Barts-MS rose-tinted-odometer: ★★★
Mouse Doctor studied zoology and as a result, he tends to use animal analogies to describe various phenomena. In the past, he has been known to use his favourite invertebrates to describe some neurologists or even groups of neurologists. Why invertebrates? If anyone comes up with the correct answer I will send you an MRI scanner lego set as a prize.
Another animal he loves are lemmings, which he uses to describe the behaviour of pharmaceutical companies, i.e. they tend to follow each other by running off a cliff together. The question on everyone’s mind is how will the BTK (Bruton Tyrosine Kinase) inhibitor MS race turnout; will it be mass suicide with them failing as a class or will they usher in the next generation of innovative MS treatments?
Our interest with BTK inhibitors started about 5 years ago when the Mouse Doctor and I almost managed to get Abbvie to fund an investigator-led study of Ibrutinib in MS. However, it was not to be as Abbvie’s partner Janssen blocked the grant. Janssen was concerned that it was too risky to test Ibrutinib in MS because of the off-target effects of Ibrutinib and its potential for serious adverse events. I suspect they were right as Ibrutinib is a dirty drug and not a very selective BTKi as it also inhibits several other kinases.
Our hypothesis was simple; we wanted a CNS penetrant drug to target B-cells and plasma cells in the CNS of pwMS. We were buoyed by the observation that several people with CNS B-cell lymphomas were having dramatic responses to Ibrutinib. Although it was never to be we continued our search for a CNS penetrant anti-B-cell and anti-plasma cell agent and eventually, we managed to convince Takeda to fund a trial of their CNS penetrant second-generation proteasome inhibitor Ixazomib in MS. This study was meant to start earlier this year and has been unfortunately delayed by COVID-19 (we are now recruiting and are due to start very soon).
Despite our failure to get Ibrutinib, a first-generation BTK-inhibitor, into MS Pharma has taken up the challenge and there are now four companies with BTKi programmes in MS (Merck KGaA, Sanofi-Genzyme, Roche and Biogen).
BTKi’s will work in MS because they inhibit B-cell activation. There is phase 2 data for two of these agents confirming this (Merck and Sanofi-Genzyme). However, most people are not aware that BTKi also inhibits macrophage and microglial activation via the Fc receptor (FcR) signalling pathway. Therefore CNS penetrant BTK inhibitors, which applies to at least three of the four BTKi’s referred to above, will also target the so-called ‘hot’ or activated microglial response and test the hypotheses whether or not this response is favourable in MS.
The problem will be dissecting-out the anti-B-cell response from the anti-microglial response in terms of efficacy. Clearly, this will be important in view of some of the issues I raised yesterday around the ‘hot microglial’ response being potentially beneficial in the pathogenesis of MS. I envisage BTKi being very effective in stopping relapses and focal MRI activity the big question will be about the impact of BTKi on the smouldering component of MS. BTKi’s may have no effect on this component of MS, improve it or even make it worse.
I note that many of the phase 3 studies will be testing BTKi against teriflunomide. Clearly, BTKi’s are likely to beat Teri in terms of their impact on relapses and focal MRI activity, but Pharma (or the lemmings) may be taking a chance of beating Teri in terms of its impact on the end-organ or the smouldering component of MS. Don’t forget ofatumumab and teriflunomide had the same effect on brain volume loss when they were compared head-2-head in the ASCLEPIOS I and ASCLEPIOS II studies despite ofatumumab being clearly superior to teriflunomide in suppressing relapses and focal MRI activity.
It is clear to me that BTK is a very important treatment target in MS and the phase 3 trials will provide additional evidence beyond the B-cell on whether or not we should be targeting macrophage and microglial activation via their Fc-receptors. Whether or not this class of treatments will fail, i.e. fall of the cliff waits for the outcomes of the phase 3 trials.
For once I going to be an optimist and give this new class of treatment a 65% chance of success, mainly due to their anti-B-cell effects, and only a 30% chance of failure, due to their microglial inhibition and yet to be identified off-target effects. What is important is that we are testing a hypothesis about the smouldering component of MS, which I consider to be the real MS and why I am so excited to be part of the story.
CoI: I sit on two BTKi phase-3 trial steering committees.