Periodic Reporting for period 4 - MCDS-Therapy (Repurposing of carbamazepine for treatment of skeletal dysplasia)
Berichtszeitraum: 2022-06-01 bis 2024-05-31
Metaphyseal chondrodysplasia, type Schmid (MCDS) is a condition caused by mutations in collagen X and affects <1/100,000 people. It presents in early childhood and causes short stature, bowing of the long bones and chronic pain. MCDS patients rely on long-term use of analgesia and may undergo surgical 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 health economic assessment of the burden of MCDS and the potential benefit of pharmacological intervention was delivered, whilst the identification of novel biomarkers helped 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 provides proof-of-principle that targeting cell-stress is an innovative and cost-effective therapeutic approach for rare diseases with this disease mechanism.
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 health economic assessment of the burden of MCDS and the potential benefit of pharmacological intervention was delivered, whilst the identification of novel biomarkers helped 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 provides 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 children with MCDS is complete with four centres recruiting participants (Newcastle, London, Melbourne and Bologna). The trial was seriously delayed by the COVID pandemic; however, this 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 was determined in WP1. A total of 11 patients were enrolled in stage 1 with 8 continuing into stage 2 and 16 further participants recruited for stage two. These participants followed a modified protocol of a 6-month observational phase and a 12-month treatment phase during which they received CBZ at the agreed dosage. The results of the trial have demonstrated that CBZ is as safe and well tolerated in children with MCDS as it is in children who do not have this condition. The results demonstrate that CBZ treatment is associated with a reduction in pain in MCDS and may be associated with an acceleration in growth and reduction in the progression of deformity in the legs. Further work is needed to confirm whether the growth and bone effects are seen in other children with MCDS where children are treated for longer periods of time.
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 drug treatment. Identifying biomarkers is a priority and a MCDS ‘biomarker signature’ was 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 identified several potential early treatment response markers and a trend towards a to partial resolution of stress and chronic inflammation with CBZ treatment. Further analysis identified two potential biomarker signatures which may be used as markers of efficacy of treatment. Further work is needed to determine whether these biomarker signatures will be seen consistently in patients with MCDS treated with CBZ.
A comprehensive health economic assessment of the socio-economic burden of MCDS and the 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 based (WP4). A Qualitative study to explore experience of patient and care givers was completed. This represented an essential step for the quantitative study of preference elicitation. A discreet choice experiment and assessment of marginal willingness to pay have been performed. These demonstrate that prevention of long-term complications and avoidance of surgery in the future were important factors for patients with MCDS in considering treatments. Estimation of budget impact and cost-effectiveness demonstrated that CBZ would be a more cost-effective intervention that current treatments.
Over the final reporting period the WP6 team have focussed on refining digital communication and outreach and preparing for the dissemination of the results of the clinical trial, health economics assessment and biomarker studies. 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. Social media has also seen real growth after the implementation of a new strategy and dedicated manager. This has increased our connection with the global MCDS community. Beacon were key partners in the preparation and delivery of the meeting at which the results of the trial were presented and the final consortium meeting where the future direction of MCDS research under by the consortium was discussed. This meeting on the 30th and 31st of May was attended by researchers, clinicians, participants in the trial and members of the public.
A large integrating project such as MCDS-Therapy requires a robust management platform (WP7) and this was in place during the final reporting period and has continued throughout MCDS.
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 drug treatment. Identifying biomarkers is a priority and a MCDS ‘biomarker signature’ was 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 identified several potential early treatment response markers and a trend towards a to partial resolution of stress and chronic inflammation with CBZ treatment. Further analysis identified two potential biomarker signatures which may be used as markers of efficacy of treatment. Further work is needed to determine whether these biomarker signatures will be seen consistently in patients with MCDS treated with CBZ.
A comprehensive health economic assessment of the socio-economic burden of MCDS and the 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 based (WP4). A Qualitative study to explore experience of patient and care givers was completed. This represented an essential step for the quantitative study of preference elicitation. A discreet choice experiment and assessment of marginal willingness to pay have been performed. These demonstrate that prevention of long-term complications and avoidance of surgery in the future were important factors for patients with MCDS in considering treatments. Estimation of budget impact and cost-effectiveness demonstrated that CBZ would be a more cost-effective intervention that current treatments.
Over the final reporting period the WP6 team have focussed on refining digital communication and outreach and preparing for the dissemination of the results of the clinical trial, health economics assessment and biomarker studies. 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. Social media has also seen real growth after the implementation of a new strategy and dedicated manager. This has increased our connection with the global MCDS community. Beacon were key partners in the preparation and delivery of the meeting at which the results of the trial were presented and the final consortium meeting where the future direction of MCDS research under by the consortium was discussed. This meeting on the 30th and 31st of May was attended by researchers, clinicians, participants in the trial and members of the public.
A large integrating project such as MCDS-Therapy requires a robust management platform (WP7) and this was in place during the final reporting period and has continued throughout MCDS.
MCDS-Therapy has progressed beyond the state-of-the-art by delivering the first investigator-led drug repurposing clinical trial for a rare bone disease. Participants in the trial have received treatment for a minimum of 12 months with the results suggesting some positive effects of CBZ in children with MCDS. Using patient serum (+/- treatment) MCDS-Therapy has identified the first potential biomarker signature, for rare bone disease. MCDS-Therapy has completed 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 has provided new insight into the socio-economic burden of this condition. Finally, we have delivered a comprehensive dissemination plan that has reached stake-holders, both within the rare bone disease community, and the much wider rare disease community as a whole. MCDS was significantly delayed by the COVID pandemic however, throughout this period we maintained the safety of all the participants and staff involved in the project and whilst the results were delayed we have brought all of the elements of the project to a successful conclusion.