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Timothy L. Vollmer, MD
Department of Neurology
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Co-Director of the RMMSC at Anschutz Medical Center

Medical Director-Rocky Mountain MS Center
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Timothy L. Vollmer M.D.
Department of Neurology
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Masters of Neurology: Lemtrada (Alemtuzumab) in MS: VIDEO


Alemtuzumab is a monoclonal antibody that targets a certain epitope called CD52. And CD52 is expressed on mature lymphocytes. So by administering alemtuzumab, very rapidly you deplete adult lymphocytes. You don't really affect pluripotent stem cells and you have a minimal effect on other cell lines. Monocytes and B cells drop out for a bit, they come back sooner, and really what you're targeting here are those T cells, different T cell populations.

Alemtuzumab is gone after it's given in just about a month. But the effects are really, really long and I think that speaks to its mechanism of action. The first phase is the depletion. It's a very selective depletion. This is not scorched earth like cyclophosphamide or something like that. After you have this depletion there is a very slow repopulation of the lymphocytes. It's fascinating because they come back differently. There's a differential repopulation.

In the naive MS patients there's a paucity of regulatory T cells. And there are way too many inflammatory T cells if you will. And that's the standard in treatment naïve and not [inaudible 01:03]. Alemtuzumab blocks out both of those. And when they come back, the regulatory portion comes back larger and more active which is why I think that we see these durable effects that's been highlighted at this conference.

The other treatment, you have to keep taking it. So you take the drug and if you stop the drug, you're going to revisit the disease. We can use any DMT as an example. I'll use natalizumab as an example. Amazing drug, alemtuzumab. It creates a blockade so it disallows naughty cells to cross into the brain space. Which works great, it's like the Great Wall of China. If you remove it, then you haven't changed the immune system, those cells will go in and wreak havoc. This drug works differently. And the way that we give it, we give 5 days in a row, it's an infused drug, 5 days of alemtuzumab, there's a year with no therapy. And then 3 days of alemtuzumab. Then, we never treat again unless they have activity, meaning a new attack, or too many spots on the MRI.

So the fact that you don't treat again is one of the major differences from every other DMT [disease modifying therapy]. We now have data that's being presented here, 6 year data. And at 6 years, the vast majority of patients have never been retreated. So 67% didn't get another course. And that's very unusual. If you took a patient off of another DMT for 6 years, you'd be revisiting the natural history of MS. So it's the first thing that I find rather different.

The second thing that's different is despite not retreating, you have a consistent improvement -- improvement -- in a lot of the clinical parameters. I'll use atrophy as an example, brain atrophy is bad for you. The MS brain atrophy is 5 to 10 times faster than the general population. It gets smaller quicker. And brain atrophy is one of the strongest correlates to disability and cognitive impairment and a lot of stuff you don't like.

And we saw as compared to the active comparator in the trial, during the two year trial we compared it against interferon-beta-1a, Rebif, that it decreased rates of atrophy more so and that's nice, but really the magic if you'll excuse the expression started around year 3. Year 3, 4, 5, we saw that brain atrophy rates continued to slow down to a normal rate. You entered into the cone of normality. And in year 6 this remains true with brain atrophy rates that are lower than the general population. Not of MS, but of the general healthy population. And that's mind-numbingly good.

I'll use another example with NEDA, no evidence of disease activity. A very important term which our field has recently adopted as a target for treatment. So when you look in year 6, over half of the patients have NEDA that year. Keeping in mind that 60-plus percent weren't even retreated, it's kind of a remarkable phenomenon.

Another important example is this term confirmed disability improvement. So in our field going back to the early trials they always talked about confirmed disability worsening or progression. And we would look for a decrease in the worsening with drug A to drug B. But we only now recently talked about confirmed disability improvement with the exam ameliorates and stays better for at least 6 months. So what we find is that there is confirmed disability improvement: 43% during the first early part and then 40 some percent going out 5 years. The 6 year data hasn't changed. You continue to see patients, in large proportions that are having confirmed disability improvement. Very, very neat.
We can't use the term cure, I don't think that's an appropriate term but I understand the desire to say that. Another term which is used in oncology is remission. And so if you have cancer, God forbid, and we treat you successfully, and you don't get retreated and you go 5 years, we're going to tell you that you're in a remission. Now that's a very charged word in multiple sclerosis, we bring "relapsing-remitting" multiple sclerosis. The term relapsing-remitting MS is not appropriate because there's no classic remission up until this drug.

And so many of us in the field actually now call it relapsing MS. We get rid of the remitting. This is a separate use of the term remission. And at face value it looks like you're in a form of remission. It doesn't mean that the disease is gone, it doesn't mean that it couldn't come back, but we have quiet on the MRI. We have quiet clinically, no history of new attack. We have quiet on exam and in fact some things we see seem to improve. I don't think the field is ready to adopt the term remission, and I struggle to find a term to describe this phenomenon but I can definitely say it's amazingly good. 

I really divide the safety concerns with alemtuzumab into three categories. The first one is infusion reactions. This is an infused drug, it's a humanized monoclonal antibody and despite that there's a lot of infusion reactions. We learned in the phase III trials that 93% of people had some type of infusion reactions. Now post approval every single MS-ologist using this drug has their own chili recipe for how to administer. And everyone thinks they have the best recipe including myself. Suffice it to say that we have learned a lot over the past few years on how to give the drug and people still have infusion reactions. And so I don't want to delay that. I tell people you're signing up for 5 days that may be very uncomfortable. Rigors, chills, spots, headaches, etc.

I think we do a good job of getting people through that. But that's not to be discounted; infusion reaction is the first category. The second category is causing auto-immunity. And let me explain, MS is an auto-immune disease, when we give you alemtuzumab, we're removing those adult lymphocytes and we give them back differentially. Meaning we give back the CD8 cells, before the CD4 cells. They don't come back all at the same time. And I think it's because of this differential return of the immune response that we set up the possibility to cause an auto-immune phenomenon.

So at 3 years we see the peak risk of thyroid auto-immune and so you're going to have shy of half the patients, 47% of patients if you look over 6 years that may have an autoimmune thyroid condition. That could be hyper, or hypo. We have a program back home where if we see a change in the numbers because we track this, of course, we send them to the friendly neighborhood endocrinologist who oftentimes does a little Synthroid magic and it works out. But I don't want to belittle the fact that it's a very high number.

Now the other autoimmune disease fortunately occurred with less frequency, there's still about a 2% risk of what's called ITP – immune thrombocytopenia. And for doctors that are familiar with chronic adult immune thrombocytopenia, I have to point out, this is not that, this is much more like a pediatric immune thrombocytopenia. You have to address it, you have to identify it because if you don't, God forbid, they can bleed. But treating it is not as hard as it may sound, we give steroids, we give Rituxan or IVIG, and it generally doesn't return. And I only point that out because again this is unique. When an adult generally has ITP, it's a different course than what we see here with this unique iatrogenically caused ITP. There's 0.3% risk of kidney dysfunction. Primarily nephritis, or nephrotic syndrome. Again, autoimmune. This is the side-effect that I like the very least because it's the hardest to treat and although going out 6 years we don't see an uptick in the signal, so it's not as if those numbers are increasing. The punch line there is the risks of auto-immunity are not increasing.

I'll jump back to immune reactions, each subsequent course we find that the drug is better tolerated.

The third category of risk after immune reactions, or infusion reactions, excuse me, auto-immune, is the risk of cancer. So that's a big, scary word, cancer. Fortunately we're not seeing that the risk of cancer is increasing over time, the numbers are very low, that's not to be discounted. But we see a 0.3% risk of thyroid cancer. A 0.3% risk of melanoma, a 0.2% risk of lymphoma. When I review the data, the 6 year data that we're seeing here today, I'm reassured that there is no new safety signal, I'm reassured that there's improvements to using radiographic optimizers and I'm blown away that this is happening largely in the absence of retreatment.

I think we're learning what it means to get it in the real world. I think we're learning what it means to have larger populations receiving this therapy and we're learning what it means to go out 6 years.

Now the phase two data sets, we actually have 10 year data which looks really, really promising. The 10 year data, the EDSS at 10 years is barely different that it started. It started at 2 and ended at 2.2, and so I think what we're learning is a sense of assurance that the effect that we see, at least for the duration studied, it's not tapering off. It's actually getting better which is weird and cool.

I think that we need to see what it's like in the real world. You know, my patients aren't generally like clinical trial patients. Clinical trial patients are 18 to 55, they have almost no comorbidities, they're very early in the disease process. And if they did other therapies, it's typically one or two. In the real world, people have diabetes, people smoke cigarettes. In the real world, they're all different ages, and so we have 50-60 year olds that are outside. In the real world, it's dirtier, it's muddier. Humans are heterogeneous and MS is heterogeneous. And so this is a very important time. We know what we know from the trials. And we know about the extension data and I'm reassured by that. I think what's to come is how this plays out in different populations. For example, rapidly worsening patients, aggressive patients. You can't really study them in the context of a phase III trial. And so it's this kind of work where we're going to learn that in the real world.

That's the zillion dollar question, and no I don't think we're there yet. We all want to be there. When you look out 6 years, over 73% of people clinically are stable or better. On the flipside, the 27% that aren't, we want to know who they are a priori and we don't know how to do that yet.

I think there is a way to do it. It's not perfect but I want to talk about in the real world doing propensity weighting. And so there is a statistical maneuver where you can look at large datasets of patients on drug A or drug B. And by propensity weighting, you can sort of adjust the baseline characteristics. This allows you at least statistically to start to compare two populations. There's many posters here talking about that kind of statistical design. And so it's that kind of work that's going to give us insights in the real world where we practice how we do that side by side. But to your point it's not going to be a head to head trial. There's no head to head that's going to carry out 6 years or 10 years.

So that's one of the things in the meeting, it is a redial on some of the stem cell registries that we're seeing. And alemtuzumab is not a stem cell transplant. Although it's probably closest comparator. In a stem cell transplant you're collecting or harvesting stem cells and sticking them on ice. And then you're essentially murdering the human if you will. You're giving them lethal doses of chemo and you're erasing their immune system permanently.

Story Source: The above story is based on materials provided by MEDPAGETODAY
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