Multiple Sclerosis Discovery -- Episode 86 with Dr. Pavan Bhargava

Full transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. A hallmark of multiple sclerosis is a new brain lesion. The active inflammation normally goes away in about 4 to 6 weeks, disappearing from contrast-enhanced detection by MRI scans. More recently, in some people with MS, researchers have found smaller longer-lasting inflammatory lesions outside the brain, in the surrounding lining called the leptomeninges, as well as evidence that they may play a role in progressive disease. The tiny compartments are associated with more severe disability, worse outcomes, and nearby gray matter demyelination. Dr. Pavan Bhargava, a neuroimmunology fellow at the Johns Hopkins University MS Center in Baltimore, Maryland, has started a phase I trial to slow progressive disease by targeting the B cells in these follicles. He is testing an anti-B cell antibody called rituximab, using the drug intrathecally—that is, injecting it directly into the cerebrospinal fluid of patients with primary or secondary progressive MS, so that more of it reaches the inflamed pockets in the brain lining. We spoke at the ECTRIMS meeting last fall in Barcelona, where he described to me the rationale for this experimental treatment approach. Interviewee – Pavan Bhargava In 2004, what was noted was that in autopsies of MS patients, there were collections of lymphoid cells in the meninges, and these aggregates of lymphoid cells were noted to abut areas of the cortex that demonstrated demyelination. So this suggested that possibly these collections of B and T lymphocytes that were in the meninges might be driving some of the cortical demyelination that is seen commonly in patients who have progressive MS. So the idea behind using rituximab intrathecally is that we want to, first of all, get as much rituximab as possible into the CSF [cerebral spinal fluid] and into the brain, because when we give rituximab IV, less than 0.1% usually gets into the CNS [central nervous system]. So we're trying to target the B cells that are found in these lymphoid follicles, and we're trying to get as much of the rituximab into the CNS as possible. So that's the rationale behind using intrathecal rituximab in progressive MS patients. Interviewer – Dan Keller Do the patients you're selecting just have visible leptomeningeal lesions, or do they have to have abnormal CSF – IgG elevated or oligoclonal bands – or how are you selecting them? Dr. Bhargava So in our trial, we are selecting patients using an MRI finding that was described now a couple of years ago that on a time-delayed post-contrast flare image, in about a third of MS patients you can actually see contrast-enhancing lesions, not in the brain parenchyma, but actually in the leptomeninges. And a recent paper from the NIH showed that in a couple of these patients who had contrast-enhancing leptomeningeal lesions, when they came to autopsy they could identify clusters of lymphocytes and macrophages that corresponded to these contrast-enhancing leptomeningeal lesions. So in our study, we're basically screening progressive MS patients with an MRI, and are only including patients in this study who do have evidence of these leptomeningeal contrast-enhancing lesions, because we feel that this is a marker of leptomeningeal inflammation in these patients.   MSDF And have you run any patients yet? Dr. Bhargava So we have 5 patients currently in the study, of whom 4 have actually completed their treatment phase of the trial. And our goal in this study is to enroll 12 patients. And the primary outcome is safety. So, you know, we want to know that using rituximab intrathecally in MS is safe. But our secondary outcomes include looking at the change in the MRI lesions that we noted at baseline, and then we're also going to look at the change in immune populations in the CSF and some biomarkers for axonal damage and chemokines that are associated with these lymphoid follicles. MSDF Are these lesions similar to ones in the brain parenchyma that come and go, or will you be sure that your treatment is what caused any difference? Dr. Bhargava So these lesions that we note on the MRI in the meninges, unlike lesions in the brain parenchyma, where you note contrast enhancement when they're new and active, and then about 4 to 8 weeks later, they stop taking up contrast, the lesions in the meninges continue to enhance for years. So there's data that these can continue to remain the same and enhance for over 3 years. So that's really why we decided to use this as a secondary endpoint, because we have not seen changes in these lesions over time. And so if we actually saw a change, it might suggest that it was secondary to our intervention. MSDF Since this is a phase I trial, do you have a control group, or you're just looking at the ones you're treating? Dr. Bhargava Yeah, so because this is a phase I trial and the primary outcome is just safety, this is open-label, and so everyone in this trial is going to receive intrathecal rituximab. MSDF When do you expect to see any results, or have you? Dr. Bhargava We will be analyzing all this data once we've accrued the patients, and we're hoping to complete recruitment in the next 3 to 4 months, and then we follow all these patients for a year. So probably at some time towards the end of next year [2016] we should have results from the trial. MSDF Is this a test of concept, not only of rituximab but of what these leptomeningeal lesions mean? Dr. Bhargava So yes and no. In a way, there's a proof of concept because if we were to see changes in these lesions that otherwise remain really stable, that might suggest that a drug that could possibly deplete B cells makes a change in these leptomeningeal lesions. But it's also possible that perhaps B cells are not a sufficient target, or that we're not able to deplete B cells that are within these structures. And so, you know, there are some confounding factors that possibly could lead to this trial not being successful. But this is what we plan to look at is, if we actually see a change in these lesions, then to us that would be a kind of a proof of concept that rituximab might be able to effect these leptomeningeal lymphoid aggregates. MSDF Is there evidence that these aggregates are pathogenic? Dr. Bhargava There is evidence in terms of previous studies where they looked in autopsies in both primary progressive and secondary progressive patients. They found that people who had evidence of meningeal follicles had more cortical demyelination compared to those who did not. So that is indirect evidence that perhaps these follicles play a role in disease progression and may be pathogenic. We don't have direct evidence yet in patients who have been, say, prospectively followed to suggest that these lesions are causing damage. MSDF Are these aggregates solely B cell, or what else is there? Dr. Bhargava You know, these aggregates have B cells, but they also have plasma cells, they have follicular helper T cells, and they have follicular dendritic cells. So there are multiple cell populations that make up these follicles, and each of these populations produce factors that keep this follicle going. And so perhaps disrupting just one component of this follicle may not be sufficient, and we may need to then expand our targets and try to target multiple cell populations at the same time. MSDF I suppose, though, if you do interrupt the sort of chain of events, it may be sufficient to break one link. Dr. Bhargava Right. That's our hope with this trial is that taking out maybe one key player in this follicle might be sufficient to then disrupt this vicious cycle, but only time will tell. MSDF Is there evidence that lymphoid aggregates may exist in the meninges in people without any evidence of any disease? Dr. Bhargava We don't know the answer for that for sure, but in the study from the NIH, they didn't really see these contrast-enhancing lesions in healthy volunteers. So that would suggest that perhaps these are not found in healthy people without disease. MSDF I'm just thinking in terms of normal brain protective mechanisms, whether things like this fight off disease. Dr. Bhargava That really would need a study looking at the meninges in people who pass away from other diseases; in, say, not autoimmune diseases. And the reason why this is such a fairly recent discovery is just because when pathologists used to look at brains at autopsy, they would just rip off the meninges and throw those away and just look at the brain. So I'm sure this question could be answered, but right now we don't know. There is actually some emerging evidence that perhaps these follicles might be seen in other CNS immune diseases, for example, Rasmussen's encephalitis. There was a study from our center where they noted presence of possible B cell follicles in biopsy material from patients with Rasmussen's encephalitis, and so it's possible that this might happen in other autoimmune disorders. But this process of ectopic lymphoid neogenesis seems to happen mostly in autoimmune diseases, like type 1 diabetes or Sjögren's syndrome or rheumatoid arthritis, and so it seems to be related to autoimmunity. MSDF If this pans out what you're doing now, would rituximab be pursued, or do you foresee other monoclonals coming along that may be more appropriate to carry forward? Dr. Bhargava I think part of that would depend on what we see in this study, and if we don't see a robust effect then we might switch to a different target. And also, you know, we may want to target more than just the B cells. You know, there are other therapies coming down the pipeline, like anti-CD19, which targets a broader range of the B cell lineage, and then perhaps we might try to target like, say, plasma cells. So I do foresee that if we continue with intrathecal therapy, we would end up trying to use other monoclonals, as well. MSDF Is this a feasible technique in many patients, a wide array, or is it very specialized and would have to be restricted? Dr. Bhargava It is not really that difficult to perform, because we basically are performing a lumbar puncture and are injecting the drug through a lumbar puncture, and so it should be feasible. Of course, it is still an invasive procedure. However, if we really did see a benefit from this, then I think it would probably be worth that effort and risk. MSDF Have we missed anything, or anything important to add on the topic? Dr. Bhargava It's important to continue to try to understand how this process is affecting the brain and whether it's actually causing damage. And I think more studies looking at perhaps imaging to see how these lesions are affecting the brain parenchyma around them may give us more insights into how pathogenic these lesions are. And then I think from our study we might begin to understand whether we're able to actually make a difference to these lesions that we're seeing. MSDF Very good, I appreciate it, thank you. Dr. Bhargava Thank you. [transition music] MSDF Thank you for listening to Episode Eighty-Six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected]. For Multiple Sclerosis Discovery, I'm Dan Keller.