Primary Progressive MS - Ben Thrower, M.D. - May 2017

thank you guys for coming out this evening I really appreciate it and as as we said earlier thank you so much to all of our sponsors who allow us to be here this this evening and keep us fat and happy with food as well so thank you everybody hopefully next month when we're here the traffic will be a little less obnoxious they said the i-85 bridge will be open on Monday is that what I heard Monday awesome for those of you who are watching this on YouTube but at home or if you may know our bridge collapsed so we've had a rough year the Falcons lost our bridge collapsed so we can only get better from from here and the Braves lost yep so tonight we are going to to spend some time talking about progressive forms of multiple sclerosis and you know when over the years that I've worked with the MS community one of the things that I think has always been difficult is when you get up in front of a group of people with MS and we talk about relapsing ms relapsing ms relapsing remitting ms relapsing forms of ms and we never had much to say about progressive forms of MS we do now have our first fda-approved treatment for a progressive form of MS we're going to talk about the big picture of progressive MS this evening see if my remote will work here so I'm going to throw this is a real-life case scenario this is a 52 year old gentleman he's in great health he's active he exercises he jogs about three miles a few times a week and he starts noticing over time that is his as he's jogging his right foot is dragging and this is subtle it's nothing dramatic it doesn't keep him from exercising but as time goes on the point at which he gets weak gets shorter and shorter and shorter so at first maybe it's at two miles now maybe it's one mile now maybe it's in both legs it's his left leg and his right leg and this progressive weakness especially with exertion just gets worse her time so what does that sound like to people ring a bell anyone have had that not on what put anyone on the spot but has anyone had a story like that or would what would you what would you label that as so that's a great description that would be about the most classic description that you can get for primary progressive multiple sclerosis primary progressive multiple sclerosis has always been Cannavaro the odd form of MS it represents about 10 to 15% of people with MS at the time of diagnosis it doesn't play by a lot of the rules that other forms of MS play by it's the one form of MS that's more common in men versus women it tends to start a little bit later in life when you look at relapsing remitting ms the typical age dogs that would be sometime maybe in the 30s women are more affected than than men and it tends to have a little bit more dramatic onset the other thing that's sort of interesting with primary progressive MS is if you look at spinal fluid evaluations a lumbar puncture a spinal tap in relapsing remitting ms over the course of that ms 95% of people with relapsing remitting ms will have abnormalities in their spinal fluid only 50% of people with primary progressive multiple sclerosis do it tends to be something that affects the spinal cord a little bit more than the brain some people with primary progressive multiple sclerosis actually have normal brain MRIs we just don't see any any of the white spots there everything that they're dealing with is actually in the spinal cord so traditionally we've talked about four types of multiple sclerosis we talked about relapsing remitting ms secondary progressive MS primary progressive MS and progressive relapsing ms there have been some new new ways of thinking about ms in terms of these categories and we've actually dropped one of those so now we're really talking about three forms of multiple sclerosis still kind of you know when you when you see a slide like this and you see these different boxes it really makes people want to think of themselves as being in a box and as humans we always want to know well what category do I fit in so a common question that we get with with multiple sclerosis is what form of MS do I have and I would say rather than thinking of yourself as being in a box or category for most people I would think of it more as sort of a spectrum over your life now I will say we're going to take primary progressive MS out of this this is for relapsing remitting ms and secondary progressive MS in primary progressive we're going to talk a little bit more about that that is sort of the you know the one that doesn't play by some of the rules if you look at people outside of primary progressive MS there's a point in their life where they've had no symptoms whatsoever and what you'll see on this graph of the little yellow arrows at the bottom those are lesions on MRI this is a person who's had no symptoms whatsoever but they've got lesions popping up on their MRI who we think in the typical person with a relapsing form of MS when their MS is diagnosed that if we could go back two years three years four years maybe even longer and if we did an MRI we probably would have seen abnormalities on MRI before they ever had their first symptom this comes up in real life sometime so let's imagine that this person who's got spots on their MRI but has never had a symptom let's imagine they also migraine headaches or maybe they are in a car accident they have a concussion and someone orders an MRI on them for your reasons nothing related to MS and we see these white spots on their brain MRI what do we do with that what do we call it so there is a term now it's called RIS radiographic isolated syndrome so this is a person who has spots on their brain MRI that sure look like MS but they've never actually had an attack or any symptoms and one of the challenges is what do you do with this this individual what do you tell them do you put them on treatment what studies have shown is that most of these individuals who have lesions very suspicious for MS on their brain MRI if you follow them over time they tend to form new lesions on their MRI and at some point they probably have symptoms it may not be four years down the line so it is one of the struggles you know do you put that person on treatment right now you know it can be a tough sell for anyone because technically you can't call that multiple sclerosis but you know it's the smoking gun before and that starts up so typically when the person like that really comes into the medical community is oops we're not there we go is when they have their first attack so the purple bar is a relapse so when the person has their first relapse usually then they're going to go show up in the medical community so this could be optic neuritis maybe the person's lost vision and eye or maybe they had a lesion in their spinal cord so they're having numbness so when you have your first attack we call that I see is a clinically isolated syndrome so we've got our is radiographic isolated syndrome and now CIS is if you have your first attack one of the questions in this individual if they've had one attack is are they going to go on and have more attacks so if you have your one attack and you have lesions suspicious for MS on your MRI you are very very likely to actually have multiple sclerosis if you have those lesions on your MRI and you have abnormalities in your spinal fluid you're often near the 100% competence range that this is ms if we follow that individual over time now you can actually call it relapsing remitting ms so they're having attacks over time but we're here to talk about progressive forms of MS so over time the natural history of relapsing remitting ms is that the relapses themselves tend to get further and further apart but what they're being replaced by is accumulation of disability so you're now not having as many attacks but you're not recovering and you're just you may be slowly getting worse if we look at the MRI we see measures of tissue damage maybe there's a little bit of loss of volume in the brain or spinal cord we see these things called t1 hypo intensities or black holes areas where the nerve viber has actually been cut or transected those measures of tissue damage we think of the underlying substrate for disability so if we look at when people are actually diagnosed with multiple sclerosis over on the left hand side of the slide so at the time of diagnosis most people start with relapsing remitting ms but about 10 to 15 percent of people will have this primary progressive form if we follow people over time so just on the right-hand side of the slide this is looking at people 11 to 15 years out what you'll see now if we take a cross-section of people with MS is now we've got a big chunk of people in green there who have a program a progressive form of MS so some of those people with relapsing remitting ms have now slowly shifted over towards the other side of that graph that we showed earlier and now they're in a progressive form of MS again it's always important to know when we showed these slides like this this is the natural history of ms the purpose of treatment whether it's you know you now we have 16 fda-approved disease modifying therapies the purpose of these treatments is hopefully that we can prevent accumulation of disability if not it slow it at a minimum if not stop it all together so when we think about progressive MS you know there are a few or no relapses if you that doesn't mean there are no relapses you can still have a tax and have a progressive form of MS it is more characterized by slow progression of disability than by attacks MRIs may not show new lesions in spite of the fact that the person may be getting worse and I will guarantee you there's somebody in this room if not several people in this room who've experienced that and it's frustrating when you come in for your doctor visit and we say you knew you had your MRI today we don't see any new lesions and we're all excited and you say yeah it's great that my pictures look great but I'm not doing great I'm getting worse and we know that happens so the MRI is a great tool but it is not a perfect measure of how people with MS are doing when people with MS have been dealing with MS for a while they can physically worsen even though their MRI is not changing when you look at people with early in this you can think back to that graph where we saw those little yellow arrows they're having attacks and they feel fine so MRI can be disconnected from how the person is doing in one of two different ways depending upon where you're at in your ms story typically what progresses them as we're looking at measures of tissue damage on MRI black holes and atrophy so differences between secondary and primary progressive MS against secondary progressive MS is the evolution of relapsing remitting ms so that's part of that spectrum primary progressive MS is primary progressive in us from day one it will never be anything other than primary progressive MS so if you are in one of those regions where you have either primary or secondary progressive MS we do think that how you got there may be differently but once you're there we think the underlying immunopathology may be very very similar both are characterized by progression of disability both are characterized by tissue damage with less inflammation and the reason it's important that we need to when we think about that so do we treat long term primary and secondary progressive MS with similar medications I would argue that most MS centers in the US and Canada would say if something works in one it should work in the other even though it may not be FDA approved one versus the other so what are some of the challenges that we see in progressive forms of MS well one of the biggest challenges is we had no fda approved treatments for altering the course of a progressive form of MS many of our disease modifying treatments really target active inflammation and active inflammation is less of a problem and progressive in this so your target that you're wanting to shoot at is just not there as much so that's been a bigger challenge neurodegeneration again tissue damage much bigger issue neuro degeneration has always been tough to deal with if we had a perfect treatment to stop neuro degeneration in multiple sclerosis what we probably would have a perfect treatment to stop Parkinson's disease and Alzheimer's disease and ALS those diseases are neurodegenerative conditions to the best of our knowledge there is no inflammation with Lou Gehrig's disease or ALS or Parkinson's disease or Alzheimer's disease so you know when you think about how much trouble we've had treating those conditions it kind of that's why part of the reason we've had so much trouble coming up with great treatments for progressive forms of MS there's been a little bit of what we call therapeutic nihilism on the part of the healthcare community nihilism meaning people just kind of test the mystic to say now we can't deal with this I don't think there's anything to offer people with progressive MS that's incorrect and we're going to talk about how not only do we now have an fda-approved treatment but we've always had things we could do for progressive forms of them as even when there was not an fda-approved treatment the other challenge I think is sometimes defining when as the person moved from relapsing remitting them as to secondary progressive MS I'm going to give you an example here and this is a real-world situation so mrs. M is a 48 year old woman with multiple sclerosis for 19 years she's been on Reba for 15 years she's had no relapses no new lesions on MRI for the least the past five years but what she does describe is that she's slowly getting a little bit worse so this is a common situation maybe she's going from using a cane to a walker or walker to using an electric scooter so even though she's not having attacks and even though her MRIs aren't changing much she's getting a little bit worse so is this relapsing remitting ms is it secondary progressive MS she's been on on an injectable medicine for a long time and she's really kind of tired of it she doesn't want to do shots anymore so she's bringing up the possibility of can I just go off treatment because I don't think this treatment is really doing anything I'm getting worse anyway so she stops the rebuild we bring her back in three months she really doesn't feel any different but on her brain MRI she's got new active inflammation so again it what it says is the MRI is sometimes disconnected she's an example of how the MRI can be disconnected in both ways she was getting worse in her MRI wasn't showing it now she feels okay not not better but the same inner MRI shows new inflammation so what do we label her as is so she was if you look at that graph she's not having attacks but she's getting worse so at face value you would want to use the term secondary progressive MS in her but when she goes off of treatment she still has active inflammation so it wouldn't be unusual for her to actually have this new lesion and have an attack or relapse so is she really relapsing remitting and I think what she points out is that we always need to remember when we're using these categories to describe ms those categories were meant to describe the natural history of ms we're not seeing the natural history of ms and a lot of people were seeing a modified version of your ms because of the treatment so she's probably in reality somewhere between relapsing remitting and secondary progressive in the new way that we're categorizing ms she would be labeled probably as secondary progressive with relapses again one and you've probably heard me and me and others say this before one of the other things were so nervous about in sticking labels on people is when we're in this setting when you're in an exam room in a clinic you know visiting with your healthcare provider we can talk about grey areas about how it's not always easy to use the right terminology third party payors insurance companies don't deal with grey areas you're either this or you're that and if you happen to be that and that doesn't meet the box to qualify for a given treatment because it's not within their guidelines they're not going to pay for that so that's one of the reasons where sometimes a little nervous about using the P word the progressive word and in multiple sclerosis because your third-party payer your insurance company could come back and say we don't want to pay for whatever treatment that you're looking at so can things in multiple sclerosis are not always neat it's sometimes very difficult to know which box people fit in some people with secondary progressive MS still have relapses some people with primary progressive MS do have active inflammation on their their MRIs so again it's not always just perfectly clear you know how to label people so what do we do for progressive forms of MS and again we're going to talk about the first fda-approved treatment in the kind of the third bullet here but we've always had the first two bullets even before we had that we've always had wellness and rehabilitation and I would argue for people with a progressive form of MS that wellness and rehabilitation piece may be more important than for someone who's diagnosed with an early form of relapsing remitting ms we've always had aggressive symptom management to improve quality of life and I stole this shamelessly from our rehab people and it's the idea of the bucket of disability that if you have some disability from your multiple sclerosis whether it's walking issues issues with fatigue there they're really two ingredients in that bucket in that bucket there is damage in the central nervous system maybe damage in the brain or spinal cord from your multiple sclerosis the other component of that bucket is deconditioning so what's the one part of that that we can fix in reverse it's the deconditioning part and so when we have looked at how people do in wellness program so we did a study here looking at people going into a 12-week wellness program every single individual that went into that wellness program for 12 weeks did better when they came out at the other end they were less disabled their energy levels were better their mood was better so we know that if we take that deconditioning part out your bucket gets smaller we don't have a way yet to fix damage in the central nervous system hopefully we will someday but for right now we know we can fix that the one of the two ingredients in that that bucket of disability symptom management the second part of what we do with MS so when you think about what affects your quality of life right now you know for some people maybe it's either gait and mobility issues maybe it's spasticity fatigue is always high on the list pain from what we call central neuropathic pain burning hypersensitivity maybe painful spasms bowel and bladder issues cognitive issues skin breakdown all of these things are potentially treatable and so even you know if we're not talking about changing the long-term course just managing those symptoms and improving quality of life whether it's through medication rehabilitation it has always been an option for us so why are there so few treatments for progressive forms of MS you know why are we just now getting our really our first unit of FDA approved option for primary progressive MS we've mentioned again tends to be less inflammatory most of our drugs or treatments are anti-inflammatory in nature clinical trials for progressive MS have always been a little more difficult to design so if you're looking at a drug that you think would stop relapses or prevent new lesions on MRI you can do a two-year trial and enroll people with relapsing remitting ms who have very active MS you know - relapses a year maybe a couple of new lesions on their MRI every year and you'll you're going to know over two years whether your treatment makes a difference for that individual if the person is not having active relapses if they're not having their MRI change very much if really what you're dealing with is slow progression that's tougher to show in a study you're probably going to have to look at more individuals in the study you may even have to study them for a longer length of time it's going to be a longer trial it's harder to show that your treatments effective and it's going to cost more money to do that so the bar is a little bit higher in progressive forms of MS with clinical studies so one of the treatments that we sometimes don't talk about very much that has been out there for a bit fda-approved for secondary progressive MS is might as antrum or nove Antron if people heard of this drug before then it's enough so it's good so the reason you've probably not heard much about it is because we really don't use it much anymore so mitoxantrone is a chemo therapeutic agent it's been used in different forms of cancer for years and years it is fda-approved for both relapsing remitting ms and secondary progressive MS when the drug got FDA approval and we started using it in multiple sclerosis we were aware that we had to be very cautious about cardiac issues there is a lifetime limit on how much mine is Antron on a human can can get before you start getting into risk of actually damaging the cardiac muscle and that damage can be permanent in some people and if you do that you get congestive heart failure so if you if you dosed might as intern the way we typically give it you could give it for about two years before you said that's it that's their lifetime limit if you receive might as an thrown even one dose you were supposed to get echocardiogram Zoar study of how well your heart is working every year for the rest of your life so it's a pretty big deal in the the warnings about - antrum what we knew from day one there was about a 1 in mm maybe 1 in 2,500 risk of leukemia as the drug got out there and people were using it more across the globe what we realized is that that risk was it really wasn't one in 2000 or 1 in 2,500 it was much higher and it was maybe as high as 1 in 100 and the thing that was so frightening about this side effect as you could see it after one dose and it was a very aggressive form of leukemia with most people dying from this we had two individuals here at Shepherd one of whom received one dose of mitoxantrone develop this leukemia and unfortunately died within about a year of onset so so you will you'll be very hard-pressed to see anyone in the United States or Canada at least using mitoxantrone in multiple sclerosis so March 28th 2017 we now have our first fda-approved treatment for primary progressive MS aqua vez Arak realism' AB this is a twice a year IV treatment it is approved for both relapsing remitting and primary progressive MS the way that this is dosed is your first dose is going to be split in two so you'll get 300 milligrams week one you'll come back two weeks later you'll do another 300 milligrams and then you get 600 milligrams every six months on that drug it is a slow infusion that it takes somewhere between four and six hours typically to run that that drug in so we try to make you comfortable you're going to be hanging out for a little bit in the infusion room the major side effect risk that we're seeing with this drug is the infusion itself you can see in fusion reactions that might be you can have itching you can have blood pressure fluctuations rarely you could see true anaphylactic reactions severe allergic reactions one of the reasons that most MS centers are very comfortable with aqua lism AB is because we've been using a drug called rituximab for a while aqua lism AB is the cousin of rituximab these are both anti cd20 monoclonal antibodies what that means they target a cell in the immune system a type of b-cell that has something called a cd20 receptor on its surface and that's all that they target so rituximab has been around for a number of years now neuro myelitis opteka a cousin of multiple sclerosis rituximab is sort of the go-to drug for that condition it is also used off-label in multiple sclerosis we've got about 140 individuals on rituximab for either neuro myelitis optica or multiple sclerosis it's my firm belief that rituximab would be FDA approved for MS right now if they hadn't developed aqua lucemon so what was it that researchers didn't like about rituximab and made them sort of shift their focus and efforts towards off the aqua lose map rituximab is is what we call chimeric antibody you'll notice on a lot of these drugs you've got nab aqua Liz zoom AB Tysabri is Natalie zoom ab limb Prada Alan - Alan - zoom AB so you've got this ma v monoclonal antibody is what that stands for in front of the ma B is a zu what zu means is that it's a humanized antibody it looks like what we have in our bot in our body naturally as as an antibody rituximab Rituxan to my knowledge is the only one that has an X I and from the MA B what that means it's chimeric it's a little bit mouse and mostly human that's what the researchers didn't like they wanted to take that mouse antibody out of the drug make it a more humanized antibody in theory that part of the rituximab that is is mouse your your immune system could react to that and make an antibody to the antibody and make it less effective so that's why they switched over to the aqua lism ab again a good safety profile when you're reading other potential side effects of this drug you will see in the package insert a mention of PML progressive multifocal leukoencephalopathy this is the side effect did no MS center ever wants to see it's a very serious brain infection approximately 23 percent of people with MS that get PML regardless of what drug they're on the cadet is responsible for it died from PML so we spend a lot of time and effort never seeing PML we want to not see that pop up there's never been a case of PML with aqua lism ab the reason that it's in the warning label is that with rituximab the sister medication there have been 10 cases globally of those the majority were in the rheumatoid arthritis of Rheumatology world when the rituximab was combined with other immunosuppressant drugs there was one in a person with multiple sclerosis it was an individual on Tysabri for a long period of time very high levels of JC virus antibody in their system and the irony is the they were being switched from Tysabri to rituximab for safety reasons when you stopped Tysabri in a high-risk individual like that there PML risk doesn't go back to zero for about six months so they stopped the Tysabri they received a dose of rituximab and within that six month window that person developed PML most people believe that really is a Tysabri case not a rituximab case but they did receive a dose of rituximab so you've got to at least count it in there so what we're counseling the individuals is that we can't say there's zero risk of PML with this new drug but it's very very low a lot of the individuals we are looking out for this drug our individuals who may have JC virus antibodies maybe they're coming off of a Tysabri and we're again we're trying to move them to something that might be as effective as Tysabri but maybe have a better safety profile so we're excited about this it is our first drug again fda-approved for primary progressive MS so would we use it in secondary progressive MS if we do so it's clearly off-label but remember we said earlier a lot of people think of primary progressive and secondary progressive as very similar you got there through a different path but once you're there they're both characterized by similar immunopathology so I think it would be certainly something on the table for for discussion again we we believe here Shepherdson we want you to know what we know and we will put anything on the table that's reasonable talk about the risk benefit ratio and see what what feels best to you as a plan going forward folks thank you again so much for being here this evening thank you again to our sponsors for for helping us be here this evening thank you guys very much yeah

Channel: Multiple Sclerosis Foundation

Views: 26,063

Rating: 4.8009048 out of 5

Keywords: MS, MSF, MSFocus, MS Focus, Multiple Sclerosis Foundation, Ben Thrower, PPMS, Primary Progressive MS, Multiple Sclerosis

Id: XC-0cssejPk

Length: 29min 59sec (1799 seconds)

Published: Wed Jun 14 2017