The MCDS-Therapy project

MCDS-Therapy is a collaboration of 11 partners from across the globe, all working together to repurpose carbamazepine to treat MCDS. We plan to develop a low cost treatment that will alleviate the pain and bone malformations commonly experienced by patients, and will work closely with patients to do so. The project has been funded by the European Union’s Horizon 2020 Research and Innovation programme for 5 years.

History of MCDS research

Type X collagen, a protein encoded by the COL10A1 gene, was first described in 1985 by researchers at Manchester University. Mutations in this gene were subsequently shown to cause the rare skeletal disease, metaphyseal chondrodysplasia type Schmid (MCDS) by several research groups across the world.

Since 1993 over 50 different mutations in COL10A1 have been identified globally; however, it has only been in the last decade that considerable progress has been made in identifying the underlying disease mechanism of MCDS. This progress has mainly been driven by the creation of genetically relevant mouse models of the condition.

Partners in MCDS-Therapy have been at the forefront of these discoveries, which have consistently demonstrated that mutant type-X collagen proteins mis-fold when they are produced and become trapped in a part of the cell called the endoplasmic reticulum (ER). This causes ER stress which has been shown to cause the characteristic problems of MCDS.

Using drugs that can alleviate this ER stress therefore has the potential to ease the symptoms of MCDS in a relatively straightforward manner. Other therapeutic options, such as restoring the collagen matrix in the bone or directly correcting the mutation, would require much more expensive and timely treatment development.

  • 1984

    Discovery of type X collagen protein.

    Reference – Kielty et al., 1985

  • 1993-94

    Identification of COL10A1 mutations in MCDS.

    Reference – Wallis et al., 1994

  • 2005-2009

    Generation and phenotyping (identifying the characteristics) of genetically relevant mouse models.

    EU contribution  – The EuroGrow project, funded by the EU, supported this work.
    Reference – Rajpar et al., 2009

  • 2005-2009

    Identification of ER stress as core disease mechanism in MCDS and other genetic skeletal diseases (GSDs).

    EU contribution  – The EuroGrow project, funded by the EU, supported this work.
    Reference – Rajpar et al., 2009 and Cameron et al., 2011

  • 2015-2017

    Pre-clinical studies using CBZ

    EU contribution – The SYBIL project, funded by the EU, supported this work.
    Reference – Mullen et al., 2017

  • 2018

    MCDS-Therapy beings

    EU contribution – Horizon 2020, funded by the EU, is supporting this work.

How will the clinical trial work?

A clinical trial aims to provide the necessary evidence that a new treatment is both safe and beneficial to patients with the condition it treats. In order to do this, it is important to be able to compare patients who are treated with the drug to those who are not. This allows you to identify the effect of the treatment.

In most trials, comparing patients on and off the treatment requires a placebo. This is a blank pill given to some patients that does not contain the treatment. This approach allows there to be an untreated (control) group, without the patients or researchers knowing who is being treated and who is not. This ensures that there is no bias when assessing the effect of the treatment.

When you are dealing with a rare disease like MCDS, the small number of patients can make this type of trial design hard to achieve. When planning our trial, the MCDS-Therapy team received guidance from the European Medicines Agency (the European organisation that approves new medicines for use, also known as the EMA), who have approved a very different design for MCDS-Therapy.

Patients enrolled on our trial will first be monitored for 12 months with no treatment provided. This will create a set of base-line data that tells us how MCDS is effecting them. This base-line will act as their control in the trial. After baseline data is collected, they will then be prescribed carbamazepine for 24 months, and its effect on the condition will be measured.

Where will the trial be conducted?

As MCDS is a very rare condition, we will be recruiting patients from around the world into our clinical trial. The first patients will be recruited in the UK by both Newcastle-upon-Tyne Hospitals NHS Foundation Trust and the Evelina London Children’s Hospital (part of Guy’s and St Thomas’ NHS Foundation Trust). After a year, recruitment will be expanded to include:

  • The Assistance Publique-Hôpitaux in Paris, France
  • Antwerp University Hospital, Belgium
  • The Murdoch Children’s Research Institute in Melbourne, Australia
  • The Rizzoli Orthopaedic Institute, in Bologna, Italy
  • The University Medical Centre Freiburg, in Germany

What is the timeline for the trial?

The trial will begin in 2018. From there it follows a number of stages:

Stage 1: 12 months
Recruitment and base-line data collected for patients recruited in UK.

Stage 2: 12 months
Patients in the UK enter a dose-finding study, which will help to identify the best dose of the drug for the treatment of MCDS with carbamazepine.
Recruitment and base line data collection begins in the non-UK clinical trial sites.

Stage 3:
All patients begin treatment with carbamazepine for a 24 month period, with the effect on their MCDS measuredthroughout the study.

What other work is being done?

Alongside the clinical trial a number of other projects are being completed that aim to ensure the drug can be accessed by patients if the trial proves successful.

Biomarker development – A biomarker is a biological signal, often a chemical produced in the body, which can be used to monitor one of the body’s processes or the effect of a drug on a disease.

There are currently no biomarkers available for MCDS. This makes it more difficult to measure the effect of a treatment on MCDS, and to identify different variations of MCDS in order to tailor treatments to individual patients.

As part of the MCDS-Therapy project Sciomics will be working to identify new biomarkers for the condition. At the same time, the team at The University Medical Centre Freiburg will be working to develop a new line of human stem cells derived MCDS cells that can be used to help to test these biomarkers.

Health Economics – Health economics is the study of the value of healthcare. It primarily aims to determine the cost-effectiveness of health interventions, such as treatments, by comparing the overall cost to society of a treatment to the overall benefit to society of treating that condition. This should help governments decide which expensive treatments should be paid for and delivered to patients.

As part of MCDS-Therapy we will be working to understand the financial cost of MCDS to patients, the healthcare system, and society, and to provide evidence that treating the condition with carbamazepine (if proved to be effective in the clinical trial) is cost-effective.

Building the MCDS community – A rare disease diagnosis can be an isolating and devastating experience. Many patients struggle to find doctors who understand their condition and treatment needs. Some may never meet someone else with the same condition. As part of the MCDS-Therapy project we aim to work with patients, to make sure that both the treatment and the clinical trial works for them. At the same time we would like to help them to connect with one another, and make their voice heard beyond the project.