S6E22 Disease Modifying Therapies with Neurologist Dr. Aaron Boster

Overcoming MS  00:00

Welcome to Living well with MS. This show comes to you from Overcoming MS, the world’s leading multiple sclerosis healthy lifestyle charity, which helps people live a full and healthy life through the Overcoming MS program. We interview a range of experts and people with multiple sclerosis. Please remember all opinions expressed are their own. Help others discover living well with MS. If you enjoy the show, please rate and review us wherever you listen to podcasts. And now let’s meet our guest.

 

Geoff Allix  00:36

Welcome to the latest edition of the Living Well with MS podcast where I’m very glad to welcome back Dr. Aaron Boster. Dr. Boster is an absolute expert in Multiple Sclerosis, and is the founder and owner of the Boster Center in Ohio, US and is here to give us some excellent expert advice on DMTs. From the latest to the oldest, so we’re going to cover the whole gamut, of DMTs. So if we get straight in, because we’re going to cover loads of DMT here. So to start off with, can you give us a broad overview of medication choices for people with MS and also how they’ve improved over the last 20-30 years? Absolutely.

 

Dr. Aaron Boster  01:21

So I would start by saying when I think about helping someone with multiple sclerosis using medicines, I divide my thoughts into three categories. When someone has an MS attack, we’re giving steroids or things similar to steroids to hasten their recovery. And so that’s one category, which hopefully if we do things, right, we don’t have to do very often. A second category of medicines is improving quality of life through treating symptoms. So as an example, if you have a bladder urgency, with risk of accidents, we give you a pill for that. Today we’re focusing on the third category of medicines, which are medicines created to change the natural history of the disease to literally modify the course of the disease in our favor. To be a little bit more granular, when we look at the medicines that have come out over the past couple of decades, we’re really trying to decrease attack rate, decrease new spots on the MRI and to slow disability progression. And those are really goals of modern MS therapies, it’s not to make you feel better in the now it’s to preserve the neurologic reserve. So that 30 years from now, you’re still active in the game,

 

Geoff Allix  02:37

When should patients start a DMT?

 

Dr. Aaron Boster  02:39

The earlier we start a disease modifying therapy, the better the human does long term. And this is not an opinion, this is very strong science supporting this idea. It when we think about some of the earliest drugs, I’ll use the medication Rebif as an example. When we first tested Rebif, we put we randomized people on a trial to either Rebif or a dummy drug, we follow them out for two years, looking at the frequency of their attacks and their disability they accrued on exam. And at the end of two years, the people on Rebif stayed on Rebif. And the people that were on placebo, then started Rebif. So they started at a two year delay, what we learned was really striking. The people that were on placebo for two years, just two years and then got on medicine. They had acrude disability they never regained. And so there was a break between the two groups and the delayed onset group never caught back up. If we take that a step further looking at more modern efficacious drugs, because we now have drugs on the market that are arguably better than the earlier drugs. We’ve done trials where we start someone on what we would consider a high efficacy drug in one group in a clinical trial. And then another group in the trial got low efficacy drugs for two years. Then at the end of two years, all the people on the low efficacy escalated to the higher efficacy. So a very similar model. And we learned the exact same thing. Two years on a lower efficacy drug resulted in a disability accumulation and they never caught back up. So there’s a the totality of evidence is very clear that the earlier we start, the better chances we’re going to have to control the disease.

 

Geoff Allix  04:21

What should people think about if they’re… there’s this huge choice with drugs now. So what are the factors that people should consider when they’re choosing?

 

Dr. Aaron Boster  04:30

A very appropriate but big question to tackle, so I want to try to unpack it a little bit. The very first thing that I as an MS neurologist think about is efficacy. And that doesn’t mean that we go on the most efficacious drug, but I want to stack the deck in your favor. So the first thing I’m going to think about is how effective is that drug? And the phrase that I’ve cultivated is I want you on the most effective drug that you’re comfortable taking. So that doesn’t mean that it’s going to be the The most effective one that’s that you’re eligible for, because it’s real big of me to tell you, hey, that’s a good one. But I’m not the one taking the medicine, you have to take it. So another way of saying that is, it’s really a mix of efficacy, tolerability, safety, and dare I say cost. Because these medicines and different healthcare systems in different countries can be very, very expensive.

 

Geoff Allix  05:24

Would you say that the more efficacious drug has the more side effects?

 

Dr. Aaron Boster  05:31

I think that if we speak in gross generalities that might be true, I think it’s becoming less and less true. So I don’t think it’s a foregone conclusion. I’ll give you an example. The medication Alemtuzumab, Lemtrada, has a tremendous amount of side effect risk up front. And then a couple of years in, there’s no risk. And so depending on where you slice that pie, you know, the risk profile changes. So it’s not as straightforward as high efficacy means high risk, although I think in gross generalities, we can kind of think like that.

 

Geoff Allix  06:06

We’re gonna get through a whole load of disease modifying therapy. So let’s, let’s get into that. So talking about the so when I say DMT, is disease modifying therapy or drugs that we’re using to treat MS. So we’re gonna go through each one on the market. So for each of these, could you tell us about how effective it is, how efficacious it is, how it works, who it works for, how its administered, and any benefits and risks that you think people should know about when considering it?

 

Dr. Aaron Boster  06:34

Sounds good. Now, the one thing I want to say, just as a caveat is I am pretty biased. So I’ll try to be as level headed as I can, but my bias may come out in some of my answers.

 

Geoff Allix  06:44

But you don’t work for a drug company or anything.

 

Dr. Aaron Boster  06:49

I’m a practicing MS. Neurologist. I just yeah, I’m just sharing with you that like, you know

 

Geoff Allix  06:53

Your biased in your beliefs rather than biased commercially

 

Dr. Aaron Boster  06:56

Correct. That’s what I meant. Yep. Yeah.

 

Geoff Allix  06:59

So we’re going to start with one that actually I’ve had, but that’s just by chance, because we’re going alphabetically, and you’ve mentioned it just now, which is Alemtuzumab, Lemtrada is its trade name.

 

Dr. Aaron Boster  07:08

Lemtrada is a monoclonal antibody. So it’s, it’s a biologic agent made in a laboratory, and it’s an antibody that has a very specific binding when you infuse it in the vein, it identifies adult B and T cells in murders them, and subsequently, the cells that grow back grow back more well behaved. Lemtrada is a discontinuous therapy. You take an infusion in the vein for five consecutive days, then you wait a full year, then you do an infusion in the vein for three days, and then you’ve been induced, then you’ve been treated. And then we’re looking for a durable effect in the absence of retreatment. We don’t retreat patients typically, unless God forbid they have breakthrough disease. My biased opinion is that on Alemtuzumab, Lemtrada is one of the most effective drugs currently available on the market. I think that its outstanding at relapse rate reduction. Its outstanding at decreasing new MRI activity. I think one of its shining elements is its ability to slow brain volume loss and to slow disability progression. I would also submit that it has some of the best data for confirmed disability improvement where some people get better. I also say that Lemtrada hands down is probably the most complex drug with the with the broadest risk profile. I’ll divide the risks in four when you take Alemtuzumab, Lemtrada there’s a high risk of infusion reactions physically during the infusion. This is not to be taken lightly. There’s actually been 13 cases of strokes during infusion, nothing to laugh at. More commonly, we’re dealing with a red rash, itchy throat tachycardia, you know, heart rate changing wicked headache, joint pain, things like that. But the infusion reactions require a careful hand we use a lot of medications to kind of ease things out. The infusion reactions don’t last much longer than the duration of the infusion. Fortunately, the second category of risk with Lemtrada, which is somewhat unique to Lemtrada is it can cause autoimmunity. So we’re treating an autoimmune condition MS. But when you take Lemtrada, there’s a 41% chance that you’ll develop an autoimmune thyroid problem. Now this is oftentimes very easily treatable, but that doesn’t make it okay. There’s a 2% risk of having an autoimmune condition with the platelets with the way that you clot your blood and there’s a Scrabble word, it’s immune thrombocytopenia, which is a doctor way of saying the platelets don’t clot. And there’s a very low risk less than a percent of autoimmune kidney or liver disease. So that’s a lot of things to consider. The third category of risk with lemtrada is infection because you’re knocking down the cells and they take six to nine months to come back. So during that period of time, there is an increased risk of infection to specifically infections that we pay very close attention to. One is the varicella, so shingles and we oftentimes at least in the United States put people on prophylaxis with medicines like Acyclovir valacyclovir, for sometimes years to protect them from getting shingles outbreaks. And we also worry about listeria, which is food poisoning. And we kind of use what I jokingly call a pregnancy diet for a period of time after the Lemtrada. Now, the fourth category risk is the lowest risk but the scariest word and that’s cancer. 0.3% risk of thyroid cancer 0.3% risk of melanoma skin cancer 0.2% risk of blood cancer lymphoma. So as you can see, we’re dealing with a very, very high efficacy drug taken in a very weird discontinuous manner, with a very significant upfront risk profile. Now to take the medication, we then check labs monthly for four years after the last dose so that we can monitor for all those risks. When you make it out past the total of the five years, you’re no longer needing to check those things because that risk tapers off. And that’s maybe Lemtrada in a nutshell.

 

Geoff Allix  11:11

So next one Cladribine or Mavenclad

 

Dr. Aaron Boster  11:14

Cladribine or Mavenclad is a micro induction therapy. These are pills that you take in a very weird way. You take a pill Monday, Tuesday, Wednesday, Thursday, Friday, so five consecutive days on the first month, and then you’re done for the month. So I always joke, it’s like a reverse birth control pill. And then on the second month, you do that again Monday, Tuesday, Wednesday, Thursday, Friday, and then you’re done for the year. So you’ve taken 10 pills that first year. And then on the anniversary, you repeat that process once five pills the first month, five pills the second month, and then you don’t take any more medicine. You’re followed and observe without being retreated unless you have new disease activity. So similar to Lemtrada, Cladribine is a discontinuous therapy. It’s a micro induction. What is it doing immunologically, it’s really focusing mostly on the B cells, it has a small impact on the T cells. And it knocks the B cells down nowhere near as far as with Lemtrada. And when they come back, they come back more well behaved. So just to highlight one aspect, memory B cells, which in the setting of MS, unfortunately, remember, your brain is a bad guy a foreign invader. When you take Cladribine, you knock your memory B cells down substantially, and they only come back about 13%. So you’re really removing somewhat of the immunologic memory. Now, the data for long term use of Mavenclad is is complicated because the trials were stopped and started. And so we don’t have complete datasets. But there are at least some patients that we follow that go out 10 years and never get retreated, which is pretty darn exciting. Now from an efficacy standpoint, I think the the the trial demonstrated a really robust reduction in relapse rate very impressive. The disability progression in the trial was eh, but I’ve been very enamored with what we see with disability progression looking long term, I actually think the medicine does a heck of a job of controlling disease progression over time. And it also does a really good job cleaning up the MRI. So I think this is a drug that deserves to be in the high efficacy category. I also feel that the risk profile is a little bit more easily tolerated maybe compared to Lemtrada. So when we need to be thinking about liver and kidney, when we take this medicine, we need to make sure that we’ve been immunized so that we don’t have opportunities to infections. Again, we have to think about varicella, things like that. There’s a very small risk of cancer, I would submit maybe about a 1% increase overall compared to the general population. There’s no pattern to the cancer and at least here in the United States. The screening is age appropriate cancer screening. So the FDA here did not recommend advanced screening. You know, when you’re over the age of the mammogram, you get the mammogram. When you’re over the age of colonoscopy, you get the colonoscopy etc. And the infection risk with with Cladribine is actually a lot less than most people would think. And that has to do with the way the drug is operating because it doesn’t knock your cells to nothing. So you always have immune cells present you can still fight most infections. So that’s Cladrabine in a nutshell.

 

Geoff Allix  14:27

I think those both relapse remitting only

 

Dr. Aaron Boster  14:32

Thank you so I should I apologize. So Lemtrada is approved for relapsing forms of MS. And so is Cladribine is approved for relapsing forms of MS. As we go through these medicines, there’s only one medicine that is approved for progressive disease state at least here in United States. So Cladribine is for relapsing forms of MS. We may see it used in clinically isolated syndrome, although it’s not licensed in the United States for that it is the rest of the world and all So for other relapsing forms of disease, absolutely,

 

Geoff Allix  15:02

Fingolimod is next.

 

Dr. Aaron Boster  15:05

Fingolimod the the brand name here United States is Gilenya. Fingolimod is a another unusual drug, it’s a pill that you take once a day. And what it does is fascinating. It causes the white blood cells to become trapped in the lymph nodes. So your white blood cells float around the bloodstream, but they periodically leave the bloodstream, they go into lymph node, and then they come back out. And there’s a lot of complicated receptor biology, which is required to get the cell out of the lymph node, when you take Gilenya it causes the white blood cells to become trapped in the lymph nodes in the spleen. So you take them out of the blood circulation. If those white blood cells aren’t in the blood, well, they can’t cross the blood brain barrier into the central compartment into the brain. And so by virtue of doing that you reduce the inflammatory cell exposure. And that has a very nice impact in decreasing relapse rate. I think Gilenya is quite good at reducing relapse rate. It’s just okay, a disability progression. I’m not terribly impressed with the data for slowing down disability progression. If I’m honest, I think Gilenya does a very good job of cleaning up new spots on the MRI and Gilenya is pretty good at slowing brain volume loss, which is a perk Gilenya is a medicine which can impact the heart just the first day you take it. And so there’s something called a potential first dose effect, where when you take the very first day, you might have a low heart rate. And so in order to mitigate that risk, we have people take the medicine under like six hours of observation, they’ll literally come into a clinic or a hospital and we do some EKGs. After the first day, that’s no longer a risk, there is an increased risk of infection because this is a functional immunosuppressant, if you will, and a very slight increased risk of skin cancer. Overall, these are very well tolerated medicines, these Gilenya and the family of medicines.

 

Geoff Allix  17:07

Next one up is one that I’ve not heard of before actually just Mitoxantrone, Noventrone.

 

Dr. Aaron Boster  17:13

Mitoxantrone or Noventrone is a trade name has really fallen out of favor internationally, it is a potent chemotherapeutic agent, like something that we would give to someone who has a cancer. And it it’s fallen out of favor because of the risk profile. But it is a very effective medicine. When I was coming up through the ranks, I’m going to date myself, but quite some time ago, we used Mitoxantrone, and it’s extremely effective for controlling aggressive disease. FDA approved for relapsing MS, including secondary progressive MS. Mitoxantrone is a blue liquid. So a lot of times people say I remember the blue liquid, and it’s infused in the vein. It’s typically given in a pulsed fashion either monthly or every three months and for a set period of time. And it knocks down the cells rather substantially, and then lets them come back. Now when you used Mitoxantrone back in the day, we would put someone on Mitoxantrone, and then we would often put them on a standard disease modifying therapy afterwards as a maintenance of sorts. And the reason we don’t use it anymore is twofold. One, there’s a risk of cancer, which is not small with with the medication. And second, there’s a risk of cardiomyopathy problems with the heart, which is dose dependent. And so for both of those reasons, we don’t see it used very much anymore, but it is a very effective high efficacy medicine. Next one up natalizumab or Tysabri. So natalizumab was arguably one of the first FDA approved high efficacy drugs. And it came out in the United States in 2004. I remarked as we make this video 20 years later, it remains one of the most effective drugs still on the market. It’s a very high efficacy medicine. This is a monoclonal antibody. So again, it’s an antibody created in a laboratory, which is infused in the vein. It’s about an hour long infusion done on typically every four weeks, sometimes every six weeks. And the way it works is fascinating. It tightens up the blood brain barrier. And I joke, it turns the blood brain barrier into the Great Wall of China. So creates such an impermeable barrier, that the autoreactive cells can’t cross into the brain, the blood brain barrier is impenetrable. And so by virtue of that you keep all of those naughty autoreactive cells outside the brain and it can attack and we found natalizumab Tysabri to be very, very effective at decreasing attacks in new lesions on the MRI. It’s also good at slowing disability progression quite a bit. The only chink in the armor of Tysabri, dare I say is brain volume. I don’t think it’s as potent at slowing brain volume loss as maybe some of the other drugs. There’s also one set substantial risk, which bluntly I think we blow out of proportion if I’m honest. And that’s a risk of a rare but potentially fatal brain infection called PML, or progressive multifocal leukoencephalopathy. Now to talk about it very briefly, there’s a virus called the JC virus. And if you look at humans over the age of 30, about half of us have been exposed and none of us care because it’s a very, not good virus, it can’t really hurt us too much, unless we massively suppress the immune response. Tysabri does this because there’s no white blood cells in the brain. And if that virus gets into the brain, it can cause a very serious infection. Fortunately, we can test people’s blood to see if they’ve been exposed to the JC virus. And that helps guide our treatment. I don’t want listeners to think that if you’re JC virus positive, you’re not allowed to have Tysabri you are, we just have to look at the statistical risk, which can be as low as 1,000th of a percent. And depending on a bunch of variables could go up to 1%. And so obviously, there’s a very robust risk benefit discussion to have with the individual. Tysabri is quite an effective medicine. Also share with you that Tysabri has a weird, energizing phenomenon that not all, but some patients experience where they’ll call it their go juice, and they really feel almost euphoric and energized when they receive the infusion,

 

Geoff Allix  21:26

The next one up Ofatumumab, which is Kesimpta

 

Dr. Aaron Boster  21:31

Ofatumumab. And by the way, neither Geoff nor I made up these words.

 

Geoff Allix  21:37

They’re actually made up on the site sort of scientifically, you could break them down into bits.

 

Dr. Aaron Boster  21:42

That’s exactly right. We could draw them out, but But suffice it to say that Ofatumumab is one of the newer high efficacy medicines to join the armamentarium just a few years old now, and it is a B cell depleted. So the so it turns out that, that when you look at the pathology of MS, the T cell is the is the cell that attacks you, but the T cell is not capable of attacking you unless the B cell helps it out and gets it riled up. And so what a B cell depleted does is it kills the adult B cells, so that there are no adult B cells available to piss the T cell off. Therefore the T cell is ineffective at attacking you. So it’s this really clever indirect mechanism and it turns out to be extremely effective in its ability to slow down multiple sclerosis. Ofatumumab and the other monocle B cell depleting monoclonal antibodies have swept the MS market and they’re the most utilized as a class the most utilized drugs. And I think that’s a combination of their high efficacy and their overall good tolerability and safety profile. Now, Ofatumumab is a self administered injection, so it’s a subcutaneous shot, it comes prepackaged in like a pen. So you don’t have to mess around with needles, you just hold a pen to your skin and click a button and it gives you the injection and you take it at home. So you don’t need to go into a clinic or an infusion environment to do that. You take a shot the first month three times. So you take one two weeks later than two weeks later and that kind of gets you loaded. Then you’re taking one injection every month. Now, some people not most but some people the first injection or two they kind of feel flu like they feel kind of punky. But after that I’ve heard of no such complaints. And it’s overall a very well tolerated injection. Ofatumumab is impressive at decreasing relapse rate very impressive. It’s also very impressive at decreasing new spots on the MRI. In the clinical trial where we studied it was called the asclepios trials. We pitted it against a drug Aubagio and it was not able to outperform Aubagio with brain volume. It did decent with disability progression. But overall I think this is a really excellent drug. And one of the advantages of Ofatumumab is you can take it at your house. So not all patients have access to infusion medicine or they live near an infusion center. There’s plenty of people that I care for in rural areas of the United States where they would have to drive six, eight hours to get to a doctor. So having access to an injection that you can do yourself which is also high efficacy is pretty superb. When you take the medicine we want to make sure that you mount a response to shingles before we get started. You know there’s a couple of laboratories that we need to screen for. But then we’re pretty much off to the races.

 

Overcoming MS  24:39

Living well with MS is listener supported. If you would like to help the charity create more episodes and other resources please visit donate dot overcoming ms.org Check out overcoming ms.org/fundraise For more ways that you can fundraise for Overcoming MS

 

Geoff Allix  24:57

One that’s very popular is Ocrelizumab, Ocrevus

 

Dr. Aaron Boster  25:01

So the first B cell depleted that was FDA approved and an EMA approved was Ocrelizumab, Ocrevus. So, this this B cell, depleater is given in the vein, it’s an IV infusion. Typically, at least in my center, we infused it over two and a half hours. And it’s given once every six months, which is rather lovely. And so many patients I take care of, in the ancient days of yesteryear, were injecting themselves with medicines daily, or taking a pill once or twice a day, or getting an infusion once a month. So to be given the opportunity to only quote have MS twice a year, unquote, where you go to an infusion center twice a year is absolutely lovely. Now the medicine, the when you when you take it, you take the first, the first infusion is a half dose, and then two weeks later, a second half dose that gets you loaded. And then it’s one full infusion every six months. And the rules of engagement are almost identical to the other B cell depleaters. So the same things I said about Ofatumumab are true for for  Ocrelizumab. But we also have to watch carefully that the antibody levels in that the white blood cell levels don’t drop too far. And so we check laboratories. And if we find that they go down, there might be an increased risk of infection. And so part of the monitoring of all B cell depleaters, but I think it’s most relevant with Ocrelizumab is to mitigate the risk of infection.

 

Geoff Allix  26:30

Now just from knowing people on some of these they talk about just before the infusion they can feel a bit worse.

 

Dr. Aaron Boster  26:38

So the way that this drug works is it depletes the B cells in the drug stays active in your blood for about four and a half months. But there’s oftentimes a durable effect and we dose every 24 weeks, which is about every six months. Now, there are a large minority of patients in my practice to report something which has colloquially been described as the crap gap this wearing off effect is argued amongst MS neurologists as whether or not it’s real. I’m of the belief it is because I don’t think 1000s upon 1000s of people all got on like a secret Discord server and agreed to come up with a fib. I don’t think that’s true. And what I what I observe or listen to patients share with me is that maybe four weeks leading into the infusion, some of their MS symptoms kind of come back, whether that be a numbness or a fatigue or migraine headaches or what have you. And then oftentimes those things kind of dissolve when they get their next dose. It does bear mentioning that like Ofatumumab, Ocrilizummab is rather highly effective. In the clinical trials we pitted it against a standard of care, drug Rebif. And it really kind of rock the Kasbah doubled Rebif’s efficacy on almost every time point, doubled it and relapse rate disability, and it shut down the future MRI lesions 98% Better than Rebif which was quite a remarkable.

 

Geoff Allix  28:09

That’s 98% better?

 

Dr. Aaron Boster  28:13

Correct. 98% better than a drug which is renowned for closing the blood brain barrier. So like really like raise the roof. It also bears mentioning that Ocrilizumab is the only drug to date, which has class one evidence proving its efficacy in Primary Progressive MS. Now here in the United States, it’s FDA approved for Primary Progressive MS. It’s the only medicine FDA approved for PPMS. And the oratorio trial where we studied that demonstrated that it could slow disability progression and brain volume loss in PPMS patients in a clinically and statistically significant fashion. And so that’s a go to drug for PPMS patients in my practice.

 

Geoff Allix  28:57

And next one Ozanimod

 

Dr. Aaron Boster  28:58

Ozanimod is a I call it a Gilenya me too drug so Gilenya is the first S1P1 receptor modulator. That’s a mouthful. That’s the class of medicines until and there are subsequently a second generation of S1P1 receptor modulators. And if I speak about Ozanimod briefly, I don’t think frankly it brings new things to the table compared to Gilenya. That’s my opinion. I think that when we studied Ozanimod, we were smarter. And so we looked at brain volume and we looked at cognition, and we were able to demonstrate some things that I think occur with all of the S1P1 receptors, but we are able to characterize them with Ozanimod. Also, the second generation S1P1 receptors Ozanimod being an example, have gamed out a titration schedule when you start the pills, which avoids that first dose monitoring. So starting Ozanimod or any of the second gen S1P1 receptors is much easier on the human being they don’t have to take a day off work to be monitored. I remain disappointed in the progression data for the second generation S1P1 receptors. So whereas I think Ozanimoddoes a decent good job in controlling new MRI lesions and relapse rates, at least a little bit to be desired as it relates to its ability to slow down progression of disability, that’s my opinion.

 

Geoff Allix  30:28

And next up, Rituximab, which is Rituxan.

 

Dr. Aaron Boster  30:36

Yep. So Rituximab is probably the oldest monoclonal antibody that we’ll be discussing today. It is a B cell depleater. So it goes in the same group as the Ufatumamab, Kesimpta, and the Ocrelizumab, Ocrevus drug. It’s not FDA approved in the United States. It does have evidence for efficacy and relapse rate. It’s not class one evidence but there are trials that support its use. And I think it’s widely accepted as being a high efficacy MS drug. I’ve even seen here in the United States some insurance carriers request, they prefer it probably because it’s less expensive than the other ones. And they want us to use that for treating patients but it’s a very nice drug. I’ve had a long history of using it before the other B cell depleaters became a commercially available.

 

Geoff Allix  31:25

In parts of the world where, you know, you’re in the US, I mean, in the UK sort of fairly well off areas of the world. But if someone’s talking about you know that some of these drugs are horrificaly expensive, I’m well aware that if cost is an issue, then that means it does. So it’s highly efficacious but much less expensive.

 

Dr. Aaron Boster  31:52

Correct. Rituximab is administered through the vein IV, just like we administer Ocralizumab so it’s given every six months in the vein. The World Health Organization recently included rituximab and one other, two other drugs as as drugs that should be available to anyone with MS worldwide. And I have treated patients in Indonesia, in other areas of the world like India, where there’s not ubiquitous access to medicines, but we were able to get a hold of Rituxan in those locations, which I think is fantastic.

 

Geoff Allix  32:30

The next one is a little bit different, I think is Siponimod or Mayzant.

 

Dr. Aaron Boster  32:35

So Mayzant, Siponimod is again, a second generation S1P1 receptor. So it’s in the family of Gilenya and Ozonimod that we spoke about earlier. Again, I think when we studied a Siponimod, Mayzant we were smarter going into design the trials. And so we actually studied Mayzant in relapsing forms of MS to include people with secondary progressive MS. And here in the United States, it had that added in in its label. When I look at the totality of the evidence, again, I view them as more similar than dissimilar. That is to say, the advantages and disadvantages of Siponimod remind me of Ozonimod, I think they’re kind of like Pepsi and Coke. And you also have avoided that first dose monitoring effect, which is lovely. And so again, patients don’t have to sit and be monitored for the six hours like with Gilynia. I’ll make the same comments with Mayzant that I made with Ozonimod, which is, I think that the disability progression data at least a little bit to be desired. Now, when I say that what I mean is it doesn’t look like it’s bringing more to the table than the injectables as far as slowing disability progression.

 

Geoff Allix  33:51

If you’re secondary progressive, it’s that the only treatment that’s approved?

 

Dr. Aaron Boster  33:58

The American… so that really gets into like nomenclature. And I’ll speak from the American perspective, the American FDA, when the S1P1 second generation came out, they they took an interesting approach, and they started to make class effect comments. And so if you look at the labeling, it says relapsing forms of MS. It kind of changed the labeling a little bit. So there’s some groups of MS neurologists that preferentially pick Mayzant for secondary progressive MS. I’m not as impressed with that data. And I think that relapsing forms of MS are relapsing forms of MS and they create a spectrum. And so there are some doctors that might reach for Mayzant in the case of someone who has SPMS although I don’t think that’s the only option on the table. I just think that has a lot to do with clever labeling.

 

Geoff Allix  34:51

And the next is a group here really an Avonex, Interferon, Refib, Extavia.

 

Dr. Aaron Boster  34:59

So these are among the very first class of medicines to come out to treat MS and they’re interferon beta products. So, interferons are part of the innate immune response actually like that we make in our own bodies. When you have, for example, you catch the flu, your immune system revs up to fight the flu. And one of the things that your immune system does is it makes a bunch of interferons and the interferons fight off the flu now of interest. The interferons that your body makes is what makes you feel flu like it’s not the bug that makes you feel headachy and have a fever and joint aches and stuff. It’s this interferon. So as you can imagine, if you bottle interferon and inject it back into your body, it can make you feel flu like and that’s an unfortunate side effect of this entire class of medicine. All the medicines that we just listed off Avonex, Plegrity, Rebif, Extevia, betaferon, are all self injections. Some of them all of them are subcutaneous with the exception of Avonex, which is an intramuscular needle. And they’re given at different frequencies whether that be every other day or twice a month, there’s a whole range, but the medicines are more similar than dissimilar. And what we believe the interferons do in the setting of MS is they tighten the blood brain barrier, not as good as Tysabri. But they still tighten the blood brain barrier. So they disallow some of the white blood cells from getting into the brain. And that has been shown to decrease attacks, new spots and slow disability but but only mildly so as compared to placebo. These medicines can decrease attacks by 30% as compared to placebo, they can slow disability progression by about 30%. So when the medicines first came out in the 90s, they were transformative. They were the very first medicines on the market. And they were a godsend. Going from nothing to something is a very big deal. However, 20 years later, as we reflect back, or 30 years later Though, they’re now considered low efficacy medicines, all things considered because of the ones that have come subsequent to them. The interferon medicines in addition for making you feel flu like they’re metabolized by the liver, and so we have to check liver enzymes and sometimes they can mess with the thyroid and so we check thyroid, rarely they can worsen depression and worsen spasticity. Bluntly, I try to avoid them in my practice because again, I start leading with my efficacy as my first tenant. And so I personally tend to shy away from them because I’m reaching for more efficacious medicines.

 

Geoff Allix  37:44

 Another one of the older ones glatiramer acetate or Copaxone.

 

Dr. Aaron Boster  37:50

This was a medicine that I grew up using quite a bit. My mentor was intimately involved in some of the development of Copaxone and Copaxone is a first line therapy. It’s an injection, which originally was once daily, and now it’s given less frequently it’s given about three times a week. And its efficacy data is really almost identical to the interferons. So we now consider it a mildly efficacious medicine, decreasing attack rate and disability by 30% compared to placebo, I would submit to you that it has a nicer side effect profile and Copaxone still has a role in some situations because glatiramer acetate doesn’t cross a cell membrane and it doesn’t stimulate a receptor and it doesn’t interfere with any other medicines. It’s interesting in the way that it works. It’s four amino acids which are in a random proprietary proportion in order which mimics myelin. So at the molecular level, when you inject Copaxone, you’re kind of showing your immune system its target, say, Hey, look at this, and then you keep doing it every ever every other day. You’re like, look, look, look, and your immune system eventually kind of gets bored because it’s been seeing that all the time. So when your immune system sees real myelin it says and I saw that yesterday, and it leads to a shift in the immune response away from a pro inflammatory to a more relaxed state. That’s the way we think that it works. The the side effect profile of Copaxone is amongst the least that we would see and I reach for Copaxone when I’m dealing with say, MS and HIV, MS and really complex cancer. I used to use Copaxone in pregnant women with MS because it’s safe in the setting of pregnancy. You can have and it’s called an idiopathic injection reaction, which is a doctor term for you give yourself a shot and then you have a terrible reaction where you feel like you’re having a panic attack. It’s exceedingly rare and it’s not remotely dangerous, but I always warn patients about it because if you didn’t know that it would scare you. And oftentimes if it happens once it never ever happens again.

 

Geoff Allix  40:00

And on to the other drug that I had to start with, which is dimethyl fumarate, or Tecfidera.

 

Dr. Aaron Boster  40:07

So dimethyl fumarate, Tecfidera is a fumaric sster, it’s a salt. It’s a pill that’s taken twice a day. I place Tecfidera dimethyl fumarate in the mid tier category. So when I’m thinking of efficacy, I think it belongs on the same shelf as Gylenia. In those medicines, I think it’s a moderately efficacious drug. I think that it does a moderately good job of decreasing attack rate, and disability progression. In MRI. I don’t think it’s nearly as good as the high efficacy, monoclonal antibodies. But I do think that it’s a significant step up from the shots. Tecfidera can cause some unique side effects. One of them is facial flushing, where some someone will take the pill, and 20 minutes later, their face is beet red, that’s not dangerous, it’s just kind of uncomfortable or a little unpleasant. And in oftentimes, people acclimate to that, or there’s some tricks that you can do to kind of mitigate that. But that’s a consideration. Also, Tecfidera can sometimes upset the stomach and cause some GI upset or diarrhea. But generally, that’s not too severe. And lastly, Tecfidera is processed by your liver. And so we have to check liver enzymes. Now, the way Tecfidera works is by tricking the cells into thinking that they’re under oxidative stress, which causes the cells to create like this antioxidant cascade of lovely, which slows down the inflammatory milieu. Rarely, and we believe this is a side effect, the Tecfidera treated patients will have a drop in their white count. And we don’t consider that to be the primary goal of the medicine to side effect. And the reason this is relevant is there’s been very rare cases of that PML infection in Tecfidera treated patients if their counts went down, which is very rare. So one of the things that we do as a safety maneuver, when we put someone on tech is we check their white blood cell count and their lymphocyte count for the first several months, six to 12 months to make sure that it’s not dropping.

 

Geoff Allix  42:18

Yeah, that’s so I was taken off that because my white blood cell count went down. And then I was giving them to snap which deliberately got rid of my white blood cell count. But in a controlled fashion, yes, intentionally. And then Diroximel fumarate, Vumerity

 

Dr. Aaron Boster  42:38

A second drug in the class with Tecfidera called Vumerity, and we’d have to be nerdy for a second. So the real name of Tecfidera is dimethyl fumarate. And the real name for humanity is Diroximel fumarate, when you take either medicine and put the pill in your mouth and it hits your stomach. The first metabolite of both medicines is a compound called monomethyl fumarate. So really, both Tecfidera and Vumerity are pro drugs leading to monomethyl fumarate. So once you get the drug in you, it’s going to do the exact same things that Tecfidera does. Vumerity is actually two pills twice a day, which is a little bit annoying for some patients, but it has slightly better GI side effects. And so some patients that had GI difficulties tolerating the the Tecfidera, were able to tolerate Vumerity a bit better. And again, from an efficacy standpoint, I think that you could almost do a copy paste as far as the efficacy of Vumerity, I would put it right next to Tecfidera.

 

Geoff Allix  43:44

And next up Plegridy.

 

Dr. Aaron Boster  43:46

So Plegridy I would lump in with all the beta interferon. So when we were talking about beta interferons a little bit ago, Plegridy is the newest beta interferon to join the market. It’s, you know, it’s only a few years old. And what they did, essentially, is they took a molecule kind of like an Avonex molecule, a beta interferon, and they added a chemical compound, which keeps it around longer. And the result is really nice. So instead of having to inject yourself, frequently, a couple times a week, you can only inject yourself twice a month. So you’re injecting every two weeks, and it’s a small needle. Now, I’m not impressed with the Plegridy data. As far as efficacy is concerned, I do believe that it’s a lower efficacy medicine, but the fact that you don’t have to jab yourself so often is very lovely. And otherwise, I would submit all the same comments when we were talking about the beta interference earlier.

 

Geoff Allix  44:42

And a couple left Ponesimod or Ponvory,

 

Dr. Aaron Boster  44:46

Ponvory is a second generation S1P1 receptor. So it’s it sits next to Ozonimod and Siponimod right. So it’s it’s a Gylenia me too drug And Ponvory was the last of the S1P1 receptors to join the armamentarium. It sort of entered into the market in a very crowded space. But all things considered, I think it’s very, very similar to the other second generation S1P1S, in that you don’t have to do a first dose monitoring, there’s a titration. And the same risk profile and largely the same efficacy, as far as doing a really good job with relapses, and a less good job, in my opinion with disability progression.

 

Geoff Allix  45:34

And I think the last one, so it’s quite a big one that we haven’t done so far. It’s at teriflunomide, or Aubagio.

 

Dr. Aaron Boster  45:40

Yes, Aubagio teriflunomide. So, so teriflunomide is a small molecule, it’s a small pill that you take, and it’s taken once a day. And it’s very interesting in the way that it works. It doesn’t kill cells, but it makes them kind of play the freeze game, so they can’t, they can’t rapidly reproduce. See, under normal circumstances, your white blood cell can either slowly make copies of itself, that’s called the salvage pathway just to keep it around. Or if there’s an insult to the to the body, and you need to quickly mount a bunch of clones, then it can make a bunch of cells really fast. And what Aubagio does is it prevents you from making cells too quickly. And so it doesn’t, it doesn’t suppress the immune system. But this shift slows down the disease process. Now, Aubagio is a very interesting molecule. If you look at it from the perspective of relapse rate, or from the perspective of new MRI lesions, it’s a low efficacy medicine, I would place it kind of in the bottom tier almost next to the shots. However, if you look at brain volume, and disability progression on exam, it does really, really impressive results. And so I at least in my practice, have found a home for this drug not up front, early in someone’s chronologic age where they’re at higher risk of lots of attacks, and lots of new MRI lesions, I tend to use this drug towards the second half of the disease, if you’ll excuse that expression, when the concern on the table is much more about maintaining brain volume and slowing disability progression, because I think it really shines there. Now Aubagio is processed by the liver, and it can cause liver enzymes to go up. And so you have to be very fastidious about checking liver enzymes monthly for the first six months, because it’s most likely going to go up during that time. We also want to make sure that you know, you don’t have latent infections like tuberculosis and things like that before we started. And also it can cause some GI upset I would say maybe even more than Tecfidera. In my personal experience, oftentimes that self resolving, I have had a handful of patients where they had persistent diarrhea and they had to stop. It very rarely can elevate blood pressure or causing neuropathy. And an interesting side effect in about 13 to 18% of patients it causes it causes a transient hair thinning. Now, we’re not talking about like your and my hair, we’re talking about that it gets thinner, you know the density and more comes out in the comb. When this occurs, it occurs at month two, and it goes away by month four. So stopping the medicine doesn’t really matter, because it’s not going to persist for a long period of time. So that’s Aubagio in a nutshell.

 

Geoff Allix  48:29

And is there anything we’ve missed or any DMTs that we haven’t talked about?

 

Dr. Aaron Boster  48:33

We’ve hit what I call the first line medicines, the injections and so those are the interferon products, the beta interferon products and Copaxone. We then talked about the second tier medicines and I would place several pills in this class Aubagio, with all the caveats that I just gave the S1P1 receptors, so Ozonimod, Siponimod The Ponvory that you mentioned in the first generation Gylenia. I would put Tecfidera and Vumerity in that second tier. I would place Mavenclad at the top of that list, I sometimes call it the king of the pills. Then we get into the proper high efficacy, monoclonal antibodies, that would be the Tysabri all of the B cell depletera so off label rituximab as well as Ocralizumab, Ofatubamab Ah, and we did forget one Ublituximab. So Ublituximab and again, I didn’t make up these words. The trade name is Briumvy, and Ublituximab Briumvy is the most recent B cell depleted to join the armamentarium. It’s an infusion in the vein as well. The first infusion is given over a four hour period, then subsequent infusions are only one hour. It’s a B cell depleted or so it goes in the same family as Ocralizumab and Ofatubamab and it works in a very, very similar fashion with largely the same efficacy data. In my personal experience, I’ve had a little bit of difficulties in patients, tolerating the initial infusions. But oftentimes, we can get them through that. And so I’m glad that we went through this exercise. I didn’t want to forget that one. Then just round up the list we talked about natalizumab. Tysabri and Alemtuzumab lemtrada in that top tier.

 

Geoff Allix  50:16

Just a couple of others that are sort of used maybe a little bit off label if you’d like but low dose Naltrexone or LDN. Have any of your patients had success with that?

 

Dr. Aaron Boster  50:27

So low dose Naltrexone is a very interesting molecule. First, Naltrexone is a molecule to combat narcotic overdose, it blocks mu receptors, which which interfere with the way narcotics work. And so when we talk about low dose naltrexone, it’s such a low dose that it really doesn’t have that effect. And there is a small amount of literature that suggests that it may have some neuro benefit. Now, there isn’t class one evidence for it. And I will simply say that there are some MS neurologists that believe vehemently that it really, really helps. I also anecdotally, I’ve had some patients that that asked for it and it report back that it helps them in certain ways. It hasn’t been robustly studied, like the disease modifying therapies. The quickly, the way that I think about it, there’s three things that have to be okay for me to recommend something that hasn’t been proven. It needs to not be too expensive and low dose Naltrexone generally isn’t. It needs to not be dangerous and low dose Naltrexone is not dangerous. And it needs to not be instead of something that I know works. So if someone came to me and said, Hey, Aaron, I want to take LDN in addition to the stuff that we’re using, I would say, Okay, I would caution, however, about using that as my exclusive treatment for MS. Because I don’t think the data is adequate enough to guarantee that we’re gonna win doing that, again, just my opinion.

 

Geoff Allix  52:00

What about things that are on the horizon? So is there any other new pharmaceuticals on the horizon that we should be looking out for?

 

Dr. Aaron Boster  52:07

There’s two that I’ll highlight that I’m particularly excited about. There’s a class of medicines, which has been around for a long time to treat cancer and is now being studied very aggressively in the setting of MS. And these are the routine tyrosine kinase inhibitors or the BTK inhibitors. Now, these BTK inhibitors are pills that you either take once or twice a day. And they mechanistically bring some things to the table that are very exciting. So one of the things that these molecules do is they block B cell signaling without depleting B cells. So earlier, we talked about several medicines that deplete B cells, which is a very effective way of treating MS. But it increases the risk of infection. Well, if a BTK inhibitor can block B cells, but doesn’t cause depletion, that’s fantastic, because we might have a similar effect without increasing the risk of infection. Secondly, we know that the MS disease involves both the adaptive immune system the B and T cells and the innate immune system, including the cells called microglia, which are in the brain. All the medicines we’ve talked about so far can’t turn off the microglia BTK inhibitors can they cross into the blood brain barrier, and they turn off these activated immune cells, which is very exciting. As we make this recording, there are no less than five manufacturers all studying BTK inhibitors at various stages, books in phase three testing. We don’t have full readouts on any of them yet. At the Boster Center for MS we’ve enrolled many patients into these trials, we’re very, very excited about them. Because we’re studying BTK inhibitors in relapsing MS in secondary progressive MS and in Primary Progressive MS. So stay tuned as that data set evolves. And as we start to get readouts of these medicines, we’re very hopeful. Now, all drugs have side effects. And that’s why we do clinical trials. And so far in the clinical trials with BTK, we’ve learned that they’re pretty rough on the liver. And there’s been some very, very serious concerns by regulatory bodies, about elevations in liver enzymes. And there’s been patients in the trials that we’ve had to stop because their liver enzymes went up too high. So more to come in the very near future.

 

Geoff Allix  52:56

We had someone from Cambridge University on the podcast, and he was some of the things we were talking 10, 15, 20 years time unless you’re a mouse. But you’re talking about one to five years I BTK inhibitors.

 

Dr. Aaron Boster  54:42

So the very first BTK inhibitor that finished its trials called Evobrutinib it now the top line data for Evobrutinib left a lot, a lot of people sad and blue because it didn’t hit. We don’t have the full data reported and all of the other trials are wrapping up. So I think we’re gonna get read out some of those other trials in the next couple years. So this is not something you’re going to have to wait 10 years for we’re looking more like three to five years is what I would guess.

 

Geoff Allix  55:10

Okay. And is there anything we’ve missed?

 

Dr. Aaron Boster  55:14

I will, I’ll point out one more class of drug which is which is coming after the BTK inhibitors. And going back to the B cell T cell signaling, you could kill a B cell, like the drugs that we talked about today. Or you could block signaling with the BTK inhibitor. Or you could interrupt the signaling by breaking the connection between the B and T cell. And there’s a medicine which is being developed. It’s not a new class of medicine, it’s new in MS called the anti CD40L Right. So that’s like a mouthful. And these anti CD40 Lygans are monoclonal antibodies that are just now starting to be tested in MS. At the Boster Center, we’re enrolling a trial for relapsing MS and in secondary progressive MS. And what they do is they they make it so the B cell doesn’t have like the little arm it needs to touch the T cell. So again, coming up with a way of interrupting signaling. And this should have a very robust effect in MS. Again, with a lower risk of infection. Now, that’s very, very early, so much more to come over the next several years.

 

Geoff Allix  56:23

With that, I’m well aware, I’ve taken up a lot of your time. So we’ll wrap up there. But thank you very much. I think it’s one to rewind and playback. For people who are interested in DMTs.

 

Dr. Aaron Boster  56:36

I’m grateful for the chance to talk with you. It’s always a really, it’s a really good interaction. And I appreciate the opportunity. It’s it’s my goal to help families impacted by MS live their very best lives despite having this condition. And I think it’s a fool of a doctor who thinks that you only take care of the disease by picking one of these DMTs and taking it. I do however, feel that DMT is one of the components to a successful treatment plan. And I again will leave today with with my comment that I want you on the most effective drug that you’re comfortable taking.

 

Geoff Allix  57:13

With that. Thank you very much for joining us and check out the show notes and do check out Dr. Boster’s YouTube channel.

 

Dr. Aaron Boster  57:19

Thank you so much. Have a great day. Thank you.

 

Overcoming MS  57:22

Thank you for listening to this episode of Living Well with MS. Please check out this episode’s show notes at overcoming ms.org/podcast you’ll find useful links and bonus information there. Don’t forget to subscribe to the podcast so you never miss an episode. And please rate and review the show to help others find us. This show is made possible by the Overcoming MS community. Our theme music is by Claire and Nev Dean, our host is Geoff Allix. Our videos are edited by Lorna Greenwood, and I’m the producer Regina Beach. Have questions or ideas to share? Email us at podcast at overcoming ms.org We’d love to hear from you. The Living Well with MS podcast is for private non commercial use and exists to educate and inspire our community of listeners. We do not offer medical advice for medical advice please contact your doctor or other licensed healthcare professional.