Where is the exact same CME for stroke, since stroke rehab is a complete failure at
10% full recovery? Or is your neurologist and stroke hospital OK with that fucking 90% failure rate? And doing nothing to get better resaults? MS got from 90% disability in the 90s to being able to prevent lots of disability today. If MS can do this, stroke can do it also. It will require leadership and a stroke strategy.
http://www.medpagetoday.com/mastery-of-medicine/neurology-mastery-in-ms/63501?
Timothy Vollmer, MD, on treatment failure rates among first- and second-generation MS drugs
Timothy Vollmer, MD, of the University of Colorado Anschutz Medical Campus, spoke with MedPage Today
at the European Committee for Treatment and Research in Multiple
Sclerosis annual meeting in September, where he presented several
posters on treatment failure rates for first- and second-generation
disease-modifying drugs in MS. Two full posters may be downloaded by
clicking here and here.
Following is a transcript of his remarks.
The
issue that led to these reports was a concept that we've been working
on for a number of years called "Maximizing Lifelong Brain Health in
MS." By that, we mean using these disease-modifying therapies to try to
minimize injury in the brain as early in the disease course as we can,
as well as helping patients to adopt a healthy lifestyle such as a good,
healthy diet to avoid diabetes, hypertension, and other diseases that
further increase disability in MS and also to help them adopt an active
lifestyle because we know that exercise improves function in multiple
sclerosis.
This concept of maximizing lifelong brain health comes out of a
growing concept called "neurological reserve." In multiple sclerosis,
about 90% of new lesion formation in the brain is actually clinically
silent at the time that it occurs. The brain is compensating for this
injury, and the injury actually is leading to not only demyelination,
but also loss of neurons and accelerated shrinkage of the brain, or loss
of brain volume.
The ability of the brain to compensate for that injury, that
subclinical injury where the patient actually feels like they're
functioning normally and they don't notice any loss in function, is
neurological reserve.
The capacity to compensate for subclinical injury, however, is
limited and there's a growing consensus in the field that the cause of
the progressive phase of MS actually may be the point where the brain
has used up that neurological reserve and now it doesn't have
neurological reserve to buffer for the subclinical disease activity. At
that point, it's also unmasked by the effects of aging. We begin to have
our brain shrink, all of us, at around age 35, and yet we don't notice
the effects of aging usually until later in life. So preserving brain
volume in early disease for MS patients is not only important for the MS
disability. It's also important to minimize the age-related changes
that we're all going to suffer as we go forward.
We now have 14 FDA-approved disease-modifying therapies, therapies
that can decrease the inflammatory attack on the brain and potentially
decrease disability and relapses. We're going to have a 15th drug
approved presumably in the next few months called ocrelizumab.
So
in thinking about these 15 drugs as we go forward, it's important to
use terminology that we can all share so we understand what we're
talking about. So to do this, I propose that we consider the early
therapies as the first-generation, first-line drugs. These are a half
dozen agents or so that were approved by the FDA for first-line use. Of
course, the early ones were the interferons that included Betaseron,
Avonex, Rebif, Plegridy. Then obviously, the glatiramer acetates,
Copaxone and Glatopa.
We also placed in this category teriflunomide or Aubagio, because it
has very similar effects on efficacy and similar tolerability issues. So
that's the first-generation drugs. They began to emerge in the early
1990s, and most were in the marketplace by the early 2000s.
More recently, though, there's been another class of first-line drugs
that are referred to as the second-generation drugs that have been
increasing their marketshare throughout the world. This includes
dimethyl fumarate, which is Tecfidera. Fingolimod, which is Gilenya, and
natalizumab, which is Tysabri. Ocrelizumab, which will be called
Ocrevus, I believe, will be the fourth member of the second-generation,
first-line drugs.
There is a third group of drugs that's really important for us to
understand where they fit, and these are the third-line agents as
approved by the FDA. In the United States, there's alemtuzumab, which is
called Lemtrada, daclizumab, which is Zinbryta, and mitoxantrone, all
approved for use in MS, but they're considered drugs to be used only
when patients have failed multiple other first-line drugs. So these are
not the drugs that we're talking about today. We're talking about the
first-generation and the second-generation first-line drugs.
The question that we were trying to address is identifying strategies
that allow you to do a better job of selecting the right
disease-modifying therapy for the individual patient to try to minimize
progression of disease, also minimize tolerability and safety issues,
and to avoid treatment failure.
Focus on Second-Generation Drugs
So, in thinking about this particular problem, though, we already
have a lot of data that has shown that, in general, the
second-generation first-line drugs are superior to the first generation.
So that's not really a key question in modern medicine today. The key
question is distinguishing between those members of the
second-generation disease-modifying therapies, and as a result, we've
been looking back at our experience with these agents -- which has
been substantial over the last eight years -- and looking at their
outcomes.
So we looked at a treatment failure definition, which means that the
patient discontinued one of these four agents in the second-generation
group either because of lack of efficacy, safety issues, or tolerability
issues, or any other issue that took them off the drug. We looked out
to a little less than three years of follow up in over 200 patients per
group.
What we found was that in one abstract we presented the comparison of
natalizumab (Tysabri) to fingolimod (Gilenya) and dimethyl fumarate
(Tecfidera). What we found is, in general, the treatment failure rate of
patients on Tysabri was actually pretty high. It was in the mid-20s,
and most of those were related to safety issues with the patients
developing evidence of an infection of the virus called JC Virus, which
can cause a very serious brain infection in patients on Tysabri. If we
looked at discontinuations for Tysabri that were not related to the
development of JC positivity, then the treatment failure rate was around
10% or a little bit less.
For Gilenya or fingolimod, the discontinuation rate was also in the
mid-20s, and that was for a combination of factors. It included lack of
efficacy, but also some tolerability issues and some access issues. But
again, the treatment failure rate over two years roughly was about 22%.
Then
with dimethyl fumarate or Tecfidera, the treatment failure rate was
even higher, between 27% to 35% depending on exactly how you measured
it. Again, it was a mixture of factors that led to discontinuation of
the treatment, but the main one was actually tolerability. Patients were
discontinuing the medication because of the side effect profile.
This is an important issue for us as we move forward, because from a
medical, cost-effective standpoint, the discontinuation of these very
expensive medications after a year or two is basically a lost
opportunity. These drugs cost around $70,000 in average wholesale price
per year, per patient. There's a substantial investment by the American
healthcare system in these drugs, and we're trying to identify best
strategies to minimize the sort of wasted investment in a drug that
patients are not going to remain on.
Benefits of Infusions
We're continuing this work and looking, again, at a group of drugs
that include ocrelizumab, which are called the anti-CD20 monoclonal
antibodies. This is a class of drugs that have actually been around
since 1996, when rituximab first emerged for use in lymphomas,
rheumatoid arthritis, and lupus. We've used this drug extensively in MS
as well, both here and in Sweden. Ocrelizumab is a newer version of
rituximab and we hope will be approved by the FDA within the next few
months.
This class of drugs is a little bit different than the other three
classes I've talked about. So Gilenya and Tecfidera are oral
medications. Gilenya is taken once a day as an oral tablet. Tecfidera is
taken twice a day as two capsules. Tysabri or natalizumab is a
once-a-month IV infusion. Then ocrelizumab and rituximab are
twice-a-year IV infusion.
We're
trying to address the issues of safety and efficacy, because there
actually is significant, comparative data on these drugs in that sense,
but we also want to look at patient tolerability. What are the aspects
of the use of these agents that patients really find attractive?
Our experience to date, although we haven't published this yet, is
that the twice-a-year IV infusions are actually very acceptable to
patients. Part of the reason is that even taking oral medication once a
day has a downside. One is just remembering to do it on a day-to-day
basis when you have a busy lifestyle, but the other issue is for many of
our patients, taking that pill reminds them that they have MS on a
daily basis and that adds to their stress that they experience during
the day.
So Tysabri or natalizumab is attractive to patients. They only deal
with it once a month. It's a highly effective drug, and outside of the
JC issue associated with this infection of the brain called PML, it is a
very tolerable drug. In general, our patients who are on that drug
prefer that over the orals. That might even be more so with the
anti-CD20s, rituximab and ocrelizumab, where it's only twice a year.
It actually leads to a possibility in the treatment of MS where for
patients who have little disability that are treated early in the
disease course maybe only have to deal with the disease twice a year.
They come in. They see us. We do the safety assessments. They get their
infusion and they're basically done for six months.
So this is a potential revolution in the treatment of MS.
We've moved
from a disease in the early 1990s that had a chance of disabling a
patient between 70% and 90% in terms of significant disability,
life-altering disability, to an era where we now have 15 agents, several
of which are highly effective agents, and may be able to completely
prevent disability progression in the majority of patients.
If we can figure out how to use these drugs in the optimal way, we
can potentially and dramatically improve health outcomes. We want to
decrease health-related costs, and improve the cost effectiveness of the
way that we use these drugs in general clinical practice.
Best Supportive Care
Our role in the disease is primarily supportive, how to treat
symptoms the best we can, try to support the patients as they move
through the different disability stages that occur in MS. In 1993,
interferon beta was approved, interferon beta-1b, which is Betaseron,
and that began the modern treatment era. Those therapies were very
important advances, but they only had a modest impact on the disease
course, about a 30% reduction in attacks, MS attacks per year and a
relatively modest effect from disability progression.
But since then, we've had, as I said, now approaching 15 therapies
approved in this space, and they vary widely in terms of their
effectiveness, their tolerability, and their safety profiles. So
treating MS right now is relatively complex because you have to know a
lot about the therapies and a lot about the risk factors associated with
those therapies to be able to select the best agent for the individual
patient that maximizes safety and also maximizes efficacy.
In the world right now, the treatment of MS is quite random. It's
unfortunate because there's undoubtedly better strategies embedded in
there that if we understood them we could use them to improve outcomes
and decrease health-related costs.
The area that I've been active in is trying to help the world to
understand that escalation therapy, which is the generally mandated
approach to MS, is not the optimal strategy. By escalation therapy, I
mean that in the United States, as well as in most other countries, the
healthcare systems actually enforce on physicians a need to use the
older therapies first and wait for patients to fail those therapies
before they're allowed to use the newer-generation drugs.
I'm not really quite sure why they think that is important. Because
if you actually look at the data, the newer drugs are just as safe, if
not safer. They're better tolerated and they're more effective. But
nevertheless in the United States, 58% of all patients that are on a
disease-modifying therapy are on that first generation of drugs.
Unfortunately, those drugs have very little impact on rate of new lesion
formation and rate of brain volume loss.
The reason I mention rate of brain volume loss is because how fast
you're losing brain volume in early life is a very strong predictor of
how much disability you're going to have in later life. So my patients
truly understand that losing brain volume is not a good thing, and yet
the first-generation therapies have a very minor effect on that
particular aspect of the disease.
So we've been discussing the strategy of optimizing therapy by
evaluating the patient for risk factors for adverse events related to
therapies, and then using that to select the best therapy in the
second-generation drugs to minimize further disease activity and try to
maximize outcomes, in other words, maximize lifelong brain health in
these patients.
That's beginning to catch on in the world. There's more centers that
treat patients the way we do, and it's being discussed at the national
and the international levels and the professional associations. I think
that over the next four or five years we'll be going through a major
revolution, just like we did rheumatoid arthritis and diabetes where
they learned to treat early with highly effective therapies to really
have a big impact on the disease ultimately for everybody's sake.
Pivot Point in MS
I think we're at a pivot point in MS, which is potentially
revolutionary because it has the potential for fundamentally changing
what's going to happen to the next generation of patients who develop
MS. In our experience here at the Rocky Mountain MS and at the
University of Colorado, we have over 3,000 patients. We have 10
clinicians and we all treat the same way. We follow algorithms based on
the data to identify the best treatment for an individual patient based
on their biological characteristics.
We've been doing this for eight years. Our patients that we catch in
very early disease, which is newly diagnosed patients, if we put them on
these second-generation, highly effective therapies, it's very common
for them to come back after a year or two and say they don't feel like
they have MS anymore, and we don't see any evidence of the MS
progression on the MRI, and most of their symptoms, particularly the
most common symptoms – which are fatigue, depression, and cognitive
problems – tend to resolve in these patients.
Those symptoms seem to be related to inflammation. So we have a lot
of evidence right now that's really suggesting that for the majority of
patients, if we can treat them early enough with the right one of these
second-generation drugs to maximize safety, we really can potentially
fundamentally change the course of the disease where they don't have to
anticipate disability in the future. They can anticipate living a normal
life and doing normal things. So MS is probably the most treatable
neurological disease in neurology today because of these advances that
we've had over the last 20 years.
For a description of this CME program, please click here.
Vollmer
disclosed financial relationships with Acorda, Biogen, Novartis,
Questcor, Teva, Sanofi, XenoPort, Daiichi Sankyo, EMD Serono, Genzyme,
Jensen Research, Eli Lilly, Ono Pharmaceuticals, Orasi Software, and
Roche.
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