a rare bone disease and will provide new insight into the socio-economic burden of a rare bone disease (or any orphan disease). Finally, we have established a comprehensive dissemination plan that will reach all stakeholders, both within the rare bone disease community, but also to the much wider rare disease community.

Website & more info

More info: https://mcds-therapy.eu/.