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From: TSS ()
Subject: Findings of MRC monitoring study of Pentosan Polysulphate treatment in CJD patients does not stop the progression of vCJD and other prion diseases
Date: July 12, 2006 at 10:29 am PST

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TSS
Findings of MRC monitoring study of PPS (does not stop vCJD)
Wed Jul 12, 2006 12:18
68.238.98.70

12 Jul: Pentosan Polysulphate & CJD

Findings of MRC monitoring study of Pentosan Polysulphate treatment in CJD patients
A Medical Research Council monitoring study of a small number of UK patients has found that a compound called Pentosan Polysulphate (PPS) does not stop the progression of vCJD and other prion diseases but the report recommends more research. The study provides qualified reassurance on some of the safety concerns that have been raised previously. The observational study of seven patients was carried out by Professor Ian Bone from Glasgow, Intraventricular Pentosan Polysulphate in Human Prion Diseases: A study of Experience in the United Kingdom, is a summary of the responses that people with prion diseases have shown to PPS.

The chemical nature of PPS means that it is unable to enter the brain if administered orally or intravenously. For the purposes of this treatment, therefore, it has been administered directly into the ventricles of each patient’s brain - a route known as intraventricular delivery. Fluid circulating around the brain from the ventricles potentially provides a route to spread PPS around the brain tissue.

Professor Bone carried out the study based on analysis of seven patients’ treatment and he stresses that the findings should not be taken as conclusive, because the report was based on a very small number of patients, treated in different ways, and because like-with-like comparisons with untreated patients were not possible. However any severe side-effects or clear benefit of PPS treatment in halting progression could have been revealed by this study. The findings are being made available now, to inform the debate over this treatment.

The MRC’s New Therapies Scrutiny Group endorsed the recommendations of Professor Bone’s report:

Further experimental work in animals will provide the most immediate source of evidence of whether or not PPS is likely to extend survival. We need better information on the extent to which PPS penetrates and spreads through the infected brain. The Medical Research Council will take this forward.
Further clinical research could be undertaken. Ideally, a formal prospective longitudinal standardised follow-up study would be required but this must be dependent on the results of the experimental animal work being encouraging. In the meantime, newly diagnosed patients should be informed verbally and in writing about current knowledge of PPS, including the risks associated with intraventricular catheterisation, when treatment options are discussed. The Medical Research Council will take forward this recommendation with the Department of Health.
Informed people opting for intraventricular PPS should undergo the procedure to fit the catheter and pump at a neurosurgical centre with appropriate experience of such surgery. However, dose initiation and escalation could be managed locally. People treated in this manner should be followed up through an approved protocol of clinical assessments and investigations.
Current patients on PPS should continue to be monitored as part of a supportive, structured review, and should be given up to date information and advice.
Professor Bone said: “Pentosan Polysulphate itself does not seem to carry a high probability of side effects from prolonged usage. However, the surgical complications of intraventricular catheter and pump placement were significant. The drug does not appear to halt the progression of the disease. Loss of brain function continues after treatment has started and, where measured by imaging, loss of brain tissue also continued. This is the first time that this mode of drug delivery has been carried out over such a prolonged period of time. The study shows that intraventricular delivery might provide a long-term alternative route for other future therapies that cannot enter the nervous system by oral or intravenous routes in situations where the surgical risks are justified.”

He went on: “The patients treated with PPS appear to have survived for unusually long periods. However, we cannot conclude with certainty that the treatment has a beneficial effect, because it was impossible to make direct comparison with similar but untreated patients. Moreover, with such small numbers the results might be a matter of chance. The report recommends specific laboratory experiments to address the uncertainties.”

Professor Ian Bone said “I am very grateful to the families and patients who participated in the study, and I hope that my report will help people who have to take difficult decisions about treatment in future. A report like this cannot always offer definite answers, and we urgently need further rigorous research to give scientists, doctors, patients and their families more information on which to base future treatment decisions.”

The co-chair of the committee, Professor Sir Michael Rawlins welcomed the study: “Professor Bone’s observations have helped cast light on a little known and difficult-to-research area. He has shown that Pentosan Polysulphate itself does not appear toxic at the modest doses given and leaves open the intriguing possibility that it may have some effect on the duration of survival. Sadly it seems that a loss of brain function continues in patients being treated with PPS. Professor Bone has also confirmed what we knew at the outset – that the surgical procedure needed to administer PPS carries a degree of risk, though is generally considered to be acceptable given the advanced stage of the disease in these patients. The recommendation that surgery be carried out in an experienced centre, and to an approved protocol, should help reduce complications associated with the surgery.”

Lester Firkins, the other co-chair, added: “This is a very important report which will inform current and future patients and their families – and also our collective knowledge of this tragic disease. I am very pleased that the MRC New Therapies Scrutiny Group agreed to advise MRC to carry out further research as a matter of urgency to fill in the gaps in the knowledge on PPS. Additionally, it should now be possible to help new patients and their families with better information on the risks of PPS by the publication of a balanced information leaflet. We are all indebted to the current patients and their families for participating in this study – and of course they must continue to benefit from appropriate monitoring and support.”

If you would like to arrange an interview please contact the MRC press office on 020 7637 6011 press.office@headoffice.mrc.ac.uk

Notes for editors:

MRC New Therapies Scrutiny Group for Prion Disease

The MRC New Therapies Scrutiny Group for Prion Disease (NTSG) was established in 2005 at the request of the Chief Medical Officer (CMO), to provide an independent source of advice on research into the development of potential therapeutics or preventative agents for prion disease. NTSG will build upon the previous work of the Department of Health CJD Therapy Advisory Group (TAG).

NTSG reports to the Medical Research Council (and other bodies when appropriate). The Group will advise MRC on the development of new therapeutic agents that could possibly be brought to bear upon this disease and will also maintain an overview of other relevant research.

The Medical Research Council

The Medical Research Council (MRC) is funded by the UK tax-payer. It aims to improve human health. The research it supports and the scientists it trains meet the needs of the health services, the pharmaceutical and other health-related industries and universities. The MRC has funded work which has led to some of the most significant discoveries and achievements in medicine in the UK.

©2006 Medical Research Council

http://www.mrc.ac.uk/index/public-interest/public-news_centre/public-press_office/public-press_2006/public-press_12_july_2006.htm

TSS

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APPROACHES TO THERAPY OF PRION DISEASES

CharlesWeissmann1 and Adriano Aguzzi2

1Department of Neurodegenerative Disease/MRC Prion Unit, Institute of
Neurology,

Queen Square, London WC1N 3BG, United Kingdom;

email: charles.weissmann@prion.ucl.ac.uk

2Institute of Neuropathology, University Hospital, CH-8091 Z¨urich,
Switzerland;

email: adriano@pathol.unizh.ch

Key Words transmissible spongiform encephalopathies, Creutzfeldt-Jakob

disease, bovine spongiform encephalopathy, proteinopathy, neuroblastoma
cells

■ Abstract Devising approaches to the therapy of transmissible spongiform
encephalopathies,

or prion diseases, is beset by many difficulties. For one, the nature of

the infectious agent, the prion, is understood only in outline, and its
composition, structure,

and mode of replication are still shrouded in mystery. In addition, the
mechanism

of pathogenesis is not well understood. Because clinical disease affects
mainly the

brain parenchyme, therapeutic agents must be able to traverse the
brain-blood barrier

(BBB) or have to be introduced directly into the cerebrospinal fluid or
brain tissue.

And finally, because the disease is usually recognized only after onset of
severe clinical

symptoms, the question arises as to whether the neurodegenerative processes
can be

reversed to any extent after a successful eradication of the agent.

THE DISEASE

snip...

PRION DISEASE THERAPY 335

ATTEMPTS AT HUMAN THERAPY

The earliest attempts to treat human prion disease, performed when the agent
was

generally assumed to be a virus, were carried out with antiviral drugs, such
as

amantadine, and were unsuccessful (137).

Quinacrine

Quinacrine, chlorpromazine, and some tricyclic derivatives with an aliphatic
side

chain were described as efficient inhibitors of PrPSc formation in murine
neuroblastoma

cells chronically infected with the Chandler scrapie isolate (138, 139).

Because quinacrine and chlorpromazine have been used in human medicine as
antimalarial

and antipsychotic drugs, respectively, and because they cross the BBB,

they were proposed as therapeutic agents for CJD patients (139). No
therapeutic

effectwas seen following quinacrine treatment of 20 patients (140) (A.
Alperovich,

quoted in Reference 141), although some transient improvement occasionally
occurred

(142). Subsequent animal experiments failed to demonstrate efficacy in the

treatment of TSEs (141), even after intraventricular infusion (135).

Amphothericin B

Amphothericin B and some of its analogues delayed the appearance of
spongiosis,

astrogliosis, and PrPSc accumulation in the brain of scrapie-infected
hamsters

(125). However, an attempt to treat a CJD patient with amphothericin B was
unsuccessful

(143). In view of its high systemic toxicity, these results dampen any

hopes that amphothericin B will prove useful in prion disease therapy.

Pentosan Polysulfate

Data presented at two prion meetings in 2002, and published recently (135),
suggest

that intraventricular administration of PPS to intracerebrally
prion-infected mice

prolonged incubation time. PPS is marketed in some countries as a treatment

for interstitial cystitis and as an anticoagulant, although its side effects
include

hemorrhage and hypersensitivity reactions.

ETHICAL CONSIDERATIONS

Recently a legal case was brought by two families whose children JS and PA,

aged 18 and 16 respectively, suffered from vCJD [DS v JS and an NHS Trust

and The Secretary of State for Health, intervenor; PA v JA and an NHS Trust
and

The Secretary of State for Health (2002) EWHC 2734 (Fam)]. They applied to

the court to permit intraventricular administration of PPS, a treatment
previously

given only to rodents and dogs. The judge heard testimony from Doh-Ura, the

Japanese researcher who had performed the animal studies; from a
neurosurgeon

336 WEISSMANN
AGUZZI

willing to administer the novel treatment; and from several respected
neurologists

who expressed reservations about it. The judge found that both young
patients had

“some enjoyment from life which is worth preserving” and that the treatment,
as

it was supported by medical opinion, would be in their “best interest” (the
legal

criterion for doctors to treat patients who lack capacity for personal
decisions)

(144). Treatment has been initiated, but no reports on the fate of the
patients have

been issued.

Physicians can thus come under pressure from the courts to
allownewtreatments

to be used without having been tested in clinical trials, although the
ruling described

above implies that such decisions would have to withstand the “Bolam” test
of

being acceptable to a reasonable body of medical opinion. The ruling also
upheld

the application of the Human Rights Act in this area, citing Articles 2 and
8, the

rights to life and to respect for family life. It is not inconceivable that
such analysis

could allow patients to circumvent clinical trials by asserting their rights
to receive

innovative therapy, and this development is of concern, particularly in the
clinical

field of human prion diseases.

We may at some stage be confronted with a therapy that can eradicate prion

infection without reversing the neural damage, which in extreme cases could
condemn

patients to years or decades of severe disability and dementia. This would

lead to an ethical dilemma as to whether treatment should be withheld if the
disease

has progressed to a severe stage. Such situations could be prevented if a
diagnostic

test could detect prion disease in its preclinical stage. Whether such a
test, if it

ever became available, would be applied to detect a disease with an
incidence of

1 in a million per year is a matter of debate; clearly it would be
practicable in the

case of familial prion diseases.

The Annual Review of Medicine is online at http://med.annualreviews.org

LITERATURE CITED...snip...end...tss

Benefits

It is possible that this treatment will slow (or even halt) progression of
disease but there is no guarantee and no present means of objectively
quantifying the degree of possibility. Any such effect, IF it were to occur
would probably be temporary. It is not possible to give any indication of
any time limit on such an effect. The possibility that any such effect could
continue throughout the duration of treatment cannot be absolutely excluded
but it seems unlikely. Clearly, the later in the disease process that such a
treatment were to be undertaken, the less likely any benefit would be seen.
Also, in late stages of disease, slowing of progression might be difficult
to objectively assess. There are, currently, no validated laboratory or
imaging assessments that could be used to give unequivocal evidence of
efficacy; one would have to rely on more subjective assessments including
everyday functional ability and serial neurological impairment examinations,
perhaps with the adjunct of neuropsychological assessments. However,
research is being undertaken to see if certain tests could be useful in
monitoring disease progression.

On the basis of current understanding, there is no realistic possibility of
actual improvement in the sense of reversal of previously established
neurological deficit. Again, this cannot be absolutely excluded but it seems
highly improbable, especially in relatively late stages of disease.

To date, at least several human individuals with prion disease have been
treated with intraventricular PPS. There are also families who have
considered the treatment and decided that they do not wish for it. There are
no hard data currently in the public domain. However, one individual (with
vCJD) is said to have not shown any clear evidence of deterioration over a
period of at least 23 months (as at February 2005). The person concerned was
at a late stage of illness at the time of treatment, with very significant
neurological impairment and it could be difficult to assess any signs of
deterioration or minor improvement in this sort of situation. This period of
apparent clinical stability could be taken as evidence that this treatment
has indeed had a beneficial effect in this one individual. However, some
individuals with prion diseases go through 'plateau' periods and, to some
extent, survival in the later stages of illness depends on the level and
quality of general nursing care provided . The present duration of apparent
clinical stability must at least suggest the possibility of some treatment
efficacy. In addition, there have been suggestions of minor clinical
improvements. However, at present, it cannot be stated that this one treated
individual provides definite evidence of efficacy of intraventricular PPS.
No information is currently available on the other treated individuals.

The best possible outcome from intraventricular PPS

On the basis of the available evidence, the best possible outcome that could
be expected after treatment with intraventricular PPS is that there may be
some temporary slowing or halting of the disease progression. However, there
is little likelihood of significant clinical improvement. Nor is there a
likelihood of permanent halting of disease progression. Of course, to some
extent, this might depend on the duration of intraventricular PPS
administration. It is not clear on what basis one would decide on the
duration of treatment.

Naturally, a treatment which stabilises an individual's condition could
conceivably lead to an individual being in a state of potential suffering
for a longer period of time. It might be proposed that any slowing of
progression or halting of progression might allow an individual to survive
longer and therefore receive future more beneficial treatment if it were to
become available. However, this would be a speculative view and, while
treatments for CJD are being researched, there is no realistic expectation
of a complete cure in the immediate future.

Additional Comments

Any conclusion concerning these above considerations, in the context of an
individual person, would necessarily involve a number of very difficult or
personal judgements about quality of life and the degree of suffering
experienced by an individual in a disease like CJD. Any such judgements are
bound to be subjective and reflect both general belief systems and personal
evaluations of the individual patient. There are clearly important issues of
consent and also issues as to the full understanding of those involved as to
the potential benefits and risks. Clearly, there are few hard data on which
to make clear decisions. At this point, the human treatment data do not
allow for any specific comments which can be made concerning problems or
benefits, aside from the facts that there are no reported major serious
complications and that there has been no obvious clinical deterioration over
some months of treatment in at least one case.

Any decision about a given patient would have to be taken in an entirely
individual way, based on a detailed assessment of both the patient and the
concerned relatives. The overriding principle should be: What is in the best
interests of the individual patient? bearing in mind that CJD is inevitably
and invariably a progressive and fatal disease.

There is, of course, an argument that such treatment should be evaluated in
the context of a properly organised clinical trial. There are no current
plans to set up such a trial and, in relation to this specific issue, the
comments of two relevant professional bodies (given in the section below)
should be noted.

Advice from relevant professional bodies

The Department of Health have statements on intraventricular PPS on their
website:

www.doh.gov.uk/cjd/pentosan_revised.htm

This includes statements of advice from the CJD Therapy Advisory Group and
the CSM.

The advice from the CJD Therapy Advisory Group can be summarised as follows:

There are insufficient clinical data to support the claim that PPS is
effective during clinical disease.

There are insufficient safety data on which to base a rational treatment
regimen in humans.

Further animal model experimental work is warranted.

Nevertheless, at the dosage used in at least one individual, there have been
no definite harmful effects attributable to the drug.

All patients with prion disease should undergo appropriate monitoring during
disease progression, in a way that allows collection of data on the natural
history of disease and on any treatments that might be given.

The advice from the CSM is similar and states further that:

"there is no evidence in support of its use as a treatment in late stage
disease".

"In the light of the limited information on PPS treatment of clinically
established vCJD it is impossible to assess the risk/benefit relationship of
PPS in these indications".

There was insufficient information to reach any conclusions about the
efficacy of treatment in [the single case known about at the time of the
statement].

They also recommended that further study of PPS should be undertaken in a
clinical trial setting.

Neither of these statements preclude the possibility of an individual
clinician deciding to treat an individual patient; such decisions remain
absolutely individual ones. However, clinicians would wish to consider any
such decisions in the light of all the available information and advice.

The case of the first individual who received this treatment was referred to
the High Court and there was a ruling in favour of this particular
individual being allowed to receive such treatment, as being in that
individual's overall best interests. However, this was an individual ruling
relating to a particular individual. It is understood that other cases have
been referred to court, but again on an individual basis.

There are important issues of consent regarding such 'experimental'
treatment, both with regard to the age of some affected individuals and also
with regard to competence (where disease affects the brain).

The Department of Health has sought to identify certain selected hospitals
where IVPPS treatment might be instituted, if there is a strong desire for
it by a family and agreement by their relevant clinician, so as to
centralise any experience with this treatment. Such centres will develop
protocols for the referral of patients and the process of arranging such
treatment (including the various potential legal issues, such as consent)
should thereby become simpler. However, there are no current plans to
establish a formal scientific trial of intraventricular PPS and the
treatment is one that is being given essentially on a speculative basis. The
present provision of IVPPS remains an individual decision between patient,
family and their immediately responsible clinician, after full understanding
and discussion of the facts as detailed above.

FLUPIRTINE
A study published in 2004 (Otto et al.) reported some beneficial effects on
cognitive function in patients with CJD but there is no evidence for
increased survival with the treatment.

Reference

Otto M et al. Efficacy of flupirtine on cognitive function in patients with
CJD: a double-blind study. Neurology 2004; 62: 714-718.

MRC PRION1
As indicated above, the MRC has funded a formal treatment trial of CJD. The
trial commenced in 2004. It is, initially, aiming to study Quinacrine.
However, it may study other possible treatments in the future. It will also
be reviewing and assessing individuals without treatment to obtain
comparative data of the natural course of illness.

http://www.cjd.ed.ac.uk/TREAT.htm

TSS

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