Host – Dan Keller
Hello, and welcome to Episode Fifty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.
This week’s podcast features an interview with Dr. Gavin Giovannoni who discusses the first experimental drug to show some benefit in a progressive form of multiple sclerosis in a major trial. The drug is ocrelizumab, and the trial is called ORATORIO. But first, here are some new items in the MS Discovery Forum.
The ocrelizumab findings were the big news at last week’s large international MS meeting in Barcelona, Spain. Our Research Roundup highlights other breaking stories from the meeting. Stay tuned for more in the days to come. We’ll be rolling out in-depth stories on some research themes we followed at the meeting. And we will have some extra meeting-related podcasts for you in the next two weeks.
Every week, MSDF lists the latest scientific papers related to MS, with links to the abstracts on PubMed. Of 138 new studies published last week, we selected three as editor’s picks.
In one study, a British team found a new reason why remyelination fails in disease. When damaged axons lose their myelin sheath, as in multiple sclerosis, they strike up a conversation with immature myelin-making cells. The axons reach out with new synapses to order the cells to grow up and make new myelin. If axons can’t call for help, as also may happen in MS, the myelin-making cells cannot respond. The team made their discovery in rat brains. They also found new synapses and telltale signaling molecules in postmortem brain lesion samples from people with MS.
In another paper, a Spanish group looked at other factors that may block the brain’s ability to repair itself after inflammatory damage. A pair of molecules, known as semaphorins, may block myelin-making cells from coming to the rescue of damaged axons. The findings come from human tissue samples and may hold promise as targets for future treatment.
Our third editor’s pick paper looks at factors influencing the intention to exercise and the execution of exercise among people with multiple sclerosis. A Danish team did an extensive review of rehabilitation and sports medicine literature. They found that health professionals can help on both fronts.
Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added two new findings from clinical trials, we updated information from another trial, and we added 10 other pieces of information to the database. The drugs with important additions are alemtuzumab, dalfampridine, fingolimod, glatiramer acetate, idebenone, natalizumab, and teriflunomide. One update summarizes the finding that fingolimod induces the expression of neuroprotective factors by human astrocytes.
And now to our interview with Dr. Gavin Giovannoni, head of neurology at Barts and The London School of Medicine and Dentistry in the U.K. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting and about the ORATORIO trial of ocrelizumab in primary progressive MS. We'll cover the Brain Health report in future podcasts with him and other authors of the report. But today, Dr. Giovannoni lays out the methodology of ORATORIO, which may explain some of the very good reduction in disease progression, observed in this trial for the first time in primary progressive MS.
Interviewer – Dan Keller
In the ORATORIO trial, what was the aim, and I guess what's the big outcome?
Interviewee – Gavin Giovannoni
Well, the ORATORIO trial is essentially a phase III trial of depleting anti-CD20 monoclonal antibody called ocrelizumab in primary-progressive MS. As you're aware, almost every trial done in primary-progressive MS has been negative. And then the motivation behind the ocrelizumab trial was based on the rituximab trial; ocrelizumab is a follow-on and rituximab is more humanized, so that should come with fewer side effects like infusion reactions and anti-drug antibodies. In that rituximab trial, there was a subgroup of the population that responded. These were people that are younger and had MRI activity.
So when we designed the ocrelizumab ORATORIO trial, we tried to enrich the study for young people and people that were more active, more enhancing lesions, and we did that. So the population is younger, and the proportion of patients with gadolinium-enhancing lesions at baseline was about a quarter of them. And we also made sure that all the patients had an abnormal CSF spinal fluid. The reason for that is in the Copaxone glatiramer acetate trial, patients who didn't have an abnormal CSF behaved very differently to those with an abnormal CSF, so we wanted to make sure that we had a homogeneous population. And we made sure they had oligoclonal bands or raised IgG in the spinal fluid simply because we we're trying to target a B cell response; so those that are CSF-negative may not be responsive to a B cell therapy.
Lots of features of this trial that we try to wait to make it positive, so we're really, really excited about the results, that people on ocrelizumab had an approximately 25% reduction in confirmed disease progression on EDSS compared to patients on placebo. And it was an event-driven, so the trial wasn't designed to be a fixed time point, it was designed as soon as you got enough events; it was like an adaptive trial, so it was quite cleverly designed in that regard. So it's great news.
Now whether the trial was positive because ocrelizumab is a more effective therapy than the others, or because it's targeting something special like the B cell, at the moment is not known. The only way we're going to find that out is if we do another primary-progressive trial with another highly effective therapy and see what happens there. But this is fantastic news for people with progressive MS. If you follow any patient forums or blogs or whatever, the most frustrated, depressed group is the primary-progressive patients; they've been neglected for years, decades. I think that's the big news, we now will have a therapy which we can offer them.
The one unknown, though, is maybe this result has been driven by a particular subgroup, and I think the regulators and the payers will want to get that data from us. Because if it is driven by a particular subgroup, they may limit the license and the payment for that particular subgroup, the responder group. And so I can't talk to that yet, because most of the subgroup and post-hoc analyses haven't been done. But potentially maybe like the rituximab trial, there will be a proportion of the patients that have characteristic features that are more responsive to the drug, and drive the trial results compared to the other group. And if that is the case, then it's still good news regardless.
As it stands now, it seems like the indication would be for people with abnormal CSF, oligoclonal bands, or elevated IgG. Is there any thought that this drug may work possibly by the same mechanism even if you're not seeing abnormal CSF?
The spinal fluid tests aren't 100% perfect, so there are people who will have false-negative results. But I've always been a big proponent of the hypothesis that the oligoclonal response in the spinal fluid is something key to this disease. We see that response in infectious diseases like neurosyphilis, measles, rubella panencephalitis, herpes; it's really a signature of its common to infectious diseases, which is why I'm still a supporter of the hypothesis that MS may be an infectious disease. You do find that in a few other autoimmune diseases, particularly the paraneoplastic plastic syndromes, that it's a signature of an intrathecal B cell response. And this drug targets B cells.
One thing it doesn't target, though, it's the long-lived plasma cell, and so CD20 actually stops being expressed, even on plasmablasts, so as soon as you go from the mature B cell to plasmablast to plasma cells, you don't deplete those with anti-CD20. So we know from rituximab data that the oligoclonal bands persist, so we need longer punctures, you don't get rid of those. But until we have long-term followup, we don't know. Maybe drugs that target the plasmablast and the plasma cell will be more effective than rituximab. We don't have any of those drugs available in MS yet.
There's one that's being developed, it's anti-CD19; CD19 gets expressed onto the plasmablast and some plasma cells, and there are some specific markers for plasma cells. But if you gave those to people with MS, you'd probably deplete them of their antibody-producing cells and make them a gamma globulin anemic. Then you'd have to probably then start supplementing with gamma globulin, so it gets quite complicated. But at the moment, the drug will be licensed, I think, for continuous use every 6 months; it won't be induction therapy. Some of the data would suggest you could potentially use it as induction therapy, so, you know, do 2 years and then wait and see if the disease comes back. But the way the drug's been developed at the moment is for continuous maintenance use. There are some concerns; can you continue to use it in the B cell depletion forever? And that's going to have to be answered with the open-label extension studies.
Since plasma cells persist and oligoclonal bands persist, if I understood you correctly, do you think that the pathology is mediated through antibody, or this depletion of B cells is acting in a different way, that the B cells are interacting either with T cells or on their own doing something?
I mean, there is pretty good evidence from the pathology literature that antibodies are very important in MS. So whether or not you accept it, there is pathological classifications of the top 1 to 4. And there is antibody and complement activation in MS lesions, and there is emerging evidence that so-called grey matter lesions and subpial lesions on the surface are particularly driven by antibody and complement. So I do think they are pathogenic. And so you may get rid of the focal inflammatory lesions that appear to be T cell-driven, whereas the cortical subpial lesions may be antibody-driven. So you may be getting rid of one pathology and not all the pathologies, which is why I remain a little bit skeptical still about whether or not this anti-CD20-depleting antibody will be effective in the long-term. So we may need additional treatment to target plasma cells.
And what you've got to ask yourself really is what's driving those oligoclonal bands. We know they are highly selected, so they're not just there. They're oligoclonal, they've undergone selection by hypermutation, so there's some antigen driving them. They respond to something, and we just haven't been able to find out what they respond to. They are pathogenic, and if we do find the cause of MS, that will almost certainly begins to cause the disease. An analogy would be herpes encephalitis; if somebody's had a herpes infection, then you take those oligoclonal bands out and you absorb them against the antigen from herpes, you remove almost all the antibodies. So they are antigen-specific in the infectious space.
We've tried for years to find out what those bands react against in MS, and we haven't found it. There's several groups still working on it, and I would encourage them to continue working it, because that may be where the action is.
The ORATORIO data was only begun to be analyzed very recently. You had mentioned that you were going to be doing subgroup analyses. Are there other analyses yet to come?
I mean, the headline results are probably in main secondary outcomes, and there's less of tertiary outcomes. We need to do subgroup analyses trying to look at brain atrophy, the time course of the progressions. I'm very interested in second progressions, because I have this theory that early progressions in progressive disease is not driven by inflammation that occurs in this epoch, it's in the past; so inflammation a year or two ago is driving progression now. And so when you design these progressive trials, a large number of people progress early. And I think it's nothing to do with the trials because it's happened before the trial. So what you then need to do is look at progressions in the future to see if they flatline or stabilize. So there's lots of luck. I think we need to play around with the data, look at the first and second confirmed progressions, incorporate the brain MRI activity as the confounder. There's lots to do, tons to do. But it's good news. The excitement about those analyses are generated because you've got a positive result.
Picking up on this idea that what you see today is the result of an insult that happened sometime before, what is the time course that you see using ocrelizumab in terms of benefit; is it so rapid that it questions whether what you said is what's operating?
Yes, it's too rapid. When you see the survival curves, they go flat very early, so this is actually saying something else which is really surprising me, which is why I think some of the activity may be driven by an anti-inflammatory, because we know that anti-inflammatory drugs have an effect quite quickly. So that's why I'm suspicious that the positive result is driven by an inflammatory core of patients, and those with the more neurodegenerative or previous inflammation are unlikely to respond. That's my worry with the drug. But let's see what their subgroup analyses show.
Anything we've missed or important to add on that?
What I want to mention to people with the disease is they shouldn't overhype expectations. The simple reason is when you've got progressive disease you've already lost reserve, so that's why you're progressing. So in early relapsing disease, you make recovery from attacks because you've got ability to recover, a reserve. And so early on you stabilize or improve, and later on you slow down progression. So I'm trying to tell people with the disease if you do go into this therapy, don't expect to improve or get better. You're much more likely to progress more slowly, which you won't notice. It's hard in an individual to say they're progressing more slowly, or you'll plateau out and stabilize. I think that must be the expectation, rather than improvement. And I think we need to manage those expectations, that people may not at a personal level find a big dramatic response in terms of their disability on the drug.
But this sounds like – getting back to the discussion of the Brain Health report – where you should diagnosis and treat rather quickly. At least now if someone comes in with primary-progressive, there may be at some point something to do from the start.
Yeah. Well, it's like with any neurodegenerative disease, the sooner you treat the more you've got to protect, and the later you treat the less you've got to protect. So this would be a call to get primary-progressive disease diagnosed as soon as possible and treat as soon as possible. And if you look at the diagnostic delay in primary-progressive disease, it's probably worse than relapsing disease. People often go years before being diagnosed. So we're going to have to sharpen up the referral pathways and the diagnostic pathways in primary-progressive disease to get that timeless brain concept across there, too.
Thank you for listening to Episode Fifty-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. Heather McDonald curated the MSDF drug database updates. 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.
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For Multiple Sclerosis Discovery, I'm Dan Keller.