Overview of MS Medications

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: May 15, 2024

Expiration Date: May 15, 2025

Estimated Time of Completion: 28 minutes

Overview of MS Medications

Alise Carlson, MD

Description

Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience

Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

ACCREDITATION

In support of improving patient care, Cleveland Clinic Center for Continuing Education is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

CREDIT DESIGNATION

• American Medical Association (AMA)

Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)

Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

• Certificate of Participation

A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

• American Board of Surgery (ABS)

Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Credit will be reported within 30 days of claiming credit.

Podcast Series Director

Imad Najm, MD
Epilepsy Center

Additional Planner/Reviewer

Cindy Willis, DNP

Faculty

Alise Carlson, MD
Mellen Center

Host

Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Overview of MS Medications

Alise Carlson, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

Alise K Carlson, MD	Vigil Neuro Consulting National MS Society Other activities from which remuneration is received or expected: Institutional Clinical Training Award ICT-1805-31154 Biogen Inc. Other activities from which remuneration is received or expected: Fellowship funding - Grant 16696-P-FEL Novartis Consulting Sanofi Consulting Other activities from which remuneration is received or expected: Advisory Board
Imad Najm, MD	Eisai Advisor or review panel participant NIH Other activities from which remuneration is received or expected: Research Funding LivaNova, PLC Advisor or review panel participant SK Life Science Inc Advisor or review panel participant Teaching and Speaking
Glen Stevens, DO, PhD	DynaMed Consulting

The following faculty have indicated they have no relationship which, in the context of their presentation(s), could be perceived as a potential conflict of interest: Cindy Willis, DNP.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

HOW TO OBTAIN AMA PRA Category 1 Credits™, ANCC Contact Hours, OR CERTIFICATE OF PARTICIPATION:

Go to: Neuro Pathways Podcast May 15, 2024 to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at [email protected].

Copyright © 2024 The Cleveland Clinic Foundation. All Rights Reserved.

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research, discoveries and clinical advances in the fields of neurology, neurosurgery, neurorehab, and psychiatry.

Glen Stevens, DO, PhD: While there is still no cure for multiple sclerosis, the landscape of disease-modifying therapies has rapidly evolved showing promise and slowing disease progression and reducing relapses. In today's episode of Neuro Pathways, we're surveying the landscape of injectable, oral, and infused medications for the management of multiple sclerosis. I'm your host, Glen Stevens, DO, PhD, neurologist, neuro-oncologist in Cleveland Clinic's Neurological Institute. Joining me for today's conversation is Alise Carlson, MD. Dr. Carlson is a neurologist in the Mellen Center for Multiple Sclerosis within Cleveland Clinic's Neurological Institute. Elise, welcome to Neuro Pathways.

Alise Carlson, MD: Hi Dr. Stevens, thank you so much for having me here today. I'm really excited to delve into this important topic.

Glen Stevens, DO, PhD: Great. So Alise, before we start, why don't you tell us a little bit about yourself, your training, how you made it to Cleveland, anything that you think our listeners would enjoy knowing about you.

Alise Carlson, MD: Absolutely, yeah. So I've been here in Cleveland for almost seven years, going on eight now, I guess. I've completed all of my training here in Cleveland. I was born and raised in Minnesota, so not making too much of a shift in terms of landscape, still sticking with the Midwest. But came for residency in 2017, completed my residency training here, and then completed a two-year fellowship in neuroimmunology with a focus on multiple sclerosis at the Mellen Center. I am just about to complete my first year of clinical practice and it's been a wonderful experience all the way through. I love the system, I love working here and feel very fulfilled in my work.

One of the reasons why I chose to go into neuroimmunology and focus on multiple sclerosis is that I have a very close family connection. I have multiple family members that have MS, and I've seen this whole spectrum where there was a time when I had family members that had no treatments or disease modifying therapies available to them, and then some family members that are more recently diagnosed and have these wonderful therapies available. So, it's been interesting to see that evolve over time.

Glen Stevens, DO, PhD: Well, Alise, I've had the pleasure of working with you over the years and I would just say that you're always a pleasure and we're very fortunate that you've decided to stay. So, congratulations.

Alise Carlson, MD: Thank you so much.

Glen Stevens, DO, PhD: I'll also mention that my mother had multiple sclerosis, was diagnosed in the '60s, and you can just imagine the treatments that were available then. I always thought that I would do multiple sclerosis, but then fell in love actually with neuro-oncology, so shifted gears. We just never quite know the direction that we're going to go, but I certainly appreciate all you do every day.

So before we dive into today's treatment options, there's clearly been significant, thankfully, advances in the field to bring us to a point where we can survey a full landscape of multiple sclerosis therapeutics, but this of course wasn't always the case for many, many years. I'm going to have you take us through the chronology if you're able to, because I'm sure that's a daunting task of MS therapeutics.

When I was training, we had this great drug called steroids, and that was really about the only thing that there was when I started training. Then the first injectable that I recall coming on the market was BETASERON, an interferon beta-1b that I think was FDA approved in the early '90s and that set off this cascade and was really, in my recollection, a game changer for patients. Since then, really, an explosion and what a great problem to have. But why don't you take us through it?

Alise Carlson, MD: Very good. Yeah, so we'll try to approach this somewhat chronologically. Talking about when these different therapies were developed and how they work, in terms of annualized relapse rate reduction, which is our primary goal with MS treatment, is to slow down the inflammatory attacks that lead to accumulation of lesions and later accumulation of disability over time.

So as you've alluded to, there have been massive changes in the treatment landscape since the initial disease modifying therapy was approved in 1993, which was the interferon beta. That was followed shortly by a few other interferon formulations, interferon beta-1a in 1995, and Glatiramer acetate in 1996. All of those medications are self-injectable medications, so patients could administer them from home subcutaneously. They all have efficacy in the ballpark of about 30% reduction versus placebo in annualized relapse rate. So like you said, significant change from no disease modifying therapy, where we would just treat acute attacks and hope for the best in the interim.

The next big step forward, which was actually quite a leap forward, was FDA approval of natalizumab, which is a monoclonal antibody. This is to this day, one of our very highly effective therapies. It's an infusion medication that's administered once monthly. In the clinical trials it actually showed annualized relapse rate reduction of between 65% and 70%, so massive reductions. We'll discuss mechanism of action and potential complications in a little bit after we run through the rest of these medications, but again, still a very frequently used medicine.

I believe the next medication to hit the market was a medication called fingolimod, which is an S1P receptor modulator. That was around 2010. Since then, there have been three additional subsequent iterations of the S1P modulator that have become progressively more targeted, in terms of tissue cross interactions over time that have minimized side effects. The fingolimod trial, again demonstrated around a 50% reduction versus placebo, and then 52% reduction compared to interferon beta-1a. Again, this is where active comparator arms started to come into play with the clinical trials. The subsequent iterations of the S1P modulators have all had active comparators apart from siponimod, which demonstrated a 55% reduction in annualized relapse rate in secondary progressive MS patients.

Shortly after fingolimod, so the initial S1P, teriflunomide was introduced. This is also an oral medication, moderate efficacy that showed around 30% to 35% reduction versus placebo. Followed very shortly by FDA approval of dimethyl fumarate, which is another oral medication that showed slightly higher efficacy at somewhere between 45% and 55% reduction in annualized relapse rate versus placebo.

Then we entered the age of monoclonal antibody treatment. So we've been using rituximab, which is an anti-CD20 monoclonal antibody for many years off-label. In MS, there haven't been any dedicated clinical trials or placebo-controlled trials against rituximab, and it's been again, used off-label for some time. In 2017, there was approval for a medication called ocrelizumab, which was the first anti-CD20 monoclonal antibody that was FDA approved specifically for MS as an indication. That showed again, about a 50% reduction compared to interferon beta-1a in the initial clinical trials. We've subsequently had another infusible monoclonal, anti-CD20 antibody approved just recently called ublituximab. Then there is now also an injectable monoclonal anti-CD20 antibody called ofatumumab on the market.

We've also had several other medications in the interim. Cladribine was introduced in about 2019, again, a moderate to high-efficacy therapy with around 60% reduction in annualized relapse rate compared to placebo. Then alemtuzumab, which is an anti-CD52 monoclonal antibody that effectively reduces B&T cells in the mid 2010s.

So as you can see, the list is long, it's quite extensive. We're lucky to have all of this in our treatment arsenal at this point in time. I think what we'll be delving into next is how these medications exist on a spectrum, in terms of their efficacy, which we've covered to a degree, but also in their safety and tolerability profiles and their route of administration, which all come into play when selecting a disease-modifying therapy.

Glen Stevens, DO, PhD: Well, the fact that we even use the term disease-modifying therapy, I have to tell you, almost makes me a little bit emotional when I think about my mother, because never would've thought back in the '70s that this would even be possible. But to change the trajectory of a patient's outcome is really fantastic and I'm so excited about it.

Before we move on, and again, because my experience was mostly just with the interferons back in the day. One of my recollections was one of the problems with the interferons was the development of antibodies. Is this common amongst the other treatments as well, or it can be, or it's very variable depending on the class of drug?

Alise Carlson, MD: It definitely varies amongst the class of drug. Certainly the neutralizing antibodies for the interferons is something to watch out for. I would say natalizumab is the other medication where we monitor for that more diligently, if we start to notice that treatment has started to become less efficacious or if patients are having suboptimal response. There's also been some investigation of neutralizing antibodies for the anti-CD20s, though that hasn't clinically turned out to be as significant of an issue as of yet.

Glen Stevens, DO, PhD: The drugs that you mentioned, are they primarily for relapsing-remitting MS, chronic progressive MS? Could be for both or I suspect most of them have been looked at in relapsing-remitting MS, is that right?

Alise Carlson, MD: That is correct, yes. So all of the medications we've covered up to this point are the FDA approved therapies for relapsing-remitting MS. Most also carry FDA approval for active secondary progressive MS, so progressive MS with concomitant relapses. Ocrelizumab is currently the only FDA approved medication for primary progressive forms of MS, and that's because in the clinical trials there was demonstration of slow disability progression on that medication. There have been many, many other clinical trials in the past and ongoing looking for other therapies to address the unmet needs in PPMS, which we can certainly discuss further. Then in terms of pediatric MS, currently fingolimod is the only FDA approved medication there, but there are active clinical trials evaluating use of ocrelizumab in the pediatric population as well.

Glen Stevens, DO, PhD: So I'm diagnosed with MS and I come and see you, I have relapsing-remitting MS. You show me the flowchart with all the drugs on there, I pass out, when I wake up, it's still there. How do you counsel me as to what drug I should take? It seems dizzying.

Alise Carlson, MD: That's right, and if you present it in that manner or present every single medication to every patient, it's just absolutely overwhelming. I typically introduce the concept of disease modifying therapy as, starting a medication that aims to correct this overactive or aberrant immune system that's causing damage and wreaking havoc in the central nervous system.

Then I explain our treatment approach, in terms of the currently prevailing treatment strategies of which there are two. So the classic or more tried and true treatment approach is what we call an escalation approach to therapy, where perhaps we choose a medication that is maybe a lower or moderate efficacy therapy with a better or more favorable safety profile, and then only escalate to a highly effective therapy if there's breakthrough disease activity. I think that that has been, again, the tried and true method just because the therapies have become more efficacious as they've become FDA approved. So leaning on the medications that we've had more experience with over time, and then again escalating to these more aggressive therapies.

More recently, there's been a lot of interest in what we call an early and highly effective treatment approach. That's really where we're starting a highly effective therapy at the time of treatment diagnosis to control the disease activity early when it's the most active and we think we can make the most impact on the long-term disease outcomes.

Glen Stevens, DO, PhD: Does that come with more risk?

Alise Carlson, MD: Yeah, so that's right, weighing the risks and benefits. So there's the concept or historically has been the concept of these more highly effective therapies carry more risk, both in terms of infection and maybe severe side effects. There's a lot of research going on, in terms of further quantifying and qualifying exactly how significant those risks are, but we also have to keep in mind that there are risks with the escalation approach as well. Those risks include a higher likelihood of breakthrough disease activity. Also, a lot of the lower or moderate efficacy therapies have more tolerability issues actually in the long run than some of these more highly effective therapies, which can lead to non-compliance. They're typically dosed more frequently as well, so that can contribute to missed doses, patient non-compliance, and the like.

It can also be really challenging to determine what the threshold of disease activity is that would indicate an escalation of therapy, and it requires diligent monitoring. By the time that someone perhaps has demonstrated that their disease is inadequately controlled on a lower moderate efficacy therapy, they could have had a potentially debilitating relapse. So it's weighing all of those things against the potential risk of maybe a less favorable safety profile. Medications that are certainly more expensive may be cost prohibitive to some patients, but on the flip side, may have better compliance over time, better tolerance, and again, decreasing overall risk of breakthrough activity.

So these are the things I think as physicians we keep in mind, but we also have to consider the fact that patients themselves all have unique goals and considerations, in terms of what they want out of a therapy. So considering things like medical comorbidities and other concomitant medications, family planning - do they plan to get pregnant soon? Some of these medications are not compatible with pregnancy or family planning. Day-to-day side effects. Cost. There's a whole spectrum of things that, again, I think both patient and provider have to really be on the same page about.

Glen Stevens, DO, PhD: Yeah, you can imagine how difficult it is for a patient sitting there. The physician says to them, we can give you the highly effective therapy or we can give you the okay therapy. Which one do you want? I mean, I understand that it's a side effect risk profile as well, but ultimately, you can imagine how difficult a decision this is for the patient as they move forward. What about combination therapies, does this exist?

Alise Carlson, MD: So combination therapies, I think that there have been providers historically that have used these. It's not something that was heavily used, I haven't seen it used in my training, so I myself don't have much experience with that. Apart from potentially using combination immunosuppressive therapies in individuals that have other non-neurological autoimmune or inflammatory conditions, where we need to carefully consider how we're combining these mechanisms of action to effectively control two different disease states.

Glen Stevens, DO, PhD: So you mentioned pregnancy and use of medications. Are there certain drugs that you can use in pregnancy?

Alise Carlson, MD: So as of now, both the FDA and EMA have lifted the restriction for use of glatiramer acetate during pregnancy, meaning it's relatively safe to continue. We don't typically advocate for continuation of any therapy into pregnancy, however, most other medications have at least some aggregate data from incidental exposures that there are adverse effects on the developing fetus. We know that teriflunomide is highly teratogenic, so that's kind of the main one we have to think about avoiding in both men and women of childbearing age, because that is not at all compatible.

There are other treatment strategies emerging, in terms of how we can time dosing and administration of medications for family planning. There's a lot of interest right now in use of the anti-CD20s in terms of transitioning patients off of other medications and then timing conception with the dosing. So optimally timing conception so that the transfer through the placenta would not start until after the first trimester. It gets very involved, but there are ways and strategies which we can address this, and essentially get patients off of their therapies while pregnant safely, and then have a clear plan for restarting therapy after delivery.

Glen Stevens, DO, PhD: My recollection was that oftentimes the patient's clinical syndrome will be more quiescent during the pregnancy and then can increase after the child is born. Is that still the general thinking?

Alise Carlson, MD: Yeah, yeah. So that is how we conceptualize this, is that the body enters a state of immune tolerance while pregnant so that we avoid rejection of the fetus. Then after the fetus is delivered, the immune system reverts back to its factory settings, and in patients with autoimmune disease can rebound to becoming more active. There are certain factors, including frequency of relapses, degree to which disease was controlled before conception, and overall disability, that we think might predict who is more at risk for postpartum relapses. So again, there are patients out there that have highly active disease that might need to be continued on therapy into the first part of their pregnancy later, and those who we have less concern about. But again, this is a topic of high interest in the field that we need to develop more good data on.

Glen Stevens, DO, PhD: So monitoring side effects and complications. Do you want to go through some of the common ones for the medications?

Alise Carlson, MD: Sure. So each of these medications do require some degree of monitoring, laboratory monitoring, and certainly imaging monitoring over time. The only medication that doesn't have required lab monitoring would be the glatiramer acetate. Most monitoring approaches for each medication hinges strongly on the mechanism of action of each individual medication. So for instance, for the fumarates, which are one of our highly utilized oral therapies. Common symptoms include GI upset, flushing, lymphopenia, and liver irritation. So we monitor LFTs and we monitor CBCs, typically every six months in those patients. A similar approach I would say to the S1P modulators, which work by sequestering lymphocytes in the peripheral lymph nodes. So those are expected to cause some degree of lymphopenia, but we have to monitor that to make sure that we're not getting into dangerous territory with the level of suppression that we're reaching there.

Other medications that require some nuanced monitoring, of course, natalizumab is one that always comes to mind simply because there's a higher risk of PML, which is very difficult to treat brain infection that can develop in patients that have previously been exposed to the JC virus, and that medication can also cause profound lymphopenia as well. So monitoring the JC virus titers in these patients, as well as blood cell counts is important. Then for other monoclonal antibodies such as anti-CD20s, typically what we're monitoring there are CD19 or CD20 counts, which we expect to see fully suppressed, and then blood cell counts and LFTs over time.

Several of the other medications have more nuanced approaches. One that requires a lot of work is the alemtuzumab, which is the anti-CD20 inhibitor. It requires not only intensive monitoring while patients are being treated, but for four years after. That one has a wide range of potential secondary autoimmune issues that can arise as well as malignancies. So all of these things, again, looping back into our treatment choice discussion, have to be considered, in terms of patients' comorbidities, what their transportation situation is like, how likely are they to be compliant with not only the dosing, but these monitoring studies and such, is important.

Glen Stevens, DO, PhD: So we'll just shift gears here for a second and talk about stem cells, transplant, bio-statins. Where are we there?

Alise Carlson, MD: Yeah, so this is again another one of the very hot topics in the MS field. There have been several trials looking at utilization of stem cell therapy, particularly autologous hematopoietic stem cell transplant. I would say that in aggregate, the data up to this point in time suggests that AHSCT has potent and durable efficacy in treatment for MS, but we still need a lot more clarification on, who is the optimal candidate for this therapy. Right now we think that it's probably a reasonable approach for patients that have highly effective MS, so a high degree of inflammation with rapid disability accumulation, and/or those that are having inadequate responses to highly effective therapies. Then we also need to better define what the safety issues and the financial costs are for these medications, for integrating this more widely because both of those things are very significant. It's a very rigorous process. So we need to make sure that we truly are identifying the best candidates for this therapy.

I think the limitations with the studies to date are that they've all included differing patient populations, so it's been hard to answer this question about who the optimal candidate is. There have also been various protocols implemented that are constantly being revised, so better defining what protocol to use, and then, how can we better define the outcome measures in these clinical trials to really nail down exactly what we can expect and what we can counsel our patients on expecting after this procedure.

Glen Stevens, DO, PhD: What do we counsel patients about vitamin D?

Alise Carlson, MD: We're certainly advocates of vitamin D repletion. It's been well-established that low vitamin D is a risk factor for MS development. We also know that low vitamin D can contribute to worsening of certain MS-related sequelae like fatigue and cognitive function. So we typically replete aggressively. All of our patients we screen for vitamin D deficiency at the time of diagnosis, and if low, again, start a high-dose repletion protocol and then recommend that they continue at least 5,000 units daily going forward.

Glen Stevens, DO, PhD: Well, Alise, I'm sure there are things that I have not asked you about. Anything that you want to discuss that we haven't touched on that you feel is important?

Alise Carlson, MD: I think just the one additional comment is that although we've made significant advances and strides, in terms of our ability to treat MS, there's still a lot to be desired. Our current therapies work primarily on treating, again, the focal, the infiltrative inflammation and have little, if any impact on the underlying mechanisms of the progressive portion of MS, which we know happens regardless of phenotype even very early on in the disease course. So we need to work on developing therapies that target the worsening of these underlying neuropathological issues, and then reversing damage and restoring function. So those I think are the things that we have to look forward to in the years to come.

Glen Stevens, DO, PhD: Well, Alise, you've been a fountain of information as I knew that you would. It's a good problem to have that we have so many medications, because not everybody's the same. Drug for patient A won't be the right drug for patient B, even if they have what appears to be the same type of disorder. Patients clearly will make choices based on side effects. I know that we could have gone into a lot more detail on that, but certainly in our field we see a lot of that, in terms of, what are the side effects of medicine, and they may choose treatment A instead of B initially for it. But proud of all the work that you guys are doing over there at the Mellen Center and looking forward for all the good things to come, and appreciate your joining us today.

Alise Carlson, MD: Thank you so much for the opportunity, it's been a pleasure.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's , all one word. And thank you for listening.