#MSVirtual2020 – Tolebrutinib Prevents Myelin Loss in Mouse Model of MS-like Demyelination
Tolebrutinib (SAR442168), an investigational oral BTK inhibitor to treat relapsing forms of multiple sclerosis (MS), was seen to prevent the loss of myelin when given to a mouse model of demyelination in a preclinical study.
The investigative therapy achieves this by preventing microglia from engulfing and destroying the myelin sheath produced by oligodendrocytes in the animals’ brain, while ensuring the survival of myelin-producing cells.
Microglia are considered the immune cells of the brain, and are responsible for protecting neurons from different types of threats. Oligodendrocytes are responsible for producing myelin — the fatty substance that wraps around and protects nerve endings — in the central nervous system (CNS; the brain and spinal cord).
Findings from this preclinical study will be presented by Sanofi Genzyme, the company that currently holds tolebrutinib’s commercial rights, in the oral presentation, “BTK signaling regulates real-time microglial dynamics and prevents demyelination in a novel in vivo model of antibody-mediated cortical demyelination,” at MSVirtual2020 that runs through Sept. 13.
Tolebrutinib, formerly known as PRN2246, is an oral and selective small molecule inhibitor of the enzyme Bruton tyrosine kinase (BTK) that is able to cross the blood-brain barrier — the semi-permeable membrane that separates the brain from the rest of the blood circulating in the body — to reach the brain.
BTK plays a key role in the activity and survival of immune B-cells, which are thought to a key driver of CNS inflammation in people with MS. By blocking the activity of BTK, tolebrutinib is expected to lower inflammation in the CNS, and elsewhere.
Tolebrutinib was originally discovered by Principia Biopharma, and is now being developed in collaboration with Sanofi.
According to the findings to be presented at MSVirtual2020, BTK inhibition can change the way microglia and oligodendrocytes interact in the CNS, ultimately preventing myelin loss.
To mimic the destruction of the myelin sheath seen in MS, investigators treated mice with man-made antibodies derived from patients. In the presence of these antibodies, microglia rapidly became active and started engulfing and destroying the myelin sheaths produced by oligodendrocytes.
But when investigators treated animals with tolebrutinib before administering the artificial antibodies, they found a “notably” lesser buildup of microglia around oligodendrocytes, and lesser reactivity toward myelin 72 hours post-surgery. Treatment also seemed to promote the survival of oligodendrocytes.
“Inhibition of BTK signaling alters microglia-oligodendrocyte interactions and limits … antibody-mediated demyelination. These findings provide a novel context to define glial interactions during immune-regulated demyelination and outline a crucial role for microglia in driving myelin loss,” the researchers wrote in the abstract.
The company will also present additional data on the effects of BTK inhibition on microglia in the poster, “Decoding Bruton’s tyrosine kinase signalling in neuroinflammation.”
Using post-mortem patient brain samples, researchers found that the BTK enzyme was present in high levels in both B-cells and microglia, particularly in samples with MS lesions.
When they analyzed the genetic profile of brains from cuprizone-treated mice — a mouse model of MS in which myelin loss and oligodendrocyte destruction is caused by the toxic agent cuprizone — they found a strong BTK-dependent inflammatory signature.
However, this pro-inflammatory genetic signature could be reverted by treating animals with an oral, brain-penetrant BTK inhibitor.
“Using the cuprizone-induced toxicity model, we extend our previous findings on the role of BTK in microglia to show that BTK-dependent inflammatory signalling in these cells can be modulated using brain-penetrant BTK inhibitors in vivo, which could abrogate microglia-driven neuroinflammation implicated in disease progression in MS,” the researchers wrote.
Sanofi will also present new safety and efficacy data from clinical trials of Aubagio (teriflunomide) and Lemtrada (alemtuzumab), two approved therapies for relapsing forms of MS. More details about the abstracts to be presented at the meeting can be found here.