CCMR One
A Trial of Bexarotene in Multiple Sclerosis
BACKGROUND
Nerve fibres in the brain and spinal cord are normally wrapped in myelin, a protective coating that functions much like the insulation around an electrical wire. In multiple sclerosis (MS), the immune system mistakenly attacks this myelin, stripping it away and exposing the underlying nerve fibres. Without this insulation nerve signals become disrupted, and over time the exposed nerve fibres degenerate, leading to permanent disability. A key goal of our research is to promote myelin regeneration, to protect nerve fibres from long-term damage.
Our first myelin repair trial built on research undertaken in Cambridge, funded by the MS Society. Researchers working in the Cambridge Centre for Myelin Repair had shown that activation of a particular cellular pathway (coordinated by a receptor called RXR-gamma) was important for myelin regeneration (Huang, Nature Neuroscience 2011). Bexarotene, a drug already used to treat cutaneous T cell lymphoma, was known to activate the RXR receptor. This provided a strong rationale for repurposing bexarotene as a potential therapy to promote remyelination in people with MS.
TRIAL DESIGN
This led us to undertake the Cambridge Centre for Myelin Repair (CCMR) One trial of bexarotene in people with relapsing-remitting MS.
We recruited participants across 2 sites, in Cambridge and Edinburgh. All had relapsing remitting MS, were aged 18-50 and were stable on dimethyl fumarate (an MS disease modifying treatment). Due to the known side effects of the drug we monitored participants very closely and 13 visits were required over the course of the trial for each participant. We measured the effects of the drugs over 6 months in two main ways. First, with a test of nerve structure, using MRI brain scans, and second with tests of nerve function, using the change in the latency of the visual evoked potential (VEP).
TRIAL RESULT
The “primary endpoint” of the trial was not met. People taking bexarotene did not have an overall improvement in the myelin content of their MS lesions seen on the MRI scans. However, there were several clear signals that the drug was promoting myelin regeneration.
First, using the MRI scans, we leaned that there were improvements in particular parts of the brain, for instance in the grey matter regions. We also learned that there was variation in remyelination between the core and rim of an MS lesion (the rim being more able to respond to the repair drugs).
Second, using the visual evoked potential (VEP), we noted that people given bexarotene had significant improvements in the conduction speed of their visual nerves, which would be consistent with remyelination.
Finally, we also noted that there was an improvement in neurofilament light chain, which correlated with the degree of remyelination. These results were encouraging as it showed we can promote myelin regeneration using this particular cellular mechanism and that this is having an impact to prevent damage of the underlying nerve fibre.
Unfortunately, bexarotene was poorly tolerated at the high doses we used. It caused hypothyroidism in all participants, elevated levels of blood lipids in most and 5/26 had to withdraw from treatment due to side effects. As a result, we do not believe people should take bexarotene at this dose for their MS.
THE FUTURE
We believe there is compelling evidence that bexarotene promotes remyelination. We are currently working to see if the same pro-remyelinating effects can be seen at smaller doses (which are associated with far fewer adverse effects), and hope to test this hypothesis in a future clinical trial. We are also taking the lessons learned from CCMR-One through to future myelin repair trials.