early in my pd quest, i met a young woman from india doing post doc research in Cal....pd research! she used to grumble about having to make proteins. i was the first pd patient she had ever met. far as i know she's still in the lab! Ibby

No, not pathetic at all. It's called being responsible.

The Ceregene failure is just as huge a disappointment to the investigators as it is to patients. In October I was at a PD conference where one of the investigators confidently talked of Phase III trials beginning in January. There was no hint of a coming failure.

Why was he so wrong? My guess: because his trial patients were doing well; he could observe improvement. He assumed the trial data would prove his observations correct. But it didn't. Why not? My guess: because some of his patients improved in the control group on the placebo effect, and because the other group had too many people with different types of PD that it diluted the results - not enough of this group had the type of PD that responds well to Ceregene therapy.

So the baby is thrown out with the bath water. This is the part I don't get. Why aren't researchers focusing like a laser beam on those who improved to find out why? And following up just as intently with those who didn't?

Because that's not how medical research works in this country. But it is exactly what Andy Grove had been talking about; how to change the research model to one that is more like the one he used to revolutionize computing at Intel - look at the outliers; both the successes and the failures.

But Andy, although worth billions, is also "just a patient." Incredibly, he has had very little influence on the process. The medical establishment is just that dense.

That's where MJFF comes back into the picture. They are more forward thinking than most orgs. Andy Grove is giving them a bunch of money; he understands what they understand. But MJFF is still bound to the way things are done (as much as they'd like to change it). They must restrict patient input in the discussion on their website because the researchers demand it.

The researchers are wrong; they need to be interacting and talking to patients. That they think they can treat or cure PD without doing so is what is really pathetic. To have one more HUGE failed trial happen because they are not paying attention to how PD in its many forms is living in patients' bodies would be a travesty - cannot they learn anything about clinical trial design from their failures? How many expensive (in dollars and lives) failed trials will it take until they get it right? How long do we have to sit silent watching them screw up?

We owe it to ourselves and to the MJFF to be vocal about this; MJFF needs to hear from the patients that we are not stupid; we are fed up with the system and they need to do something about it. Instead they are coddling the researchers and letting them stay in their comfortably-funded cocoons at an arms length from pesky patients.

MJFF is a great organization trying its best to get things done in an unworkable system. We are not helping them by remaining silent or only giving them praise. Speaking out and seeking answers to our questions is responsible - NOT pathetic!

After reading 2 days of posting on the MJFF vs patient info skirmish. I now THINK I understand what seems to be the focus of the PD Project. Using extracted quotes it looks like we have about a dozen or more volunteers who can develop an information database of carefully screened patient info usable by those attempting to find a cure and/or develop new and/or improved treatments. Some work has already been submitted for beta testing but identification of more data element input is needed. A " global e=mail database" ????? is also mentioned.
May I respectfully suggest simply forwarding this thread to MJFF and see if it lights a lamp. If, not press on and "get er done"!!

IF YOU BUILD IT THEY WILL COME Bob C

I emailed the thread to Michael yesterday bandido, and I hope to see you at the next project meeting. I just used that quote somewhere too......."build it" et al, that is, not "get 'er done."

How much more can we think alike than to come up with the same idea? There is a way to include patients; and there are plenty of smarts to figure out a way to bring about a new paradigm that I think is achievable.

Linda H. post has one example.

Onward in peace; but don't hesitate to assert yourself when bullied by the "professionals" who are not skilled for the new era of online communication for medical research
paula

I borrowed this list from the Pipeline Project (I think Linda H. compiled it - thanks Linda) to show the sheer magnitude of the potential treatments that showed great initial promise only to be buried in what researchers call "The Valley of Death" between initial trials and FDA approval.

My own take on why this may be occurring follows below in a separate reply. I think CS and some others here have come to similar conclusions, but to the extent that it may offer some thoughts that haven't been introduced, I'll offer it up. Also courtesy of the Pipeline Project. with slight modifications to fit this discussion.

BTW, this list only covers the period 2004 to mid-year 2008. but I believe if you extended it back to every year since the introduction of Sinemet, the ratio of success to failure would be about the same or a little worse. My reasons for this conjecture, and why Sinemet has been both a blessing and a curse, are in the separate reply that follows.

Greg
______

Terminated PD Experimental Treatments 2004 - present

GDNF (Neurotrophic factor) – recombinant GDNf delivered by pump infusion method

Sponsor: Amgen, Inc.

Phase II trials terminated in September 2004.

Comments: Amgen announced in June 2004 that, “Six months of treatment with GDNF delivered to the putamen failed to improve UPDRS scores compared to placebo. There was “evidence of alteration of brain function,” a likely reference to changes on neuroimaging, but improvement on UPDRS scores did not meet the primary endpoint of the trial.
Initially, Amgen announced that all subjects were entered in an open label extension study to resolve differing trial results. But in Sept. 2004, Amgen sent letter to clinical investigators halting further clinical studies, due to safety concerns – development of lesions in the cerebellum of 4 test monkeys and "anti-r-metHuGDNF neutralizing antibodies found in two of the study participants to date.”

CEP-1347 (Kinases Inhibitor)

Sponsor: Cephalon, Inc.

Phase II / III Trial discontinued in May 2005

Comments: “The study was concluded early, after an average of 21.4 months of follow-up, when a planned interim analysis demonstrated that it would be futile to continue experimental treatment. In contrast to research in animal models that predicted favorable disease-modifying outcomes, we found CEP-1347 to be an ineffective treatment in early Parkinson disease. "

NS2330 (Monoamine Uptake Inhibitor)

Sponsor: Neurosearch, Inc.

Phase III canceled Jan. 2006

Comments: "Results from three comprehensive Phase II studies in Alzheimer’s and Parkinson’s diseases with tesofensine (NS2330) did not meet the criteria we had defined together with our partner Boehringer Ingelheim for starting up Phase III clinical studies. Boehringer Ingelheim terminated the tesofensine partnership in January 2006." Further development for PD has been halted.

GPI 1485 (Neuroimmunophilin Ligand))

Sponsor: Symphony Neuro Development Company

Phase III terminated in March 2006

Comments: In March 2006 citing a lack of evidence of clinical benefit, Symphony Neuro Development Company stopped further drug treatment in its open-label study of GPI 1485 in Parkinson’s disease patients who had previously participated in the completed 2 year double blind efficacy study .

Phase III was not initiated..

"While the treatment was well tolerated and posed no significant safety issues, the treatment group failed to show an improvement in the primary endpoint of the trial which was percent change of baseline of brain uptake of [123I}Beta-CIT as measured by SPECT Scanning, a measure of the brain dopamine system that degenerates in Parkinson’s disease.... In addition, none of the exploratory clinical endpoints showed clinically meaningful benefit after 24 months of therapy....”

E2007 (perampanel ) (AMPA receptor antagonist)

Sponsor: Eisai Inc.
Phase III trials terminated in Oct. 2007 and April 2008.

Comments: “In Oct. 2007, Eisai announced one of its Phase III studies (#301) "did not meet its primary endpoint comparing perampanel (E2007) to placebo as an add-on to levodopa therapy for 764 idiopathic Parkinson's disease patients over 30 weeks. The primary endpoint was reduction in "off" time - defined as the length of time that Parkinson's symptoms return as the effect of levodopa wears off. Perampanel was well tolerated with no significant safety issues... Two additional Phase III studies (#302 and #309) will proceed as planned."

“ In April 2008, following the completion of two Phase III Studies , Eisai decided to discontinue their PD research program for E2007. The sponsor reported the studies "did not show a significant difference in the primary endpoint of reduction of "off" time ...the third Parkinson's disease Phase III study and open label treatment extension studies" were also terminated. “

Sarizotan (EMD 128130) - (Dopamine Agonist)

Sponsor: Merck KGaA

Phase III terminated in June 2006.

Comments: “Double-blind Phase III studies did not confirm Phase II results or results from preclinical studies. In June 2006, "Merck KGaA decided, after analysis of data from Phase III clinical trials not to file for approval and not to pursue further development of the compound. Merck said a statistically significant difference between sarizotan and placebo could not be demonstrated in the late-stage clinical studies."

Vadova (IPX054) -Levodopa

Sponsor: IMPAX Laboratories, Inc.
Received “non-approvable letter from FDA in March 2006, and Jan. 2008. Sponsor terminated development in April 2008

Comments: The FDA issued IMPAX a "Non-approvable letter in March 2006, but Impax filed more papers to answer regulators' concerns. The FDA rejected the drug again in January 2008, saying this time the drug could be confused with other marketed versions of carbidopa/levodopa and could lead to medication errors."

Istradefylline (KW- 6002) - (Adenosine Receptor Antagonist)

Sponsor: Kyowa Pharmaceutical, Inc.

Phase III development suspended in North America in June 2008.

Comments: On June 3, 2008, Kyowa Pharmaceutical, suspended the development of istradfeylline in North America. A letter from the company President stated, "On February 25, 2008, Kyowa received a “Not Approvable” letter from the U.S. Food and Drug Administration (FDA) for istradefylline and subsequently had discussions with the FDA about options for further development. After reviewing these options, Kyowa has decided to suspend development of istradefylline in North America at this time. This decision was not related to any safety issues concerning istradefylline." "According to Dr. Mark Stacy, the trial may not have been optimally designed to reflect istradefylline's true efficacy. While at first glance the 12% to 14% reduction in "off" time from baseline appears "disappointing," Dr. Stacy said it must be kept in mind that the vast majority of these patients had advanced motor scores and were being treated with 2 or more drugs. In addition, although the trial's enrollment criteria required that patients have a minimum of 2 hours of "off" time per day, Dr. Stacy said once the data were analyzed, the researchers found that the average amount of "off" time in study subjects was 6 hours every day….Furthermore, he said, the measurement tool used to determine "off" and "on" time was likely not sensitive enough. "If we'd used a more precise tool we'd probably have bubbled up better data," he said.

Source: Medscape News, June 5, 2008

___________________________________

PD Drugs approved by FDA 2004 - present


Azilect (Rasagiline) (MAO –B inhibitor) - approved for early PD.

Neupro Rotigiotine transdermal system (patch) – reformulation of dopamine agonist. All patches recalled indefinitely in North America due to manufacturing problem.

Parcopa – reformulation - orally disintegrating carbidopa/levodopap tablets

Requip XL (once-a-day) – Reformulation of dopamine agonist

Zelapar – dissolving tabs – reformulation of seligiline

Source: Parkinson Pipeline Project, Treatments in Development database

________________________________________

Copyright © 2004-2006 Parkinson Pipeline Project.
All rights reserved. Revised: 07/27/08.

Unfortunately the list of "failed"/terminated treatments is even longer. We will be updating the list to add Spheramine (Bayer/ Titan) and now CERE-120 (Ceregene).
Linda

There may be an important pattern in the seemingly uninterrupted failure of drugs and biologics showing great promise for Parkinson's disease in early clinical trials to make it to the finish line. In the GDNF trials, in the trials recently discontinued with Spheramine, and now Ceregene, on which even "seen it all" clinical researchers would have bet the farm on it's success. 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 which failed to meet statistical endpoints in placebo-controlled double-blind phase II or III trials.

Could anyone who had seen Spheramine trial participant Peggy Willocks in 2000 before her surgery doubt in any way that her procedure 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 which could not be attributable to a placebo response?

It seems 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, it may be that it's not the data that is wrong in recent clinical trials; it is that scientists keep trying to fit the square peg of data from Parkinson's trials into a round hole of inappropriate clinical trial design.

A child can see that the symptoms from patient to patient vary so dramatically that one would intuitively assume that we are looking at different diseases. How do we make the leap to the assumption that despite the evidence of our eyes, we all have (with some 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 because the discovery that carbidopa/levodopa dramatically ameliorated 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, the medical community came to the (I think erroneous) conclusion that we all suffer from the same exact 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 the often repeated comparison, was the disease that left your mind clear while trapping you in a body that was eventually 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 the frontal cortex to some degree in almost all patients. And it appears to affect other areas of the brain as well. Could it be that we have been so mesmerized for the last 200 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 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 outlined 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 among all or nearly all of the patient population, such as in most, but not all cases, 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.

A "multiple diseases" or "variants on a single disease" model would also explain why Phase I trials often show stunning results while later larger trials "fail." That is, assume for a moment that there are 5 varieties of "PD." In a small open-label Phase I trial with 7 participants, the odds of getting all seven, or six of seven, patients with the same form of the disease are low but will occur now and again. But when you expand the number of participants to 100 or 500 in a Phase II or Phase III trial, the odds against all or most patients having the same variant in the same cohort increases exponentially. The result will almost always be a failure to meet endpoints designed for a single disease with no variants.

Andy Grove asked during his speech at the Society for Neuroscience in 2007, 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(s), 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 thrown away. If so, it is a mistake of gigantic significance for us all.

One anecdote to wrap this up and also connect it to the "patient participation" theme of this thread. When I advanced this idea at a PD meeting last summer, I looked across at an English neuroscientist who was nodding his head "yes" the entire time I was speaking. Interestingly, however, he remained silent. Unless it was just a Parkinson's "head bob" (that would be a delicious irony), he was reluctant to state his agreement in a conference room filled with his peers. He was not going to swim against the current of models for PD held dear by the eminent neuroscientists sitting around the table. He would not join the token patient who had said "hey look, perhaps you folks who have spent your entire professional lives living under one model of PD and clinical trials designed around that model, have got it wrong." That was a risk only the patient, with no reputation to protect and no money to lose, would take that day. And that is as good a reason as any to include patients, with voices, at the table.

Maybe we found a needle in the haystack - Sinemet - too early. Maybe it's almost universal success among PD patients has blinded the neuroscience community to the real, multi-headed beast we may be dealing with. Blinded by science, indeed.

It's time for them to take their blindfolds off. They are for the most part trying to get it right. I think they just need some help from us to see what is right in front of them. They may be astonished to see a whole new world where they can forge a track record of success rather than failure. Wouldn't that be something?

Greg Wasson

Parkinson’s Action Network (PAN) Senior Advisor – Legislation
Parkinson Pipeline Project
World Parkinson Congress 2010 Patients Advisory Committee

Diagnosed in 1995

Another disappointment was the antioxidant MitoQ . It was expected to be much more effective than CoQ10 because it targets the mitochondria, specifically. The phase two trial showed no benefit at all.

Prior to phase 2, they published this:

"If it works, what will MitoQ do?

It is anticipated that MitoQ will slow or arrest the progression of Parkinson's disease symptoms."

If it works...It didn't.

"A 12-month study in patients in Parkinson's disease showed mitoQ to be well tolerated; however, there was no significant effect on disease progression. Dr. Barry Snow, Department of Neurology, Auckland Hospital, New Zealand and Principal Investigator of the trial of mitoQ in Parkinson's disease, believes that the lack of efficacy in Parkinson's Disease may have been due to the large number of impaired cells in that disease; these cells may have had limited or no ability to regenerate, and thus could not benefit from mitoQ's antioxidant properties. The Company believes mitoQ has therapeutic potential in diseases where cell regeneration occurs, such as hepatological and dermatological disorders."

http://www.bio-medicine.org/medicine...8R-29-17636-2/

##############################

The trial included "120 participants with untreated early onset of PD."

Did it matter to the researchers what kind of symptoms the patients had? Tremor dominant? Akinetic rigid dominant? Did it only matter to them that the participants had had no treatment and were at the beginning of their disease?

So, the company is now focused on other conditions that may benefit from MitoQ. They have given up on PD. Nevermind that a subset of PD patients might benefit if given the opportunity.

We need larger trials with patients identified as having specific symptoms or genetic mutations, etc.

For example, were there any patients in that trial with LRRK2 mutations? Do the researchers even KNOW?

{Greg, I didn't read your eloquent discussion til after I posted this. There are more and more scientists talking about PD as a constellation of disorders. The discovery of the LRRK2 mutations also has affected their thinking about the origins of the disease. Clearly there are many causes of PD, early and late, sporadic or not. It just makes sense that many causes result in many disorders, with some common denominaters.}

http://clinicaltrials.gov/ct2/show/N...A%3ANZ&rank=23

Why PWP should be included in the research process? one example ... the old-timers will remember this one....

In 2003 the first-ever online survey of PWP - "Impact of Parkinson's Disease on the Quality of Life," was conducted by Harris Interactive and was supported by Amarin Pharmaceuticals and sponsored by WE MOVE (Worldwide Education and Awareness for Movement Disorders). PLWP (People Living With Parkinson's), an online grassroots patients' group was instrumental publicizing the survey and in obtaining responses.The results were discussed in the opening session of the American Neurological Association's 2003 annual meeting. The findings greatly "surprised "the neurological establishment.

The "surprise" was that the survey revealed "the non-motor symptoms that Parkinson's disease patients experience, such as loss of energy and pain, appear to have a greater impact on their quality of life than the motor symptoms typically associated with the disease, such as
tremor. This surprising finding of a new Harris Interactive(R) study may alter the way physicians assess and treat their patients, according to top Parkinson's disease researchers."

Although the results of the survey might have been a surprise to the scientists, many PWP responded to it with the equivalent of "DUH!" or "If you had just asked us we could have told you about non-motor symptons a long time ago."

These are excerpts from a discussion of the survery at the 2003 ANA meeting

See https://listserv.utoronto.ca/cgi-bin...sn&D=1&F=P&P=1 670

for the full text of "Panel Discussion of Harris Interactive Patient-Based Study Focuses on New Data to Help Physicians Understand Their Patients' Need to Improve Quality of Life" (it was posted on the Parkinsn listserv by our pal Murray Charters who surely has been looking down on us and intently watchinig the new possibilities of scientific networking on the Internet ...)

"According to the study findings, top reported unmet needs of PD patients include the disabling symptoms and emotional stress that accompany their "off" time... Fifty-three percent of patients report that they are dissatisfied with the amount of "off" time theyexperience. Although they are not the most frequently occurring symptoms during "off" time, loss of energy, walking
problems and pain are reported as the most disabling symptoms PD patients' experiences.

According to the survey, these symptoms force patients to make many accommodations to their daily lives, which in turn, have a significant impact on their quality of life. PD patients report that their ability to walk, drive, work, read and talk is impaired during "off" time. These problems appear to be amplified in PD patients who are also depressed, a
condition that more than one-third of survey respondents reported experiencing. In addition, the unpredictability of "off" time exacts an emotional cost on PD patients, leaving them depressed, feeling hopeless and embarrassed."

The Complexity of Medication Dosing

"On average, Parkinson's patients who participated in the survey take 19 pills per day, with some taking as many as 100 pills per day. In addition, more than half (59 percent) of patients reported swallowing difficulties.

"Many of my Parkinson's patients express a high level of discontent with not only multiple doses of medications but the feeling that many of their most troubling symptoms are not being addressed," stated Dr. Koller. "The way neurologists treat Parkinson's disease and the future development of innovative therapies will now need to address both motor and
non-motor symptoms."

Hopes for New Treatments

"When asked to reveal their preferences for new Parkinson's treatments, survey respondents highlighted the desire for fewer side effects, a more predictable response and improvement in daily "off" time, characteristics considered three to four times more important than the other seven options provided in the survey.

(Judith) "Blazer, representing the patient information and advocacy group WE MOVE, explained, "Historically, Parkinson's patients were treated according to the identifiable physical limitations associated with the disease. As the Harris Interactive study points out, the importance of the non-motor symptoms experienced during 'off' time has often been overlooked in treating Parkinson's patients."

"The data from this study will be instrumental in assisting physicians in providing care for their Parkinson's patients. We are pleased to be able to support this important study," said Michael Coffee, President and COO, Amarin Pharmaceuticals.


"This is a key finding," said panelist Matthew B. Stern, MD, Parker Family Professor of Neurology and Director,Parkinson's Disease and Movement Disorders Center, University of Pennsylvania Health System. "Parkinson's is a complex
disease that has identifiable motor and non-motor symptoms. Non-motor symptoms can include pain, loss of energy, sleep disturbances and anxiety. Although these symptoms may not be immediately apparent to the physician, they are highly significant to the patient's quality of life -- a cue to physicians to take a more global view of the disease and how it is treated."

AS a result of this survey and bettter understanding of PD as actually lived with by PWP, there has been more research into understanding and treating non-motor symptoms of PD.

But PD patients still don't have a place at the table when research and clinical trials are being planned , developed and analyzed.

linda

www.pdpipeline.org

Excellent comments and very articulate, thank you. I would like to point out, though, that I really don't think sinemet "works" for all PDers. Our experience with it is that it takes a LONG time to kick in, doesn't last very long, doesn't really relieve all PD symptoms (including tremor which bothers my husband to no end), and at some point we will be facing dyskenisias, so how is that the "gold standard"? It's just the best they have come up with so far, to treat a multi-systemic condition they have no clue what causes.

Cynical? And getting more so everyday, as I am now reading "Our Daily Meds" which is a riveting book on how the pharmacuetical companies literally create a disease out of thin air and then market the heck out of a new drug developed to treat it (usually a pill a day for life, and the younger you start taking them the better, what an annuity for Big Pharma!!). It includes details on how drugs actually get approved, which I also found incredible. When you have at least two pharma reps forr every senator/congressman in DC, that is a hell of a problem, but that's for another discussion.

Thanks for your comments here, you are right on.