BTK Inhibitors in the Treatment of MS

What is Bruton’s Tyrosine Kinase (BTK)?

Bruton’s Tyrosine Kinase, or BTK, is an enzyme in the body that plays a role in the activity of B cells.  B cells, which are important cells in the immune system, have been found to play a critical role in multiple sclerosis.  This has been emphasised by the success of therapies that target B cells in multiple sclerosis, such as ocrelizumab and rituximab.

What is a Bruton’s Tyrosine Kinase inhibitor (BTKi)?

Considering the importance of BTK in the function of B cells and the role that B cells play in multiple sclerosis, there has been interest in developing therapies that could inhibit BTK.  These treatments work by blocking the action of BTK, which also then impacts on the activity of B cells.   As a collective, these types of treatments are termed Bruton’s Tyrosine Kinase inhibitor therapies (or BTK inhibitors).

There are several different BTK inhibitor therapies that are being tested in multiple sclerosis.  These are:

• • Evobrutinib – phase II and phase III trials in relapsing-remitting multiple sclerosis
  • Tolebrutinib – phase II and phase III trials in relapsing multiple sclerosis, non-relapsing secondary progressive multiple sclerosis and primary progressive multiple sclerosis
  • Fenebrutinib – phase II and phase III trials in relapsing multiple sclerosis and primary progressive multiple sclerosis
  • Remibrutinib – phase III trials in relapsing multiple sclerosis
  • Orelabrutinib – phase II trial in relapsing-remitting multiple sclerosis

All of these trials differ in terms of their number of participants, trial length and control group.

What is the latest news?

Bruton’s Tyrosine Kinase inhibitors (BTKi) for the treatment of multiple sclerosis have been back in the news recently for two main reasons.  These are:

1. 1. There have been some safety concerns identified in some participants in ongoing clinical trials.  These safety issues relate to potential side-effects on the liver caused by these therapies.  In late November, the US FDA put a partial hold on clinical trials using fenebrutinib due to these concerns.  Earlier this year, these liver side-effects were also observed for evobrutinib, which halted further trials (the ongoing trial was allowed to continue).  Similarly, tolebrutinib trials in myasthenia gravis were stopped, with drug-induced liver injuries provided as the reason.

1. 2. Phase III trial results of evobrutinib for the treatment of relapsing multiple sclerosis were announced, which suggested that the study did not meet its objectives.  In particular, it was found that evobrutinib did not significantly reduce relapse rate when compared with teriflunomide.  More information on these trial results can be accessed here.

What does this mean for the future?

An unsuccessful Phase III trial and safety concerns over other therapies means that the future for this class of treatments is looking less promising than it once was.  However, just as with positive results, we need to be careful not to jump to conclusions when it comes to negative results as well.   The results of this trial will need to be analysed further to see whether or not some people living with MS did see benefits from the treatment, even if there was no significant improvements observed overall.

The safety concerns are obviously worrying and need to be taken seriously.  With trials paused, it will be important to see if this side-effect can be better understood and establish whether steps can be taken to reduce any risks associated with the use of these treatments in the future.  We will continue to provide further updates on these other therapies, including any results of the trials, when they are made available.

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