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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. back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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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.
back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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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. back to top |
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