http://www.biomedcentral.com/news/20011114/04
14 November 2001
As Britain continues to agonise over
the politics of treatment for multiple sclerosis, more sophisticated approaches
to combat the disease have been developed that could leave today's debates
over the cost-effectiveness of some licensed drugs far behind. The new
approaches could also overcome worries about the ethics of using cannabis
as a treatment for the disease.
In the foreseeable future it should
be possible to assess an individuals' genetic makeup to target MS therapies
for maximum benefit. "We don't know enough yet, but with all the tools
becoming available, it is just a matter of time," said Roland Martin, a
neuro-immunologist at the US National Institutes of Health, Bethesda, Maryland.
Eventually, researchers believe they may also be able to exploit the body's
own cannabis-like compounds to help treat the symptoms of MS without the
unwanted psychological disturbances associated with cannabis.
Multiple sclerosis sufferers in Britain
have spent the past few weeks on a roller coaster. After a protracted review
process, the National Institute for Clinical Excellence (NICE) — which
advises the NHS on best practice for England and Wales — concluded at the
end of October 2001 that two licensed immunotherapies, beta interferon
and glatiramer acetate, should not be recommended for treatment of the
disease. The decision centres on doubts about the cost-effectiveness of
the treatments in the long term and what NICE calls their 'modest' benefit
to patients. While NICE accepts that patients already receiving the treatments
should be allowed to continue, new patients will not be entitled to receive
them on the NHS.
The Multiple Sclerosis Society, which
represents patients, said last week that it would appeal. "While NICE has
muddled its way through more than two years of appraisal, hundreds of people
have become too disabled to qualify for the drugs," the society said. NICE
said it has not yet issued any formal guidance to the NHS on the basis
of its decision, but will do so in December 2001, depending on the appeal
process.
But the Department of Health also
threw out a crumb of comfort to patients, confirming that it was in confidential
discussions with four manufacturers of beta interferon and glatiramer acetate
about ways to provide the drugs affordably to all patients while monitoring
effectiveness over a longer period than the two or three years typical
of conventional clinical trials. "Our discussions are looking at a range
of options, including the possibility of a 'risk-sharing' scheme," said
the DOH. Under such a scheme, all patients would be monitored and if the
drugs worked, the NHS would continue to pay for them; if the drugs failed,
the payments to manufacturers would be reduced on a sliding scale. Patients'
groups welcomed the proposals.
There was one more piece of good
news. David Blunkett, the UK Home Secretary, said that the law could be
changed to allow the legal prescribing of cannabis for the treatment of
the certain diseases, including MS, if ongoing trials prove the drug is
effective. Researchers involved in the trials, such as John Zajicek of
Derriford Hospital, Plymouth, who heads a major trial for the Medical Research
Council, have welcomed the announcement, saying that patients who might
be deterred from using cannabis because of its stigma would now be able
to participate in trials. Certain other countries, including Canada and
Belgium, have already licensed cannabis for trials for medicinal purposes.
Britain's reluctance to use beta
interferon and glatiramer has raised the eyebrows of some researchers and
clinicians in other industrialized countries. "I can definitely see the
argument that there are limited resources and that they should be used
to give equal access to health," said Martin at NIH. "But I think the evidence
that these drugs really do something beneficial is now firm enough to justify
their use." The MS Society estimates that about 2% of Britain's 85,000
MS patients currently receive the drugs, compared with 12 to 15% in northern
European countries and the United States. Treatment costs have been estimated
at around $10,000 a year but advocates argue that these costs should be
set against the lost productivity of working adults and parents disabled
by the disease.
Few claim that either beta interferon
or glatiramer acetate have a spectacular effect on the course of MS; the
available data from large trials suggest that they both reduce the number
of exacerbations of the disease by about 30% and may delay the progression
of disease. But Martin argues that the efficacy of the treatments may appear
weak in trials in part because multiple sclerosis patients are a heterogeneous
group, some of whom may be genetically predisposed to benefit from certain
treatments, others not. As a result, 'responders' and 'nonresponders' are
lumped together and any effect on responders is diluted in the overall
data.
"This disease is genetically very
complex and there are maybe 50 or 100 genes that contribute to susceptibility,"
said Martin. It is too simplistic to assume that one drug fits all, he
argued. Instead, tools should be used to tease out differences between
individuals, such as gene expression profiling, using new tools such as
cDNA microarrays, combined with the use of magnetic resonance imaging to
study the disease process as it happens. The resulting knowledge should
enable the targeting of combination therapies in the foreseeable future.
"When you look at cancer treatments, this approach has been studied much
more," Martin continued. "I think auto-immune diseases will be considered
in the same way very soon."
Back in Britain, researchers are
refining the idea of using cannabis to treat multiple sclerosis — and coming
up with some intriguing new findings. David Baker and colleagues at the
Institute of Neurology, University College London, have found that the
body's endogenous cannabis-like substances such as anandamide — meaning
'inner bliss' in Sanskrit — can help to reduce muscle spasticity and tremor
when administered to mice with an MS-like condition called chronic relapsing
experimental allergic encephalomyelitis (CREAE). Unlike exogenous cannabinoids,
such as delta 9 tetra-hydrocannabinol (THC), these endocannabinoids do
not seem to produce psychological effects.
Equally interesting, Baker's group
find that they can reduce tremor and spasticity by using other compounds
to stop the normal breakdown and removal of anandamide and other endocannabinoids
in the areas where nerve tissues are being damaged. These compounds, synthetic
fatty acids, — such as AM404 — selectively block the reuptake of the endocannabinoids,
rather as Prozac and similar drugs block the reuptake of serotonin in the
brain. "We get the same results as with strong cannabinoid agonists, but
without the side effect profile," said Baker. He warns that the approach
is still experimental, but believes that pharmaceutical companies are likely
to be more interested in this approach than using cannabis itself, even
in the light of recent announcements of a relaxation in the law concerning
cannabis possession and use.
In 2000, Baker's group provided the
first solid evidence that cannabinoids can reduce muscle tremor and spasticity
in mice with CREAE. The findings strengthened the case for the current
trials of cannabis itself as an MS therapy.
Links for this article
Baker D, Pryce G, Croxford JL,et
al.: Endocannabinoids control spasticity and tremor in a multiple sclerosis
model. FASEB J 2001, 10.1096/fj.00-0399fje.
© 1999-2001 BioMed Central Ltd
Phyllida Brown
http://www.fasebj.org/cgi/content/abstract/00-0399fjev1