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Hi All,

Has it occurred to anyone else that there may be an important pattern in the
seemingly unbroken string of failures of very promising new PD therapies to
make it past stage 2 clinical trials? In the GDNF trials, in the recently
discontinued trials of Spheramine, in the Neuroimmunophilin Ligand trials a few
years back, in fact in the forty years since the development of the gold
standard of carbidopa/levodopa, there have been a remarkable number of trials
that appeared to have dramatic results on patients in early clinical stages but
subsequently failed to meet statistical endpoints in placebo-controlled
double-blind phase 2 trials. 

Could anyone who had seen PWP Peggy Willocks in 2000 before her Spheramine
surgery doubt in any way that her surgery had a dramatic and lasting positive
effect on her ability to function. Does anyone doubt that the film of some of
the GDNF clinical trial participants before and after receiving that biologic
showed clearly that some of them responded in a way that could not be
attributable to a placebo response? 

Could it possibly be that some patients are legitimately responding in a
dramatic fashion to these experimental therapies, while others are not,
regardless of the presence of placebo controls? Is it possible that the reason
for these apparently topsy-turvy, now-you-see-it-now-you-don't results are
themselves the result of clinical trials which are fundamentally flawed in
their design. That is, if "idiopathic Parkinson's disease" is in fact a bundle
of related diseases as has been increasingly discussed, and may well be a
disease, or diseases, which affects many more parts of the brain than had
traditionally been assumed, it may well be that it's not the data that is wrong
in recent clinical trials, it is the square peg of data which scientists are
trying to fit the into what they refuse to recognize as the round hole of
current clinical trial design.

A child can see that the symptoms from patient to patient very so dramatically
that one would intuitively assume that he or she was looking at different
diseases. How do we make the leap to the assumption that despite the evidence
of our eyes, we all have (with rare exceptions) "idiopathic Parkinson's
disease"? It is rather ironic that this so-called “designer disease” can only
be diagnosed through clinical observation. Clinical observation alone would
lead the average person to assume that more than one disease, or form of the
disease, is present in the population. But since the discovery that
carbidopa/levodopa dramatically ameliorates the symptoms of PD in almost all
patients regardless of their presenting symptoms, and because we can detect a
dramatic loss of dopaminergic cells in "PD" patients through brain scans and at
autopsy, we leap to the conclusion that we all suffer from the exact same
malady.

It seems to me that the existence of several variants on what we call one
disease would explain the varying results or effects on patients with regard to
new experimental therapies. We know so little about the disease in the larger
sense that we even call it "idiopathic," meaning of unknown origin. Remember,
only a few short years ago, even a movement disorder specialist would have told
you that Parkinson's, in an oft-repeated comparison, was the disease that left
your mind clear while trapping you in a body that would eventually lave you
completely immobilized, while Alzheimer's was the disease that destroyed your
mind while leaving your body intact. I don't think that any movement disorder
specialist worth his or her credentials would make that same statement today
about Parkinson's disease. We know that it affects frontal cortex to some
degree in almost every patient. And it appears to affect other areas of the
brain as well. Could it be that we have been so mesmerized for the last 190
years by the massive and dramatically observable destruction that Parkinson's
does to the portion of the brain devoted to movement that we failed to
recognize what in hindsight should have been obvious secondary symptoms of the
disease or a set of related diseases?

We all know that a new paradigm of Parkinson's disease is emerging that in some
ways is consistent with the view of Parkinson's I have described above. What we
will finally learn about Parkinson's and its causes, and the dramatic variance
of symptom constellations among individual patients, remains to be seen. But I
think that it's time to take a good hard look at clinical trials and their
results in light of this emerging new view of what we had assumed was a single
disease. If Parkinson's is indeed a cluster of related diseases it would make
sense that some therapeutic applications would work for all or nearly all of
the patient population, such as carbidopa/levodopa. It would also make sense
that certain dopamine agonists would work among a large portion of the
population, but leave a significant minority of patients unaffected or with a
negative response to the therapy.

Perhaps most importantly, it would explain why year after year, decade after
decade, we have been getting to large phase 2 trials and winding up with
statistical endpoints that may in fact be unachievable for most therapeutic
applications because only certain patients with certain variants of the disease
are going to respond. It may be that bad trial management in some cases
(disconnected catheters and poor infusion techniques in the GDNF trials) and
placebo effect itself are "noise" that interferes with a proper interpretation
of what these drugs are doing to patients. A proper interpretation of this
pattern of clinical trial failures may mean having to conclude that the trial
design itself is based on the false premise that we all have the same variant
of the same disease.

As PWP and Intel founder Andy Grove has asked, why aren't we learning from our
failures? Why do we keep coming at the same problem from the same position with
the same set of assumptions? Why don't we at least entertain the notion that
the way we test new therapies is inconsistent with the disease, or diseases,
that we are trying to cure. In fact, one would almost think that the refusal to
budge from the current thinking about Parkinson's clinical trials reflects some
of the cognitive damage that Parkinson's does in the tendency of patients to
exhibit a stubborn inability to move from one approach to another. All the
while, we may be throwing away the baby with the bathwater, as therapy after
therapy that may in fact address major problems for some of the patient
population, are deemed to be failures and tossed aside. If so, it is a mistake
of gigantic proportions, and one which has tremendous significance for us all.

I hope I haven't stated the obvious, or shown my ignorance of clinical trial
design and biomedical science, but when I advanced this idea at a PD meeting
two weeks ago, I looked across the room at a top British neuroscientist who
nodded his head "yes" the entire time I was speaking. Interestingly, however,
he remained silent.

Just thinking out loud,

Greg

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