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Tuesday, September 3, 2013

Approved Disease-Modifying Therapies for MS: How Will Recent Data Impact Their Utility?

Dr. Lublin:
I want to discuss "The Approved Disease-Modifying Therapies for MS: How Will Recent Data Impact Their Utility?"

So here's the CombiRx trial, which is a trial that was funded by NIH. I was the principal investigator. So we have 1,008 patients. We randomized them to either receive interferon beta-1a once weekly, or glatiramer acetate, or both.
But everybody took eight injections, so it was a matching placebo, but there was no full placebo-placebo arm. Everybody got something. And we wanted to see if the combination would be superior. What we showed is that for annualized relapse rate at 3 years, there was no real difference between the combination and the better of the two agents. And so it turned out that glatiramer acetate actually did the best alone, and both the combinations of glatiramer acetate were significant better than interferon beta-1a over 3 years.
The other thing you should pay attention to here is how low these relapse rates are. That's one exacerbation every 9 years, every 8 years. Even for interferon beta-1a, that's one exacerbation every 6 to 7 years. These are extremely low rates for our agents.
For MRI, in fact, the combination was significantly better at reducing gadolinium-enhancing lesions, combined unique activity, and also for a new metric called disease activity-free status. But that's all driven by the MRI, and it's an interesting paradox that even when we went out into our extension phase, we couldn't account clinically for that MRI difference. And so we're looking to see what that means over time.
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Dr. Lublin:
This is a paper that came out of Vancouver in JAMA, trying to make comparisons of what happens to people over time when they're put on interferon as opposed to those that weren't.

The problem here is that you're comparing apples, oranges, pears, and persimmons, because you're taking individuals who you choose to put on therapy, individuals who either you or they choose not to go on therapy, versus natural history controls. If you just take individuals in the 21st century who are on placebo and compare them to people who are on active agents—interferon beta or glatiramer acetate—in the 1990s, placebo was better. They had lower relapse rates on placebo in the last 5 to 6 years than they did on active drug in the '90s.
Now, they will tell you that they've made statistical adjustments for all of the underlying differences between the populations. And you do this to try and eliminate bias. In this study, they concluded that there was no effect on disability progression over time. A similar study done in Italy several years ago came to just the opposite conclusion. Again, if you want to see if one treatment's better than another, even no treatment, you've got to do it in a controlled study.
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Dr. Lublin:
Fingolimod has been approved now for a couple of years. It was the first orally available agent, and this was based on initially two studies, TRANSFORMS and FREEDOMS, and then a third study, FREEDOMS II.

In the developmental program, they showed in FREEDOMS here that fingolimod was superior to placebo. There wasn't much difference between 0.5 and 1.25 [mg], so only the 0.5 [mg] was approved. The side effect profile of 0.5 [mg] was better than 1.25 [mg], and it worked on reducing annualized relapse rate. It worked on MRI. And it worked on disability measures.
The other study they did was a 1-year study going head-to-head against interferon beta-1a given once weekly, and in terms of reduction of annualized relapse rate, it was superior.
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Dr. Lublin:
When you took the individuals who had been on the interferon beta-1a and then switched them onto fingolimod, you got a reduction. These are open-label extension studies. They show you that you're probably getting an effect, but they're not as rigorous as when you have them under the controlled clinical trial experience.

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Dr. Lublin:
Their third phase 3 trial was the FREEDOMS II. It confirmed the annualized relapse rate reduction. Here was the 48%. And what didn't happen in this trial was they didn't have a change in disability. It just works out that way.

What's been interesting in the FREEDOMS developmental program is that fingolimod's the only therapy we have that, to my mind, makes sense when you look at brain volume measurements. And I choose that word carefully. I'm looking at brain volume, not brain atrophy, because atrophy presumes you actually know what the pathologic cause is of the change in brain volume. And what was nice about the fingolimod program is, at every measurement—6 months, 12 months, 24 [months], even out into extension—there was more loss of brain tissue in the placebo group than in the treated group. And that mirrors the clinical effect, and it makes sense. We don't have that with any other agent that's out there at the present time that I've seen.
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Dr. Lublin:
Also, early onset of effect. So one of the things that we've argued about over the years is how quickly these drugs work. And one could even make the argument that we shouldn't pay much attention to the first 3 months of on-study behavior, because we may be skewing our entire population response by activity that's happening early on before the drug could take effect.

In this particular analysis of fingolimod they showed that there's an effect very early on. So free from confirmed relapse at 3 months, 6 months. The numbers stay the same, suggesting that the benefit's coming on fairly rapidly.
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Dr. Lublin:
Now, let's switch to teriflunomide. So teriflunomide has been around also for a little bit now. It was our second oral agent. This was their first pivotal trial, the TEMSO study. Again, randomizing individuals to two doses plus placebo.

And what they found was that there was a 30-some percent reduction—modest reduction—compared to placebo. The higher dose also reduced disability here by about 30%. And so that was a good result. It ultimately led to approval.
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Dr. Lublin:
TOWER was their second phase 3 placebo-controlled study. Similar results, a little better reduction here in [the] 14 [mg], and in fact, while both doses were approved, we prefer the 14 [mg]. And what's interesting here with TOWER and TEMSO is both studies produced a reduction in disability.

So even though this is a relatively modest reduction in annualized relapse rate, this is the only agent that's approved that reduced disability significantly in their two studies.
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Dr. Lublin:
This is the disability numbers. And again, it's in the 14-mg dose. Reasonably well tolerated. This is the side effect profile: hair thinning, diarrhea, nausea, and neutropenia. Actually, pretty reasonably well tolerated. The hair thinning is more upsetting to hear about than the reality of it, but nevertheless it's there, and we have to tell folks about it.

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Dr. Lublin:
So now we have three pills over the course of two and a half years. So this is dimethyl fumarate. It just came out based on two studies.

The first was this DEFINE study comparing dimethyl fumarate twice daily and three times daily, and fortunately twice daily was no different—actually, even a little bit better—than three times daily.
In this study, there was a difference in disability in the twice-daily, so it succeeded in the major outcomes, and it also had differences in effects on MRI.
In all of the studies that we're showing you, both the ones that have led to approved agents and the ones that Bob will show you that are in the pipeline all have this consistency of effect—that they reduce annualized relapse rate, they reduce gadolinium-enhancing lesion number, they reduce volumes and such. And even if they don't have a significant effect on disability, they all trend in the right direction. So there's a certain consistency there that gives us confidence that our agents are working.
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Dr. Lublin:
Okay, their second phase 3 study was CONFIRM. Here, there is, again, the two doses—240 mg twice daily, three times daily—versus placebo. And then they had an active comparator—smaller numbers, but active comparator—of glatiramer acetate not as a direct comparison, because it wasn't powered as a head-to-head study, but as a tracking arm to just give you an idea of where it sits.

So here, again, similar results to what they saw in their initial study. And this study, three times daily did better than two times daily, but not significantly better. And those numbers were higher than what we saw for glatiramer acetate, but not necessarily significantly different. But they did not make a significant change in EDSS progression. Similar therapeutic effect on all of the MRI metrics. So based on these two studies, this drug got approved last month.
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Dr. Lublin:
This was a study, RESTORE, looking at what happens when you stop natalizumab. So natalizumab has a couple of issues associated with it. A very good agent; we've had good results with it. But you know there's this issue of PML. And there's also been this issue of potential rebound when you stop the drug.

And so they did this study, taking people who had been on natalizumab, and then stopping them for 24 weeks. It's an interesting design. And then seeing if you can alter their behavior over those 25 weeks by either having them on nothing, interferon beta-1a once weekly, glatiramer acetate, or pulses of methylprednisolone.
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Dr. Lublin:
And the answer was that they all got activity back, and the activity started to come back at 12 to 16 weeks, around the same time as you started to see a loss of the biological effect of and binding to the receptor from the agent, and it was both clinical and by MRI.

And I think probably the take-home message is, don't leave patients off of natalizumab for 24 weeks, that there is this issue of potential rebound, and what we're seeing is that we ought to get them onto something else much sooner, if at all possible.
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Dr. Lublin:
So from the update on current agents, a combination of interferon beta-1a and glatiramer acetate was no better than GA alone.

Data highlighting the clinical benefits of fingolimod in patients with MS continue to accumulate. The clinical efficacy of teriflunomide is confirmed in two randomized placebo-controlled trials. Dimethyl fumarate is efficacious and was recently approved for the treatment of MS. Interruption of natalizumab treatment results in a high rate of recurrence of MRI and clinical disease activity.
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