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.
Barts-MS rose-tinted-odometer: zero stars or one ★ depending on your disposition
I prepared this post not knowing that Prof. Laura Airas has submitted a guest post in response to a request from the Mouse Doctor. Before reading this post please make sure you read her blog post first. It provides an important counterbalance to my contrarian view below. Thank you.
More than 20 years ago, when I was a junior researcher, doing my PhD, I started a research collaboration with Dr Richard Banati, who worked in the Queen Square Brain Bank and the Imperial College PET imaging unit. Richard was investigating activated microglia in multiple sclerosis. The collaboration was very fruitful and led to the very first study of an imaging molecule called PK11195 that could label activated microglia.
In the study (see below), we elegantly showed that people with MS (pwMS) had widespread microglial activation in their brains. Their brains, in fact, lit up like Christmas trees with so-called ‘hot’ or activated microglia. The assumption, which is now dogma, from this and other studies is that these microglia must be bad for pwMS. This has led to many research and drug discovery programmes to find treatments to switch off hot microglia.
Now dial forward 20 years and finally, a follow-up study from Finland that shows that pwMS with a lit Christmas tree in their heads do worse in the longterm, i.e. pwMS with more microglial activation as determined by PK11195 staining had more disease progression that was independent of relapses. The implication is that PK11195 is a good marker of smouldering MS and if we switch off this marker we will improve long-term outcomes.
In an email exchange with colleagues, I challenged this thinking. Is the PK11195 signal, or hot microglial response, the chicken or the egg? The microglial response may not be causal but simply associated with a worse outcome in MS. Just maybe the microglia are responding to what is causing MS and are not the primary drivers of the MS pathology. Therefore if you switch off the microglial response you may not improve MS outcomes but actually make them worse.
I even provided some early odds of this happening. I predicted that a drug that switches off the microglial response had only about a 20% chance of improving MS outcomes. I balanced this by saying that I thought that a microglial inhibitor had about a 60% chance of actually making MS worse. I was then challenged that these odds were simply a guess; like an unskilled poker player. I disagree. Firstly, poker is a game of skill and the most skilled poker players make a relatively decent living from their skills. Secondly, there is a scientific process behind making accurate predictions (see post-script), which I try to apply. Finally, we need to apply science to the microglial prediction at hand.
The Science: In the smouldering or slowly expanding MS lesion the hot microglia are lined up like soldiers fighting an enemy at the edge of the lesion. They remind me of a Greek phalanx.
A Military Phalanx
These microglia are not malignant cells, which makes me think they are simply doing their job. Now what if these microglia are responding to something in the surrounding tissue, for example, a slow viral infection? Switching them off may actually make the slow viral infection worse. In addition, microglia have very important function clearing up debris in the nervous system and maintaining the health of synapses and neurons in general.
Figure 1 (from Frischer et al., Ann Neurol 2015): (A, B) Early active plaques (EAL) were defined by macrophages immunoreactive for minor myelin proteins (MOG positive macrophages right insert in A) as well as major myelin proteins (PLP positive macrophages left insert in A). (C, D) Smoldering plaques (also called slowly expanding plaques) typically showed a rather inactive centre with no or few macrophages, surrounded by a rim of activated microglia. Only few of these macrophages or microglia cells contained early myelin degradation products. Inserts depict plaque edge. (E, F) Inactive plaques revealed a sharp plaque border without or only few macrophages or activated microglia (insert). (G, H) Completely remyelinated plaques typically containing few macrophages without early myelin degradation products were classified as shadow plaques. Shadow plaques presented with a sharp plaque edge and were associated with fibrillary gliosis.
More Science: Importantly, defects in the signalling pathway of CSF-1 (colony-stimulating factor 1), which is also known as macrophage colony-stimulating factor (M-CSF), cause progressive dementia and disease of the cerebral white matter called a leukoencephalopathy. CSF-1 is a microglial stimulant. This is a warning that inhibiting microglia indiscriminately is unlikely to be good for the brain and particularly a damaged MS brain. This is why I have given greater odds to a microglial inhibitor making MS worse than making MS better.
I am also aware that there are different types of microglia, different types of microglial responses and hence we may have to be more selective in how we target microglia in MS. Despite this, I think we as an MS community need to take a step back and challenge the current dogma that the microglial response in MS is necessarily bad. If we don’t we may be unpleasantly surprised and disappointed with the outcome of clinical trials targeting hot microglia and smouldering MS.
P.S. If you are interested in reading about the science of prediction I would recommend ‘Superforecasting: The Art and Science of Prediction’ by Dan Gardner and Philip Tetlock; a remarkable book that provides important insights and lessons to avoid unconscious biases and it teaches you a little poker as well 😉
Sucksdorff et al. Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis. Brain, awaa275, https://doi.org/10.1093/brain/awaa275 Published: 02 October 2020.
Overactivation of microglia is associated with most neurodegenerative diseases. In this study we examined whether PET-measurable innate immune cell activation predicts multiple sclerosis disease progression. Activation of microglia/macrophages was measured using the 18-kDa translocator protein (TSPO)-binding radioligand 11C-PK11195 and PET imaging in 69 patients with multiple sclerosis and 18 age- and sex-matched healthy controls. Radioligand binding was evaluated as the distribution volume ratio from dynamic PET images. Conventional MRI and disability measurements using the Expanded Disability Status Scale were performed for patients at baseline and 4.1 ± 1.9 (mean ± standard deviation) years later. Fifty-one (74%) of the patients were free of relapses during the follow-up period. Patients had increased activation of innate immune cells in the normal-appearing white matter and in the thalamus compared to the healthy control group (P = 0.033 and P = 0.003, respectively, Wilcoxon). Forward-type stepwise logistic regression was used to assess the best variables predicting disease progression. Baseline innate immune cell activation in the normal-appearing white matter was a significant predictor of later progression when the entire multiple sclerosis cohort was assessed [odds ratio (OR) = 4.26; P = 0.048]. In the patient subgroup free of relapses there was an association between macrophage/microglia activation in the perilesional normal-appearing white matter and disease progression (OR = 4.57; P = 0.013). None of the conventional MRI parameters measured at baseline associated with later progression. Our results strongly suggest that innate immune cell activation contributes to the diffuse neural damage leading to multiple sclerosis disease progression independent of relapses.
This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.
