Transcript - Platform/Combination Therapy Selection in Multiple Sclerosis

HOLLY ATKINSON, MD: Hello, I'm Dr. Holly Atkinson. And welcome to MS Conversations. Today we will be discussing platform and combination therapy for MS. And I'm pleased to be joined by two experts today. To my right is Dr. Rick Munschauer who is professor and chairman of neurology at the State University of New York, Buffalo School of Medicine. And next to Dr. Munschauer is Dr. William Stuart, medical director of the MS Center of Atlanta. Welcome to both of you.

WILLIAM STUART, MD: Well, thank you.

HOLLY ATKINSON, MD: Bill, let's start with you and talk about platform therapy. First, what are the critical criteria to use in selecting platform therapies?

WILLIAM STUART, MD: Well, in selecting or going on to platform therapy the patient first of all has an accurate diagnosis of MS. I think the doctor who deals with MS patients has to not accept the diagnosis, if they come in for a second opinion. You have to make sure they have the disease.

At that point, the way I approach it is to look at the balance between the outcome that the drug can bring in terms of controlling the disease and then the ease that the patient has of how it fits into their life. And whether they develop side effects and are able to be compliant with the drug over the long period of time they have to stay on treatment, which is as far as we know is at least 10, 20 or 30 years.

HOLLY ATKINSON, MD: Now, Rick, you certainly have found that the compliance issue is a major one and that the side effect profile is very important on the patient side.

FREDERICK MUNSCHAUER, MD: It certainly is. You have to be able to select a therapy that the patient can understand why they need to take it, feel empowered that taking it will result in improved long-term outcomes. And then have it be a therapy that they can tolerate over the long term. And from the physician's point of view, just as Bill said, you have to make sure that you're picking the therapy most likely to improve the course of the disease.

HOLLY ATKINSON, MD: Now of course, the sine qua non of MS is disability and relapse and progression of the disease. How do the ABCR drugs compare in these three critical areas, Bill?

WILLIAM STUART, MD: Well, I think that if you look at the outcome data on the various drugs that are available in the platform category, they are reasonably close together. And we're really looking at an arguable difference, but they all kind of settle out at about a 35–40 percent level of effectiveness, which leaves the MS patient in a 50–60 percent gap. So that the risk of accumulating the most important thing which you mentioned Holly which is disability is still more than a 2 to 1 likelihood.

When I look at these drugs I probably weigh the other side of the issue much more heavily.

HOLLY ATKINSON, MD: And when you say that, you mean the side effect profile and the compliance in the patient issues. Well, talk to us about that a little more. How do you go about thinking through that and making decisions with particular patients.

WILLIAM STUART, MD: Well, it's very hard to keep patients on a drug that is injectable with side effects for a decade or more. In fact, new data would suggest that we're not very successful at it. So at the very beginning you have to present the reason for being on the drug in a way that's convincing to them. And what that implies is that you're believable and that you believe in the treatment. You can't just give them the various boxes of information and ask the patient to go and read them and bring the one back that they want to go on because that shows the patient that you really don't have an opinion. Well, that's what they came to see you for is an opinion.

They don't then get from the doctor this sense of professionalism and commitment to a treatment. I think that's very important.

Secondly, you have to get their caregiver committed to it as well whether it's not a caregiver, whether it's a wife, which is usually a caregiver, if it's a male patient, and/or a friend. You have to convince them of the significance of the treatment because in the studies, that's just as important as a patient being convinced. So this kind of supportive symbiosis is very important.

And then you have to give them a sense of hope. What we typically do at our center is to present their disease in the light of expectation that we can realistically define for them. And oddly enough even when you present to a patient the likelihood that they may have more serious than average disease, if they get a firm understanding of it and then a sense of commitment that you're going to do something about it, they feel much more relaxed about the whole issue.

HOLLY ATKINSON, MD: I know, Rick, you look for the teachable moment.

FREDERICK MUNSCHAUER, MD: Yes, I think it's really quite important. Successful therapy is predicated upon instructing patients about reasonable expectations. As Bill has said before, all of our therapies for MS are only partial therapies. People on these therapies may and, in fact, probably will have evidence of disease activity and, if not, disease progression. But we know that these drugs have revolutionized our care of MS. And to teach people the reasonable expectations that these drugs alone, the so-called platform therapy, reduce disease activity by 30–40 percent is a good thing. And patients need to feel empowered to take their therapy and to recognize that this as a first level of care are therapies that will really improve outcomes. And I think that's really it.

Now some people can get buy with very little disease activity on these drugs, but more commonly people can and will experience a disease activity and then that's where if you've established reasonable expectations and a good relationship with the physician, and if the physician can communicate an empathetic hope to the patient, that, "Look I've got more things in my holster that I can try if you were to have trouble on platform therapy." And that kind of long-term relationship is also very therapeutic.

HOLLY ATKINSON, MD: Bill, when we look at the drugs now available in the platform therapy category, what about neutralizing antibodies? Talk to us about that.

WILLIAM STUART, MD: Well, I think they're very important. I've not understood the debate that has been going on over the last several years over why they're not important. Recently I had an opportunity to present some material to some PharmD people and they didn't seem to have as much reluctance to accept the concept of neutralizing antibodies as our colleagues. I think they're very important.

And I think when you're looking at trying to get started on a treatment that is, let's just arbitrarily say might have 50 percent effectiveness that if you run a risk of taking 35–40 percent of those patients out of long-term benefit, they've done a disservice to them. And I think that's not right, particularly if there is cross reactivity to the different antibodies created by the different interferons.

If there were not, if it were singular reactivity unique to the interferon, it might not be as difficult a problem. Then you could solve it by simply monitoring them closely and switching should antibodies develop. I think the cross reactivity makes it very essential that you start with the least immunogenic drug.

HOLLY ATKINSON, MD: Which is?

WILLIAM STUART, MD: For me, it's Avonex. Their data clearly shows that it's Avonex. And if you look at that issue of how many, let's say you think about treating MS in a public health sense and you want to get the best drug for the patients that are under your care, which may be a 100 or 200. That if you look at it in that sense, then look at comparative to the arguable differences in outcome, there isn't any question about it. That the antibody issue far outweighs what could be conceded as differences in outcome, at least for a long-term, over a long-term basis.

HOLLY ATKINSON, MD: Now, Rick, is this something that you take into account when you're —

FREDERICK MUNSCHAUER, MD: Oh, absolutely. Interferons now have been in practice widely for about eight years. And in the original phase III clinical trials that showed the efficacy over two years, we sort of missed the fact that when you administer these biologic proteins to people in super physiologic doses that you can develop antibodies against interferon. It's become clear in the last few years that when people are being administered beta-interferon for more than two years that the emergence of neutralizing antibodies is as clearly associated with the loss of therapeutic efficacy. So to Bill's point, it's prudent to pick the least immunogenic drug first.

But I think it also helps neurologists in trying to understand why when somebody is put on a platform interferon, Avonex, Betaseron, Rebif, it's in the differential diagnosis of why somebody may not be doing well. And this is what I think the neurologist has to factor into the profile. They've had a patient on interferon for over a year and they seem to have disease activity either clinically or by MR that in the differential diagnosis of that is that they've developed neutralizing antibodies. And that is, as we gain experience with these drugs, one of the complicated issues in their use.

It shouldn't come as a surprise. Neurologists certainly have seen that with antibodies from everything from insulin to erythropoietin to Botox. It is just one of those issues about platform therapies. We don't know what to do about it. If you're antibody positive, as Bill said, the antibodies cross react with all other interferon preparations, so it doesn't make sense to switch from one interferon to the other. So maybe the strategy upfront is to pick the least immunogenic so that you avoid that problem.

The differences between the interferons are quite striking. It's 5 percent with Avonex, 25 percent with Rebif and up to 45 percent with Betaseron. So that really is one of the differentiating factors amongst the interferons.

WILLIAM STUART, MD: I think it's kind of a tragedy really that the marketing techniques have disguised the significance of neutralizing antibodies.

HOLLY ATKINSON, MD: You've raised the issue, Rick, of relapse and how to approach that. When do you expect relapse given the ABCRs. What's the period of time that you —

WILLIAM STUART, MD: Well, I don't know that there is any important period of time. I mean you could put somebody on an interferon and have a relapse the week you're getting them started. It's a kind of randomness and relapses; I look at relapses more as a random event in an area of the nervous system that is very compact and significant in terms of function and nothing more than that.

They can have unique effect long-term on the patient if they're repetitive in those areas, but more often than not, they're not. So counting them is not an issue. We don't change our direction on the basis of one relapse or even two unless they're very significant. And then I wouldn't change it by changing the interferon, I'd go to another step.

FREDERICK MUNSCHAUER, MD: Holly, this is one of the questions that we struggle with daily as people taking care of MS. You establish somebody on a platform therapy and what amount of disease activity constitutes inadequate control of the disease. And I agree with Bill that measuring it just in terms of exacerbations can be difficult because exacerbations can occur with different intensities and severities and different frequencies.

But I must admit that when I have a patient on platform therapy and they experience an exacerbation, I'm disappointed. And that happens a great deal. And it makes me rethink — or they progress in disability too, or progress cognitively, or even if their MRI shows it, a substantial increase in activity — then I begin to get the feeling that they've broken through platform therapy. And you know, we don't want to throw the baby out with the bath water. It's not that the platform therapies don't work. It's just that they're inadequate in controlling the full expression of the disease.

The majority of people with hypertension need two drugs. We wouldn't think of treating complicated bacterial infections like tuberculosis with a single drug. Why do we think that we have to treat MS with a single drug?

So I think we have to in the modern concept of therapeutics, we have to be aware that just because somebody has disease activity, it doesn't mean that the platform isn't working. It may just mean that it's not working to the extent required to control the illness.

WILLIAM STUART, MD: Rick's point speaks to the other point that the two significant things about MS are how much disease there is occurring in the brain and the rate at which it's occurring, but also where it's occurring. And so these two issues you know when you finished evaluating your patient. So when you start them on the drug, you have a pretty good sense where they might have new trouble and you make decisions accordingly.

We often will go to second and third level treatments in patients who have very little MS, relative to other patients, but it may be in the wrong place. And you know that if it continues that they'll have high level disability.

HOLLY ATKINSON, MD: Well, you've said, Bill, that switching interferons is not necessarily the approach, certainly with the neutralizing antibodies, if that's a problem. Tell us how you think through the management of breakthrough disease.

WILLIAM STUART, MD: Well, I start patients on a platform drug and I predominantly use Avonex because I start them knowing that at least 50 percent of the patients are going to be back within a year or two with disease that's advancing in spite of being on the platform drug.

So at that point, we've actually already introduced the idea to the patient so should it happen and they come in, they're not surprised by it. Then we sit down with them and we talk about the objectives of adding the second drug and what we think is the most useful second drug to add which we believe is some combination of steroid infused intravenously, usually methyl prednisolone.

HOLLY ATKINSON, MD: Rick?

FREDERICK MUNSCHAUER, MD: I agree with Bill. Although there are interferons that are administered at a higher milligram dosage, there is no clear evidence that increasing the dose of any interferon product will result in a definite improvement in clinical responsiveness. The one study that looked at the two interferon-1as head-to-head showed a very small difference. One patient out of 10 was benefited by using Rebif over Avonex and that was just in the first six months and those differences disappeared in the second six-month interval.

So it strikes to me that it is missing the point or at least not being aggressive enough to switch between various interferon preparations. I think you know like calcium channel blockers or beta blockers that you're probably nearer the plateau of dose effectiveness, efficacy curves with interferon in terms of doses.

So I agree with Bill, I think we're much more likely in breakthrough disease to get a handle on the disease by adding a second drug that could be either additive or potentially synergistic with the platform therapy. That's a model that's widely used in medicine.

WILLIAM STUART, MD: Switching or increasing a drug is a traditional technique for doctors in a patient who is not doing well on the one that they started to begin with. It's faster in a busy schedule to write a prescription that's either dosing up or different. But it doesn't address the problem and that is given the arguable differences between the outcomes in these studies, when these patients start to worsen, they're just not going to get enough of a response from anything like that to be to their benefit. Now you can get far more protection for them by adding on Solu-Medrol.

That's difficult because it's a type of treatment protocol that most neurologists are not engaged in, particularly within their own offices. It requires more monitoring and it requires more time on their part and their staff's time. And as I said, it's already being compounded into an already busy schedule.

MS patients are more difficult in terms of implementing their care than the average neurologic disease. These are practical issues, I think, that are affecting our ability to get patients on complex therapies.

HOLLY ATKINSON, MD: Now what about combination therapy, Bill? What are you looking for in the combination agent in terms of being synergistic with the interferons?

WILLIAM STUART, MD: Well, we're looking for a drug that works differently. If you can approach the process of controlling the immune response by an agent that has some potential for working differently, you have a greater likelihood of some synergism or hope for it at least.

You're looking for a drug that is tolerable by the patient who is already on their platform drug. So it doesn't have any antagonism or increased toxicity with the combination. And you're looking for the drug that they can take for a long period of time without its own accrual of side effects. And then finally, you're looking for a drug that's affordable. This is already an expensive treatment model so that when you go to a second drug and, we'll talk later, a third drug, you want it to be affordable and for them to again be compliant because compliance doesn't go away. It's a continuing problem.

FREDERICK MUNSCHAUER, MD: In addition to that, I would just add that the ideal combination drug is a drug with all the qualities that Bill had mentioned, but one that we have an inkling that it may be effective in MS. And we do have that with pulse steroids. In a study done by Zivadinov and published. He found that intermittent pulse steroids by — as a single therapy were associated with slowing of brain atrophy and significantly better disability scores in patients treated just with pulse steroids over time. And we've had some other small studies that have looked at drugs such as methotrexate or even azathioprine that have showed us not with Class I randomized phase III clinical trials, but at least a body of literature that would support that other agents may indeed have a favorable effect on disease activity and progression in MS. And those are the kinds of drugs that Bill is talking about that make sense to work in combination.

HOLLY ATKINSON, MD: Well, Bill, given what we have in the armamentarium now, how do you think through which of the combination therapies to use?

WILLIAM STUART, MD: Well, we at the second level a group met as a consensus panel and the decision of the group was to use steroids and I'm in agreement with that. I think it's the easiest, the most inexpensive and a drug to give that has some proven benefit in MS. So that is currently the second level.

Now what the future holds, I don't know. I think that this whole algorithm is going to change with drugs that may be — will create a fourth category and/or be in several different categories. So we'll just have to have a wait-and-see on that. But I think right now it's IV steroid.

HOLLY ATKINSON, MD: And what do you progress to on the third level, Rick?

FREDERICK MUNSCHAUER, MD: I think that there is no clear path. I think the real issue is recognizing that even people on platform plus steroids (methylprednisolone) administered on bolus way may not control people's disease. And I think you really need to be open to the fact that you may go to a third level drug.

And here various protocols differ. There is a large prospective trial going on now that compares people who are on Avonex, who experience disease activity and progression. And they're randomized to either IV methylprednisolone or methotrexate which is given orally once a week or a combination of both. That trial is called the ACT (A-C-T) trial and it's a very large multicenter trial that really explores in a two by two factorial design this issue of a second or a third drug and uses two drugs that we have some preliminary information on it.

That's at the level of a study. What does a clinician do when he's sitting there and there is a patient in front of him that's been on platform therapy, been on steroids and you're still not comfortable you have the disease under control. That's where I think we — a lot of clinical intuition and experience, unfortunately in the absence of really good data, is now being employed. But the philosophy is a sound one.

Do you have any ideas about what would you do?

WILLIAM STUART, MD: I think the move from platform drugs to IV steroids is a relatively easy one. Most neurologists could probably make that move if they just would work it through a little bit.

The next move for the third level is time to batten down the hatches. The patients who move into that category that need that kind of treatment, it's an all or none kind of a treatment. And if you can't control the disease with that level of treatment, the patient is going to be in a lot of trouble.

It involves using drugs that significantly suppress the immune system in a way that is just above being dangerous. And that's a relatively delicate titration. Most neurologists probably will not ever want to be involved in that. But we're hopeful that enough of them will that we'll be able to absorb those patients out of the MS population and get them treated. But it's much, much more complicated.

FREDERICK MUNSCHAUER, MD: I think today it really is based on your aggressiveness of treatment as it is based on your assessment of how rapidly progressive the patient is. Clearly we've all had patients who are rapidly losing function. Those people, as one very famous neurologist says, "You give them Hail Mary therapy" where you need to be maximally aggressive in a relatively short period of time in order to try to gain control of the disease but not expose the patient to excessive risk. And drugs classically used for that are mitoxantrone whose trade name is Novantrone or cyclophosphamide, trade name Cytoxan. Both of those therapies are major immunosuppressive therapies. Both of them are associated with significant and potentially life-threatening side effects.

However, when you see someone rapidly deteriorating then that kind of malignant disease progression requires a equally aggressive therapy.

WILLIAM STUART, MD: I think that another way to think about it is that in the patient who is worsening through the various levels of treatment, in the stage 1 and the stage 2, you're always behind them. You're chasing the disease. You're chasing with the hope that it will slow down and you can catch it.

But when you get to the point where you are thinking about stage 3, now you've got to really put the after-burners on. Get in front of it. Stop it. Or you lose all potential to help the patient. These treatments in that category vary all the way from oral agents to intravenous treatments. As Rick mentioned, some of them can be done comfortably as an outpatient, but some need to be done as inpatient techniques. It's just depends on the individual case.

HOLLY ATKINSON, MD: We have just a few moments left so I'd like to finish by getting each of you to give the practicing neurologist some key take-home points here in terms of approaching treatment. Rick?

FREDERICK MUNSCHAUER, MD: I think that have respect for the disease. That MS is a disease that disables frequently if not the majority of patients. And have a respect that if you haven't controlled the disease clinically or, in my opinion, by MRI criteria too, that you need to escalate therapy. Platform therapy is effective, but frequently and, in fact, I would say in most cases, it's insufficient. And you need to add in a second drug.

I think the practicing neurologist will be most comfortable with IV methylprednisolone. If IV methylprednisolone plus an interferon doesn't control the disease, then I think we have to make a judgment about how rapidly progressive it is. In people who are rapidly progressive, major immunosuppressive therapy with mitoxantrone or cyclophosphamide is indicated. And people falling just short of that, but with still active disease, one of the routine immunosuppressive drugs which would include methotrexate, azathioprine, CellCept may be indeed needed aggressively to try to control the disease.

And just as Bill said, I think you have to try and stay ahead of the inflammatory process. And neurologists shouldn't be shy about it. We're not shy about treating epilepsy with multiple drugs. I think this concept of treating MS with multiple drugs; caveat with that is we don't have the phase III controlled trials that say this is the right thing to do. But you know what, we don't have that kind of information in so many branches of medicine.

I think we'll come up with better drugs. There is a drug coming out that's going to be presented for FDA approval called Antegren that may be 50 percent more effective than interferons in which case this new drug may become our new platform therapy. And we'll have to reassess our whole MS therapeutics.

But the parting thought I have for neurologists is — I like the way Bill said it — is stay ahead of the disease.

WILLIAM STUART, MD: Our most common sequencing in our clinic would be Avonex as a platform drug. IV Solu-Medrol in variable sequencing, always pulsing it, to avoid side effects as a second level. And then at the third level there is a fork in the road and it's either to an oral agent, which may or may not work and have to come back to the intravenous agent. The oral agent that we prefer is CellCept which is a newer drug, but sometimes hard to get approved. And our intravenous agent that we prefer is Cytoxan.

But just to end this rather serious conversation with a little levity and to quote a famous neurologist, Houston Merritt, who when asked by a resident about his high fees he said, "Well, there ain't no tainted money, there just ain't enough." And to kind of paraphrase that for MS, in MS there ain't no tainted treatment, there just ain't enough."

HOLLY ATKINSON, MD: Thank you both for a wonderful conversation.

WILLIAM STUART, MD: You're very welcome.

HOLLY ATKINSON, MD: And thank you for joining us. I'm Dr. Holly Atkinson.