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Repurposing of carbamazepine for treatment of skeletal dysplasia

Periodic Reporting for period 3 - MCDS-Therapy (Repurposing of carbamazepine for treatment of skeletal dysplasia)

Período documentado: 2020-12-01 hasta 2022-05-31

Metaphyseal chondrodysplasia, type Schmid (MCDS) is a skeletal dysplasia resulting from mutations in collagen X and affects <1/100,000 of the population. It presents in early childhood and has debilitating effects throughout life, including short stature, bowing and malalignment of the long bones with resulting chronic pain. MCDS patients rely on long-term use of analgesia and also undergo numerous orthopaedic interventions to correct deformities. MCDS results from cell stress induced by the accumulation of mutant collagen X, which can be alleviated and bone growth restored in mice models of MCDS through the administration of carbamazepine (cbz).

The goal of MCDS-Therapy is to advance the repurposing of CBZ to deliver the first non-surgical therapeutic intervention for MCDS. 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 be delivered, whilst the identification of novel biomarkers will determine clinical efficacy.

MCDS-Therapy is aligned with “SC1-PM-08-2017: New therapies for rare diseases” which advances the development of therapeutic options for rare diseases. MCDS-Therapy will provide proof-of-principle that targeting cell-stress is an innovative and cost-effective therapeutic approach for rare diseases with this disease mechanism.
The MCDS-Therapy trial of cbz in the treatment of children with MCDS is now full underway in four centres around the world (Newcastle, London, Melbourne and Bologna). The trial was seriously delayed by the COVID pandemic; however, the delay did not compromise the ability of the trial to demonstrate whether cbz is effective in improving the quality of life in children with MCDS. Optimal cbz dosage has been determined (WP1) and 11 children in the two UK sites are now currently receiving cbz (WP2). An additional set of patients have now been enrolled in Melbourne and Bologna (n=18) and are currently completing a revised 6-months baseline period before commencement of cbz treatment.

Defining clinical end points for rare disease trials is often a challenge, particularly for rare bone disease in which improved bone growth may not be apparent during the course of drug treatment. Identifying biomarkers is therefore a priority and a MCDS ‘biomarker signature’ was previously identified using serum samples from mouse models of MCDS (+/- cbz treatment). Serum samples have been collected from all UK patients (n=9; base line + treatment) and analysed on the ‘scioDiscover assay’ platform (n=47 samples in total). Preliminary analysis has identified several potential early treatment response markers and a trend towards a to partial resolution of stress and chronic inflammation as a result of the cbz treatment.

A comprehensive health economic assessment of the socio-economic burden of MCDS and the potential benefit of pharmacological intervention is important and 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 based (WP4). A Qualitative study to explore perceptions and experience of patient and care givers were completed at this stage. This represents an essential step for the quantitative study of preference elicitation. Progress was made on quantitative preference survey design as of attribute selection, ranking and definition levels.

Over the third reporting period the WP6 team have focussed on refining digital communication and outreach in order to continue our work despite the challenges of COVID-19. Through improved website SEO, an expanded and more diverse blog, and refined copy with more accessible language, we have increased the traffic to the MCDS-Therapy website, and its impact on our audience. Social media has also seen real growth after the implementation of a new social media strategy and dedicated manager. This in turn has increased our connection with the global MCDS community.

A large integrating project such as MCDS-Therapy requires a robust management platform (WP7) and this was in place during the 1st reporting period. Procedures for the efficient coordination and administration of MCDS-Therapy, such as the operational committees, are now established and functioned efficiently during the 3rd reporting period.
In the first 54 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. All children recruited to the UK sites at the start of the trial have now been receiving cbz for over a year and it is being tolerated well. Using patient serum (+/- treatment) MCDS-Therapy has identified the first potential biomarker signature, indeed no biomarker signature currently exists for any rare bone 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. Finally, we have established a comprehensive dissemination plan that will reach all stake-holders, both within the rare bone disease community, but all also the much wider rare disease community as a whole. MCDS was significantly delayed by the COVID pandemic however, throughout this period we have maintained the safety of all of the participants and staff involved in the project and whilst the results will be delayed, we remain confident that the project will be brought to a successful conclusion.