Hans:

Dr. Lieberman has been very candid.  Below is my point by point response to
his comments:

#1) > To document actual 100% to everyones satisfaction slowing of disease
> progression is at this time with the technology available lacking.
> Whether slowing of progression is slowing of motor progression or whether
> this will translate into slowing of progression of the dementia is NOT
> measured by this or any study.

I fully agree.  That is part of my point.

#2) > To show slowing of progression by UPDRS motor scores with a drug such
as
> mirapex or requip (or in the past eldepryl) which themselves improve the
> scores is not possible, even if you at one time stop all drugs and wait
one,
> two, or three months to the baseline state to appear.

This is true.  But the study compares two drugs - pramipexole to levodopa,
and suggests that pramipexole is better than levodopa.  If the clinical
correlation is lacking, for whatever technical and practical reasons, and we
do not know whether indeed the change in decay will ultimately translate
into a slowing down of some of the manifestations of the disease process,
then all that can be claimed is that the measured decay in radioisotope
uptake was different.  We can then express the HOPE that this reflects a
change in disease progression, which, by Dr. Lieberman's proposition #1
above has not been proved.

Is it possible that the same long term effects of the drugs which would
require a "one, two or three month withdrawal to reach baseline" are
artifactually causing the changes in decay?  That question is not addressed
by Dr. Lieberman or by the article.

#3) > This is why investigators have turned to imaging techniques spect and
pet.
> These measure a function of the remaining nigral neurons.
> Is this an exact function one to which everyone will agree? No.

We agree.  One concern is that we are not given information about the effect
of pramipexole (or levodopa) on the CIT uptake.  That is, if you measure CIT
uptake before and after pramipexole  - what is the effect of pramipexole (or
levodopa) before we even try to measure decay in uptake over time?  Perhaps
that would give a clue as to the cause of the discrepancy.

Is it possible that treatment induces uptake or binding sites which are
unrelated or  irrelevant to the progression of the disease?  Yes. How likely
is that?  Who knows?  These studies do not measure surviving cells like some
animal microscopic autoradiography studies do.  These are macroscopic
studies which measure the uptake of a radioisotope, which we assume is an
indirect measure of a surviving "function" of dopamine systems.

#4) > Is it more reasonable to use these techniques than UPDRS? Yes.

I disagree. It is not more reasonable.  It is different. Ultimately, a
technique is good in medical terms if it can be shown to have clinical
relevance.

Is it possible that measuring CIT uptake may become as useful as measuring
plaque burden in multiple sclerosis?  It's possible.  But first it has to be
validated.

It is also clear that in the initial design of the study, the experts chose
to measure the UPDRS as their clinical measure.  One trusts that they chose
what the whole consortium of investigators felt was the most likely to be
successful in supporting their hypothesis - but it did not.  Then we have to
back-pedal to understand what the cause for the discrepancy is.


> Is the lesser decrease on spect with mirapex, or pet with requip, a
measure
> of slowing of progression? Yes.

Why?  How do we know that?  That is assuming the result.  Indeed, this is
the crux of the matter.  That is the question that these studies were
designed to answer.  In the absence of clinical validation, there is room
for much skepticism.  Of interest is that in the PET study with Requip and
[18F]-DOPA uptake, they were also unable to show a clinical correlation.
Indeed, in the PET study with Requip, the patients on levodopa did better
clinically on the clinical scales than those on Requip.  If we try to rely
once more on the "residual" effects of drugs to explain this discrepancy,
then we are faced with the fact that the half life of levodopa is shorter
than that of pramipexole or ropinirole - this should, if anything, make the
clinical scales favor the agonists since the effects of levodopa should wear
off faster.  Yet, what is found is either no change, or clinical change in
favor of levodopa, despite the changes in radiolabelled marker uptake decay.

> Is it a sufficiently good measure to allow the companies to say so
according
> to fda standards? No.

I am glad.  The truth is that it shouldn't matter whether the FDA would
allow it.  The question is whether it is scientifically justified to claim
it.  We are in the era of "evidence based medicine."

> Can there be differences in interpretation of the data by neurologists and
> pd experts? Yes.

Of course.  That is what feeds the growth of ideas.

> Is the interpretation of the doctor, who said pd is not slowed, more valid
> than mine? Only time will tell.

Agreed.  My statement is that the data in the article do not support the
claim.  If we have to wait for time to tell, the claim should not be made.
We can express all the hope and optimism we can and want, and we should
clearly label it as such: hope.

I worry about endorsing such claims even with the label hope, particularly
when endorsing such claims will give a particular drug an unearned marketing
advantage over the others.

Jorge Romero, MD

----- Original Message -----
From: "Hans van der Genugten" <[log in to unmask]>
To: <[log in to unmask]>
Sent: Sunday, April 07, 2002 11:30 PM
Subject: Fw: Mirapex DOES OR DOES NOT Slow Progression of PD ??


> Hi Jorge and all,
>
> As promised, I sent Jorge's remarks regarding the JAMA article to Abe
> Lieberman, and asked Abe for his comments on Jorge's remarks.
>
> Hans.
>
> [My question]
> Dear Abe,
>
> As I understand it, in your view the JAMA article indicates that
pramipexole
> DOES slow down the progression of PD. I forwarded the version modified by
> you (placed on the NPF site in the news section) to another
PD-mailinglist.
>
> A doctor on that list responded by stating that "THEY DO NOT CLAIM THAT
> THEY FOUND THAT PRAMIPEXOLE SLOWS DOWN THE PROGRESSION
> OF THE DISEASE."
>
> Since these two opinions are contradictory, I'm forwarding his statements,
> and would like your respons to his remarks.
>
> Hans van der Genugten
> [log in to unmask]
>
> [Jorge's remarks]
> It is interesting how the lay press and media have taken the article and
> spun out that mirapex delays the progression of Parkinson's Disease.
>
> THAT IS NOT WHAT THE ARTICLE SAYS.  It is important to read the article
> carefully.
>
> 1) What these people measured was radioactive CIT uptake.  They also
> measure the progression of clinical disease by doing UPDRS scales scores.
>
> 2) Although the CIT uptake is ASSUMED to be a measure of disease
> progression, the investigators themselves stated "in prior longitudinal
> studies there has been NO CLEAR CORRELATION between change in
> [123I]betaCIT or [18F]DOPA uptake and the change in the UPDRS score.
>
> 3) Indeed this study also confirmed that LACK of correlation between the
> radioisotope uptake and the clinical measures of disease progression.
>
> 4) They showed slowing down of the decay in radioactive CIT uptake in
> patients treated with pramipexole,, but they were UNABLE to show that at
34
> or 46 months there was any difference in the clinical UPDRS scores in
favor
> of pramipexole.
>
> 5) They were very cagey in how they have fed the data to the press.  They
> indicate that they "correlated" their results with the UPDRS scale.  What
> they did not indicate is that when they "correlated" the CIT data with the
> UPDRS scale, they found NO CORRELATION.
>
> 6) Thus, the claim of slowing down the disease progression is specious.
>
> 7)  Does it surprise you that the research, the article and the publicity
> have been funded by Pharmacia and Boehringer Ingelheim who manufacture
> and distribute pramipexole?
>
> 8) There were many excellent contributors to the data - from major US and
> international centers.  Even in the summary of the data they were honest
in
> their conclusion:  These imaging data highlight the need to further
compare
> imaging and clinical endpoints of PD progression in long term studies."
>
> 9) THe article states the facts;  the media and press releases that have
> followed the article have distorted the findings beyond recognition.
>
> THEY DO NOT CLAIM THAT THEY FOUND THAT PRAMIPEXOLE SLOWS
> DOWN THE PROGRESSION OF THE DISEASE.
>
> [Comment from dr Lieberman]
> The comment from the doctor above is important and should be read
carefully.
> To document actual 100% to everyones satisfaction slowing of disease
> progression is at this time with the technology available lacking.
> Whether slowing of progression is slowing of motor progression or whether
> this will translate into slowing of progression of the dementia is NOT
> measured by this or any study.
> To show slowing of progression by UPDRS motor scores with a drug such as
> mirapex or requip (or in the past eldepryl) which themselves improve the
> scores is not possible, even if you at one time stop all drugs and wait
one,
> two, or three months to the baseline state to appear.
> This is why investigators have turned to imaging techniques spect and pet.
> These measure a function of the remaining nigral neurons.
> Is this an exact function one to which everyone will agree? No.
> Is it more reasonable to use these techniques than UPDRS? Yes.
> Is the lesser decrease on spect with mirapex, or pet with requip, a
measure
> of slowing of progression? Yes.
> Is it a sufficiently good measure to allow the companies to say so
according
> to fda standards? No.
> Can there be differences in interpretation of the data by neurologists and
> pd experts? Yes.
> Is the interpretation of the doctor, who said pd is not slowed, more valid
> than mine? Only time will tell.
> Abe Lieberman.

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