The next couple of decades promise to
bring major advances in the development of new therapies for MS. But the
current state of affairs offers a good example of how the high costs of
new drugs preclude many patients from using them, begging the question:
if cost is a barrier to patients using a new generation of
disease-altering drugs, might not this barrier actually increase overall
costs associated with the disease?
| Aug
1, 2005 |
| By:
Anthony
J. Sinskey, Stan
N. Finkelstein, Scott
M. Cooper |
| Pharmaceutical
Discovery |
|
Anthony J. Sinskey
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If you're one of the millions of people who watch NBC's hit drama
"The West Wing" each week, you know that the fictional
President Jed Bartlet suffers from multiple sclerosis (MS) and, in a
previous season, nearly lost his job because of the disease. It wasn't
that he was disabled by it, but rather that he failed to tell the
country he was an MS sufferer when he ran for reelection.
Stan N. Finkelstein
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Bartlet missed an opportunity when first diagnosed with the disease to
use his presidential "bully pulpit" to educate the public
about multiple sclerosis — a chronic, unpredictable neurological
disease affecting the central nervous system — and dispel some myths.
MS is neither contagious nor directly inherited; it is not considered a
fatal disease and the majority of those afflicted do not become severely
disabled. Although it can flare up — as we write, Bartlet has been
unable to fulfill some of his duties at a summit meeting in China—
"most individuals with MS have a normal life expectancy but have to
learn how to handle the chronic symptoms of the disease" (1).
Scott M. Cooper
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In the fictional world of "The West Wing," as in the real
world, there is as yet no cure for MS. But there are some powerful
drugs, introduced in the 1990s, that can really help to slow the course
of the disease in some patients, helping diminish the symptoms.
Practice guidelines for MS in the United States and Canada, where
more than 500,000 people suffer from the disease, recommend
disease-modifying agents for most patients, but at any given time only
20% are using the drugs. And less than three-fourths of total MS
patients have even tried these drugs. Why is that? A study by
researchers from the MIT Program on the Pharmaceutical Industry (POPI,
Cambridge, Massachusetts, USA) — including two of this column's
authors — and from Thomson Medstat (Ann Arbor, Michigan, USA), with
support from Wyeth (Madison, New Jersey, USA), shows a direct link
between the out-of-pocket costs to patients in the form of health plan
copayments and utilization (2). In a nutshell, when a patient's
financial liability goes up, she or he is less likely to use a drug —
even if it really helps.
Figure 1. In multiple sclerosis,
the single cell membrane myelin sheath is deteriorated, leaving
the axon unprotected.
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In and of itself, such a finding shouldn't come as a particular
surprise. What is perhaps of greatest interest, though, are the
implications for tailoring insurance policies to influence the use of
disease-modifying drugs by reducing price-related barriers to beneficial
treatment. If the results were enhanced quality of care or quality of
life, wouldn't it be worth it?
Getting to New Therapies
Key to understanding multiple sclerosis is a fatty tissue called
myelin that surrounds and protects axons, which are elongated extensions
of nerve cells, or the neurons that send information to target cells in
the brain and spinal cord. Patients with MS lose myelin in multiple
areas of the central nervous system (CNS); this leaves behind scar
tissue called sclerosis (the damaged areas also are known as plaques or
lesions). In some cases, the nerve fiber itself is damaged or broken.
Myelin does more than simply
protect nerve fibers, however. It also makes possible the work of these
fibers by speeding up the conduction of nerve signals from point to
point. Without myelin, or with damaged myelin, the ability of the nerves
to conduct electrical impulses to and from the brain is disrupted. The
MS sufferer experiences this interference in the form of the various
symptoms of the disease, which fall into several categories: visual,
motor, sensory, coordination/balance, bowel/bladder/sexual and
cognitive. These present themselves in four courses of the disease.
In what is called
relapsing–remitting MS, patients experience clearly-defined flare-ups
during which they experience worsening of neurologic function, followed
by partial or complete recovery periods free of disease progression.
This type of MS is the most common form at the time of initial diagnosis
and afflicts approximately 85% of patients. Primary–progressive MS is
a slow but nearly continuous worsening of the disease from the onset and
has no distinct relapses or remissions. This relatively rare form of the
disease encompasses about 10% of patients. In secondary–progressive
MS, patients experience an initial relapsing–remitting period,
followed by a steadily worsening disease course. Some 50% of people with
relapsing–remitting MS develop this form of the disease within 10
years of their initial diagnosis. The final course is
progressive–relapsing, a relatively rare course afflicting about 5% of
patients. It is a steadily worsening disease from onset, with clear
acute relapses along the way that might or might not feature a recovery
period. Between relapses, the disease continues to progress.
For decades, little could be done
to alter the course of the disease for MS patients other than ease some
of the symptoms, such as fatigue and muscle spasms. Then researchers
began to work on MS as an autoimmune disease triggered when the immune
system goes awry and attacks the body itself.
Armed with expanding knowledge
about the disease, scientists were able to develop treatments that
address the autoimmune component of MS, affecting the process of
demyelination and controlling relapses. These treatments work by
regulating aspects of the immune system and sometimes are referred to as
the "ABC" treatments — A for Avonex (Biogen Inc., Cambridge,
Massachusetts, USA) (3); B for Betaseron (Berlex, Montville, New Jersey,
USA) (4) and C for Copaxone (Teva Neuroscience, Kansas City, Missouri,
USA) (5). There's also an "R" for Rebif (6), made by Serono
(Rockland, Massachusetts, USA) and Pfizer (Manhattan, New York, USA),
which doesn't quite fit in the mnemonic ABC scheme. Both A and B are
beta interferons.
Beta Interferon
Beta interferon (IFN-b) is one of a
group of naturally occurring biochemicals in the human body that
regulate the functioning of the immune system. Essentially, IFN-b
reduces the level of interferon gamma (IFN-g), known to be associated
with the MS disease process. Beta interferon appears to block white
blood cells from attacking the myelin and, specifically, to stop T cells
(a type of white blood cell) from releasing cytokines (immune system
signaling molecules) that would otherwise cause inflammation. Further,
IFN-b seems to interfere with the process of summoning new immune system
cells to the site of inflammation.
Studies of the efficacy of beta
interferons in both relapsing–remitting and secondary–progressive MS
show that the drug is quite effective at reducing relapses and the
burden of disease. Most studies also imply that IFN-b has a positive
effect on the disease's long-term progression, although the evidence for
this is not as clear.
The numbers are promising. In
relapsing–remitting MS, the use of beta interferon has been shown to
reduce the number of relapses and their severity by upwards of 25%,
depending upon the dose. The reduction in lesion load (as measured with
MRI scans) is upwards of 70%. And these results come with relatively
minimal side effects — primarily flu-like symptoms such as fever,
night sweats and muscle aches that often subside after a few months and
respond well to over-the-counter treatments such as ibuprofen. In far
fewer patients, severe depression results.
The Costs
One of the big drawbacks for these
new drugs, which have proven to be so effective in ameliorating — if
not curing — MS, is the expense. They can cost in excess of $10,000
per patient per year (7). And that is only part of the direct cost. Some
estimate that MS patients incur overall healthcare costs at a rate two
to three times higher than do people without MS. On top of that, there
are the indirect costs — loss of productivity, loss of income,
disability payments and lost opportunity costs that result from time
spent receiving treatment. According to Thomas Morrow, president of the
National Association of Managed Care Physicians (Glen Allen, Virginia,
USA), "On average, using 1994 dollars, patients may lose about
$18,000 annually. The total costs annually may be as much as $34,000 per
patient" (8).
Given the high cost of the drugs
themselves and of associated copayments, the research that finds a link
between cost and usage is rather intuitive. But if cost is a barrier to
patients using the new generation of disease-altering drugs, might it
not be worth considering that the barrier actually increases overall
costs?
The POPI/Medstat research showed
that out-of-pocket payments influenced the use of these newer drugs, and
particularly that the higher the share of drug expenditures going toward
out-of-pocket payments for drugs, the lower the use. Patients with MS
must weigh the potential benefits of new therapies against the need to
use their disposable income in other ways. Then, on top of the cost
issues, there is the issue of time. The POPI research also found that
patients were waiting, on average, more than 305 days between their MS
diagnosis and their first prescription for a disease-altering drug. That
wait of nearly a year only serves to increase the indirect costs
associated with multiple sclerosis.
Should insurance companies reduce
copayments to spur a higher utilization rate of MS disease-modifying
drugs? This would certainly be a good thing for MS patients and might
reduce the utilization of other healthcare services, thus reducing those
costs. Further, the indirect costs associated with MS might be reduced.
But insurance companies and policymakers, when setting payment policies,
need to be concerned with whether disease-modifying MS drugs might
increase total healthcare plan costs, resulting in higher premiums or
other coverage limits. These all are considerations for further
research.
The Next Breakthroughs
No matter what the healthcare plans
work out with respect to cost and time, research is moving forward on
the multiple sclerosis front. Much of the current MS research focuses on
how the lesions the disease causes can be repaired. The next generation
of interferons promises incremental improvements in treatment. And as we
move forward on the personalized medicine front, drugs should get even
better because they will be targeted to the individual characteristics
of the MS patient.
At present, there are about 70 MS
drugs and therapies being investigated worldwide; most are in Phase I
and II trials. Three Phase III trials being conducted include two for a
new drug developed jointly by Biogen Idec and Elan (Dublin, Ireland)
called Tysabri (9). It is "considered the most exciting of the
pipeline drugs and the first in a new class of compounds known as
selective adhesion molecule inhibitors. [It] appears to inhibit immune
cell migration across the blood–brain barrier that leads to
inflammation or destruction of the myelin sheath and eventual nerve cell
death. One trial tests [Tysabri] against a placebo; the other tests [Tysabri]
in combination with Biogen Idec's interferon product, Avonex. The third
Phase III trial under way is an NIH-sponsored double-blind,
placebo-controlled combination study involving 1000 patients that
compares Avonex and Copaxone as monotherapies and in combination.
Combination treatments are under active research since the current drugs
are only partially effective, particularly where the combined drugs
might target different aspects of MS" (10).
Major advances are predicted for
the next two decades, according to Stephen Reingold, the National
Multiple Sclerosis Society's (New York, New York, USA) vice president of
research programs. He anticipates medications that actually prevent the
progression of MS and that repair damaged tissue (10).
Two decades won't be soon enough
for the fictional President Bartlet on "The West Wing." Those
who suffer from MS in real life will wait as well, with appetent
anticipation. But the research path that lies before drug developers
appears to be very promising.
Anthony J. Sinskey and Stan
N. Finkelstein are co-directors of the Program on the Pharmaceutical
Industry (POPI) in Cambridge, Massachusetts, USA, and members of the Pharmaceutical
Discovery editorial advisory board. Finkelstein is a senior research
scientist at MIT Sloan School of Management in Cambridge. Sinskey is a
professor of microbiology at MIT in Cambridge. Scott M. Cooper,
an affiliate and frequent collaborator of POPI researchers, is a
visiting scholar in the MIT Department of Biology.
References
1. National Institute of
Neurological Disorders and Stroke (NINDS). "NINDS Multiple
Sclerosis Information Page." At www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm
2. R.J. Ozminkowski, W.D. Marder et
al., "The Use of Disease-Altering New Drugs for Multiple Sclerosis
3. Treatment in Private Sector Health Plans." Clinical
Therapeutics. In press.
3. Information at www.avonex.com/msavProject/avonex.portal
4. The drug is known as Betaferon
in Europe and is manufactured by Schering. The U.S. version, known as
Betaseron, is made by Schering's associate Berlex. Information at www.betaseron.com
5. Information at www.mswatch.com/therapy
6. Information at www.rebif.com
7. Drug Topics Red Book. (Montvale,
NJ, Thomson Medical Economics), 2002.
8. "Managing the Treatment
Costs of Multiple Sclerosis in a Managed Care Setting" (1/29/04),
at www.mult-sclerosis.org/news/Jan2004/ManagingTreatmentCostsofMS.html
Accessed 12/23/04.
9. Until Fall 2004, this drug was
known as Antegren. The FDA, concerned about prescription errors, ordered
a name change when it was decided that Antegren was too similar to the
names of two other drugs on the market. Information at www.tysabri.com
10. L. Richards, Modern Drug
Discovery, December, 21–23 (2004).
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