Jeff Alex (4:20)

What should people think about if they're consider this huge amount of choice for drugs now? So what should, what are the factors that people should consider when they're choosing?

Dr. Aaron Boster (4:29)

That's 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 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 in different healthcare systems in different countries can be very, very expensive.

Jeff Alex (5:23)

Just as an aside, would you say that the more efficacious drug has the more side effects then?

Dr. Aaron Boster (5:31)

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 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 we're.

Jeff Alex (6:06)

Going to get through a whole load of disease modifying therapy. So let's, let's get into that. So talking about the so what, when I say dmt, it's disease modifying therapy or drugs that we're using to treat Ms. So we're going to 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 it's administered and any benefits and risks that you think people should know about when considering it.

Dr. Aaron Boster (6:34)

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

Jeff Alex (6:44)

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

Dr. Aaron Boster (6:47)

No, no, no. I'm a practicing Ms. Neurologist. I just, I'm just sharing with you that like, you know, I have some.

Jeff Alex (6:53)

You're biased in your beliefs rather than biased commercially.

Dr. Aaron Boster (6:56)

Correct? That's what I meant. Yep, yep.

Jeff Alex (6:59)

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

Dr. Aaron Boster (7:08)

Lemtrada is a monoclonal antibody. So 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 and 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 alemtuzumab Limtrada is one of the most effective drugs currently available on the market. I think that it's outstanding at relapse rate reduction, it's outstanding at decreasing new MRIs 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 into 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. Two specific 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 or 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 Limtrada in a nutshell.

Jeff Alex (11:11)

So next one. Cladribine or 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 observed without being retreated unless you have new disease activity. So similar to alemtuzumab, 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. When they come back, they come back more well behaved. Just to highlight one aspect, memory, B cells which in the setting of ms, unfortunately remember your brain as 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%. You're really removing somewhat of the immunologic memory. Now the data for long term use of Mavenclad is complicated because the trials were stopped and started and so we don't have complete data. 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 opportunistic 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 of the age of the mammogram, you get the mammogram. When you're of the age of colonoscopy, you get the colonoscopy, etc. Um, 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 cladribine in a nutshell.

Jeff Alex (14:25)

And just, just I think are those both relapse remitting only or.

Dr. Aaron Boster (14:32)

Thank you. So I should, and I apologize, I didn't do it. 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 the 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 also for other relapsing forms of disease. Absolutely.

Jeff Alex (15:02)

Fingolimod is the next I've got on my list. Or Gilenya.

Dr. Aaron Boster (15:05)

So Fingolimod, the brand name here in the United States is Gilenia. Fingolimod is 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. Your white blood cells float around the bloodstream, but they periodically leave the bloodstream, they go in the 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 Gilenia, 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 Gilinia is quite good at reducing relapse rate. It's just okay at disability progression. I'm not terribly impressed with the data for slowing down disability progression, if I'm honest. I think Juliania does a very good job of cleaning up new spots on the mri. And Julian is pretty good at slowing brain volume loss, which is a perk. Giuliania 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 it 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 Gilenia and the family of medicines.

Jeff Alex (17:07)

And next one up is one that I've not heard of before actually, which is metoxantrone or Navantrone.

Dr. Aaron Boster (17:13)

Mitozantrone or Novantrone 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 Mitozantrone 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, oh 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 use mitoxantrone, back in the day we would put someone on a mitozantro 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 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.

Jeff Alex (18:36)

Next one up. Net Elizumab or Tysabri.

Dr. Aaron Boster (18:39)

Yep. So Natalizumab was arguably one of the first FDA approved high efficacy drugs and it came out in the United States in 2004. I remark 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 it 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't 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 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 1000th 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. I'll 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.

Jeff Alex (21:26)

And the next one upatumumab, which is Qasimta Ufatumumab.

Dr. Aaron Boster (21:32)

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

Jeff Alex (21:37)

They're actually made up, aren't they? Sort of. Scientifically, you can break them down into.

Dr. Aaron Boster (21:40)

Bits and say, that's exactly right, we could draw them out. But. But suffice it to say that ufatuumab is one of the newer high efficacy medicines to join the Armatarium, just a few years old now and it is a B cell depleter. So it turns out that when you look at the pathology of ms, the T cell is the cell that attacks you, but the T cell is not capable of attacking you unless the B cell helps it out, gets it riled up. And so what a B cell depleter 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. Ufatumumab and the other monoclonal 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, Ufotumab 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 and then 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. Ufotumumab 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, it's called the Exclepios trials, we pitted it against a drug, a baggio, and it was not able to outperform a baggio with brain volume. It did decent with disability progression. But overall I think this is a really excellent drug. One of the advantages of ufatumumab is you can take it at your house. So not all patients have access to infusion medicine or they live near an INF 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 laboratories that we need to screen for, but then we're pretty much off to the races.

Jeff Alex (24:39)

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Jeff Alex (24:55)

For overcoming Ms. One that's very popular is ocrelizumab or ocrebus.

Dr. Aaron Boster (25:01)

So the first B cell depleter that was FDA approved and EMA approved was ocrelizumab Ocrevus. So this, this B cell depleter is given in the vein. It's an IV infusion. Typically, at least in my center, we infuse 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, end quote, where you go to an infusion center twice a year is absolutely lovely. Now, the medicine, 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 depleters. So the same things I said about ufotumumab are true for, for ocrelizumab. With ocrelizumab, we also have to watch carefully that the antibody levels and 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 depleters, but I think it's most relevant with ocrelizumab is to mitigate the risk of infection just from.

Jeff Alex (26:31)

Knowing people on some of these, they, they talk about just before the infusion, they can feel a bit worse.

Dr. Aaron Boster (26:38)

Yeah, so, so the way that this drug works is it depletes the B cells and the, 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, 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 thousands upon thousands 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 Tumumab, ocrelizumab is rather highly effective. In the clinical trials we pitted it against a standard of care drug, Rebif, and it really kind of rocked the casbah. It doubled Rebif's efficacy on almost every time point, doubled it in relapse rate, disability, and it shut down Future MRI lesions 98% better than Rebif, which was quite a remarkable. So this is another.

Jeff Alex (28:10)

That's not just 98, 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 ocrelizumab 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 pms. 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.

Jeff Alex (28:57)

And next one, Ozanimod or Zonimod is.

Dr. Aaron Boster (29:01)

A, I call it a Gilenia. Me too drug. So Gilenia is the first S1P1 receptor modulator. That's a mouthful. That's the class of medicine, the pill. And there are subsequently a second generation of S1P1 receptor modulators. And if I speak about Ozanamon briefly, I don't think, frankly, it brings new things to the table compared to Julinea. 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 were able to characterize them with ozonimod. Also, the second generation S1P1 receptors, ozanamod being an example, have gamed out a titration schedule when you start the pills which avoids that first dose monitoring. So starting a Zonimod or any of the second gen S1 P1 receptors is much easier on the human being. They don't have to take a day off work to be monitored and have EKGs, et cetera. I remain disappointed in the progression data for the second generation S1 P1 receptors. So whereas I think Ozanamod does a decent good job in controlling new MRI lesions and relapse rates, it leaves a little bit to be desired as it relates to its ability to slow down progression of disability. That's my opinion.

Jeff Alex (30:28)

And next up, Rituximab, which is various name Rituxan MAP therapy.

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 depleter. So it goes in the same group as the ufatumumab QTA and the Ocrelizum 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, I have a long history of using it before the other B cell depleters became commercially available.

Jeff Alex (31:25)

So in parts of the world where, I mean, you know, you're, you're in the U.S. i mean in the U.K. so the fairly well off areas of the world. But if, if someone's talking about, you know, some of these drugs are horrifically expensive. I'm, I'm well aware that if cost is an issue, it does. So it's highly efficacious, but much less expensive.

Dr. Aaron Boster (31:52)

Correct. Rituxan is administered through the vein IV just like we administer ocrelizumab. So it's given every six months in the vein. The World Health Organization recently included Rituximab and one other two other drugs 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.

Jeff Alex (32:30)

The next one, a little bit different I think is Suponimod or Mayzent.

Dr. Aaron Boster (32:34)

Yes. So Mayence is again a second generation S1P1 receptor. So it's in the family of Julienia in Ozonimod that we spoke about earlier. Again, I think when we studied Supanama and Mayzent, we were smarter going in to design the trials. And so we actually studied Maison in relapsing forms of Ms. To include people with secondary progressive Ms. And here in the United States it had that added 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 Supanamide remind me of Zanamide. 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 Juliana. I'll make the same comments with Mason that I made with the Zonimod, which is, I think that the disability progression data leaves 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.

Jeff Alex (33:51)

But if you're secondary progressive is that the only treatment is 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 S1 P1 second generation came out, they, they took an interesting approach and they started to make class effect comments. If you look at the labeling, it says relapsing forms of ms, it kind of changed the labeling a little bit. There's some groups of Ms. Neurologists that preferentially pick Mason 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 Mayzent 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.

Jeff Alex (34:51)

And the next is a group here, really, and Avonex, Betaferon, Refib, Xtavia.

Dr. Aaron Boster (35:00)

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 interferon 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 it's an unfortunate side effect of this entire class of medicine. All the medicines that we just listed off Avonex, plenty of Rebif, Extavia, beta, seron, 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. That has been shown to decrease attacks, new spots and slow disability, 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 tenet. And so I personally tend to shy away from them because I'm reaching for more efficacious medicines and another one of.

Jeff Alex (37:45)

The older ones, glatiruma acetate or copaxone.

Dr. Aaron Boster (37:49)

So 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 gluterimera acetate doesn't cross a cell membrane and it doesn't stimulate a receptor that 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 and 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, 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, 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 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. In 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 the 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.

Jeff Alex (40:00)

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

Dr. Aaron Boster (40:08)

So dimethyl fumarate, tecfidera is A fumaric ester. 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 gilenia 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. And 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 someone will take the pill and 20 minutes later their face is beat red. That's not dangerous. It's just kind of uncomfortable or a little unpleasant. And 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. Generally that's not too severe. 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 this antioxidant cascade of lovely which slows down the inflammatory milieu. Rarely, and we believe this is a side effect, the tecfidera treated patient will have a drop in their white count. And we don't consider that to be the primary goal of the medicine. It's a side effect. And the reason this is relevant is there's been very rare cases of that PML infection in techfidera 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.

Jeff Alex (42:17)

Yeah, that's. So I was taken off that because my white blood cell count went down. And then I was given alumtus map which deliberately got rid of my white blood cell count.

Dr. Aaron Boster (42:26)

Ironically, but in a controlled fashion.

Jeff Alex (42:29)

Yes, intentionally. And then diroxamil fumarate or Vimerity.

Dr. Aaron Boster (42:37)

So there's a second drug in the class with tecfidera called Vumerity and we have to be nerdy for a second. So the real name of Tecfidera is dimethyl fumarate. And the real name for Vumerity is diroxamo 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 Vomeri 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 humility, I would put it right next to Tech Federa.

Jeff Alex (43:44)

And next up, Plaguity.

Dr. Aaron Boster (43:46)

So plaguity I would lump in with all the beta interference. So when we were talking about beta interference a little bit ago, Polarity 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 Pellegrity 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 interferons earlier and just a couple left.

Jeff Alex (44:43)

So upon Esimod or Ponvory, Ponvori is.

Dr. Aaron Boster (44:47)

A second generation S1P1 receptor. So it sits next to Ozonomod in saponimode. Right. So it's a Gilenia me too drug. And Ponvori was the last of the S1P1 receptors to join the armamentarium. And 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 S1Ps 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.

Jeff Alex (45:34)

And I think the last one, so it's quite a big one that we haven't done so far, is teraflutamide or, yes, baggio teraflutamide.

Dr. Aaron Boster (45:42)

So teraflutamide 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 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 a baggio 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, a Baggio 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 in 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 upfront 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, a baggio 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 tech Federa in my personal experience, oftentimes that's 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 cause a 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 you're in 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 a Baggio in a, in a nutshell.

Jeff Alex (48:29)

And is there anything we've missed or any DMT 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, Abagio, with all the caveats that I just gave the S1P1 receptors. So zanamod, Saponimod, the Ponvori medicine that you mentioned and the first generation Juliania, 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 depleters, so off label rituximab as well as ocrelizumab, ufatumumab. Ah, and we did forget one, Ublatuximab. So ublatuximab and again I didn't make up these words. The trade name is Brienvi and ublatuximab BR is the most recent B cell depleter to join the Armatarium. 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 depleter, so it goes in the same family as ocrelizumab and ufotumab 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 to round out the list, we talked about Natalizumab Tysabri and Alemtuzumab Lemtrada in that top tier and just.

Jeff Alex (50:16)

A couple of others that are sort of used maybe a little bit off label if you 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, 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 have had some patients that, that ask for it and report back that it helps them in certain ways. It hasn't been robustly studied like the disease modifying therapies 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, for Ms. Because I don't think the data is adequate enough to, to guarantee that we're going to win doing that. Again, just my opinion.

Jeff Alex (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 brute 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 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 these 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, mostly 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 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.

Jeff Alex (54:25)

But it is near. We had someone from Cambridge University on the podcast and he was. Some of the things we were talking 10, 15, 20 years time that. Yeah, unless you're a mouse.

Dr. Aaron Boster (54:37)

Yeah, that's exactly right.

Jeff Alex (54:38)

So, but you're talking like one to five years. Are you BTK inhibitors?

Dr. Aaron Boster (54:42)

So the very first BTK inhibitor that finished its trial is called Evobrutinib. 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 in all of the other trials are wrapping up. So I think we're going to get readouts on 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.

Jeff Alex (55:10)

Okay. And is there anything we've missed?

Dr. Aaron Boster (55:14)

I would. 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 a 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 CD40 ligand. So that's like a mouthful. And these Anti CD40 ligands are monoclonal antibodies that are just now starting to be tested at 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.

Jeff Alex (56:23)

Okay. And 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 play back for people who are interested in their DMTs.

Dr. Aaron Boster (56:37)

I'm grateful for the chance to talk with you. It's always a really good interaction and I appreciate the opportunity. 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 my comment that I want you on the most effective drug that you're comfortable taking.

Jeff Alex (57:13)

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

Dr. Aaron Boster (57:19)

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

Jeff Alex (57:20)

Thank you.

Jeff Alex (57:22)

Thank you for listening to this episode of Living well with Ms. Please check out this episode's show notes@overcomingms.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 this show is made possible by the Overcoming Ms. Community. Our theme music is by Claire and Mav Dean. Our host is Jeff Alex. Our videos are edited by Lorna Greenwood and I'm the producer, Regina Beach. Have questions or ideas to share? Email us@podcastvercomingms.org we'd love to hear from you. The Living Room with Ms. Podcast is for private, non commercial use and exists to educate, 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.