http://neurology.thelancet.com

Pardon my language, but screw neuroprotecton. I want neurogenesis!

Like I always say, I'm an instant fan of whatever works......but the thing is, there are people whose lives were ruined over this halt, and we are their hope. Hey, this stuff does grow new cells, if that is what you mean....as demonstrated by autopsy. And so I continue on.....

Happy Thanksgiving.
Paula

It seems the "big pharma" is at the point where they will only give us a hope
of a cure at intervals of 5 years at a time,
big pharma, has no integrity...it is looking for gold,
and
if we are made well
-their well goes dry.
I am praying about this present apathy.
but I am Thankful we do have a cure, although we need to see the evidence
of that cure ASAP.

hi all,

i have been too wrapped up in my research on levodopa... and also seem to have been circulating in a world where people either really don't believe big pharma is capable of being naughty in a large scale, intentional sort of way (i.e., putting the bottom line before all else, including ethics, decency, and all that is right) or people who just pretend to believe same because it is in their best interest (obviously, they don't have pd) to cozy up to industry....

anyway, my point is that i have completely missed the pd perspective, i mean the down and dirty, gritty, in the trenches, have-asked-all-the-questions-it-has been-possible-to-ask-of-all-the-players-that-would-talk-to-you perspective on what really happened with gdnf.

i get the impression that it might come to rest on the idea that the kibosh (sp?) could have been put on gdnf because it actually worked - is that right? i am sure that this whole ordeal is as complex as the day is long, but if someone could give me a summary of what has gone on since the trial stopped - i am particularly interested in any conversations with amgen, researchers and any other organizations or entities that may have been involved - that would be great - or just refer me somewhere if any of it is posted anywhere, maybe?

thanks,
Boann

http://www.pdpipeline.org/yy_gdnf/gdnf_overview.htm

I am out for the day but that and links from it should get you going quite aways. I'll be in touch.

Paula

As Paula wrote, there is a lot of information on GDNF trial halt on the Parkinson Pipeline Project site. I'm copying the most recent summary here. The PPP has been following the progress of GDNF for a number of years, even before the treatment halt by Amgen. We do not believe the disclosed data supports their decision. We do believe there is a need for the Parkinson's scientific and patient advocacy community to review all new information and come to a scientific consensus on continuing research on GDNF delivery by infusion. A summit meeting on this was last held in 2004 by the Michael J Fox Foundation. We believe it is time fvor another such meetign, but one that includes patients this time.

The phase I and phase II GDNF trials did not study neuroprotection. They were designed to study efficacy of treatment for symptoms and safety. However long-term data from the phase I trials in Kentucky and the UK suggestd that GDNF also provides neuroprotection and neurorestoration (see below) We believe further study is needed.

Updated Summary of GDNF Research (August 2006)
from Parkinson Pipeline Project

Since the announcement of the GDNF Phase II six-month trial results and the subsequent halt by Amgen of the trial and of treatments to all trial participants, three issues have been raised.
1. The study failed to meet its clinical endpoint, which was a 25% improvement in UPDRS scores after 6 months.
2. Some patients developed antibodies to GDNF.
3. Four trial monkeys developed cerebellar lesions.

All of these -- the trial design, the statistics, and the safety issues -- have since been challenged. Additionally, important data held by the sponsor has not been released to the scientific community and the public, in opposition to the principle of transparency in biomedical research.

A reappraisal is needed of the new evidence that has been accumulating since the scientific summit meeting on GDNF in October 2004.
Safety issues:
1. Brain lesions found in monkey brains of experimental primates were cited by Amgen as the primary reason to halt GDNF trials and treatment in August 2004. On the request of several study doctors, the FDA reviewed these findings in January, 2005. Reports from that meeting indicate that FDA agreed to allow the existing GDNF participants to continue in the study, and recommended additional analyses before proceeding with new subjects. It is believed that lesions were seen only in monkeys that had been abruptly withdrawn from very high doses of GDNF. But Amgen has not released their monkey toxicology data, that could prove or disprove this explanation. The company claims to be preparing an article for publication (now 2 years later).
2. In the May 2006 issue of Neurosurgical Focus, however, researchers at the University of Kentucky confirmed that there has been no brain damage or long term side effects among their trial patients, and that they believe the research should continue. “There was also no evidence of GDNF-induced cerebellar toxicity, as evaluated using magnetic resonance imaging analysis and clinical testing…. Safety concerns with GDNF therapy can be closely monitored and managed.” (16 )
3. In related investigations, the University of Kentucky researchers also reported in the April 2006 issue of Experimental Neurology, that they found "no imaging evidence of cerebellar injury in human subjects undergoing intracerebral GDNF infusion." (17 )
4. Indeed, according to Richard Penn, one of the Phase II trial doctors, “no clinically significant adverse effects were ever seen in patients from either phase, some of whom took GDNF for 3 years.” (18)
5. The other key safety issue regarding development of antibodies by several participants was known at the time the initial results were released. Although this was a concern, no harmful effects from this condition were seen for GDNF or for other treatments where it has occurred. It is likely the antibodies occurred only in patients whose catheters became dislodged during the course of treatment - a problem that could be easily remedied. These patients were not getting the GDNF into the brain; instead it was being pumped into other parts of the body. The extent of catheter dislodgements and its effect on the results has not been made available to the public by Amgen

Pathological Evidence
The brain autopsy of one of the Bristol study participants, who died of an unrelated heart attack in 2005, revealed that dopamine-containing nerve fibers lost in Parkinson’s disease had sprouted back in the region where GDNF had been infused. “This is the first neuropathological evidence that infusion of GDNF in humans causes sprouting of dopamine fibers, in association with a reduction in the severity of Parkinson’s,” stated Dr. Seth Love, who studied the tissue. This is also the first time any potential treatment has been shown to halt disease progression and possibly reverse the loss of nerve fibers in Parkinson’s. (19 )

Statistical analysis:
The statistical analysis and conclusions of the Amgen phase II study (Lang, et.al) (15) have now been challenged in the current issue of the Journal of Neuroscience Methods.
“The study was found to be underpowered and thus incapable of ruling out a large effect of GDNF on Parkinson disease… The study in no way contradicts the large clinical benefits seen in previous open-label studies … Furthermore there is no suggestion whatsoever of a significant “placebo effect.” (20)

Study design:
In the Lang article itself inconsistencies were noted between the Phase I trials and the Amgen Phase II trial -- different GDNF dosages, catheters (diameter size, number of ports), and infusion methods (constant versus pulsed), which it was admitted, may have accounted for differing outcomes.(15) In a review of the Amgen study, Dr. Roger Barker states “… this trial has not shown any efficacy for methodological rather than scientific reasons.” (21)
The study outcome should have been described as “inconclusive,” rather than “negative” and further trials should have been initiated.
Efficacy:

Amgen’s 12 month data on the Phase II study has also not been released. However, researchers at the University of Kentucky reported on the status of GDNF trial participants one year after Amgen halted all GDNF trials. They concluded that “unilateral administration of GDNF results in significant, sustained bilateral benefits.. . The results from 1-year intraputaminal GDNF infusion in our study are consistent with extensive animal data and the Bristol Phase I trial results, in which it has been stated that trophic factor treatment can be both protective and restorative. …
And “given the following three considerations:
1. that advanced PD is profoundly debilitating and life-threatening;
2. that the known safety concerns can be closely monitored and medically managed; and
3. that the methodology used in the two Phase I trials shows strong indications of efficacy,
We believe that additional Phase II clinical trials are warranted to continue developing the approach featuring intraputaminal delivery of trophic factors for treating PD.”
http://www.pdpipeline.org/yy_gdnf/gdnf_overview.htm

I've been trekking around Universal Studios with a three year old today and am exhausted but I wanted to respond to one of Boann's comments.

Concerning drug companies being naughty on a large scale and putting profits first. I'm afraid it's actually worse than that. It's not considered naughty. It's "what they do"....it's accepted.

I've talked to researchers at the table who have stated that with a little smile and a shoulder shrug as if to say, "boys will be boys.".

What differentiates this study is the results were NOT conclusive and too many researchers disagreed with the halt. They have been forced to find other sources and delivery methods for GDNF because Amgen owns the patent on BOTH and won't use it.

You don't just have to be a patient to understand the significance of this act. You have to be one who has had it long enough to be suffering. Even patients don't think they are worth the money spent if it isn't profitable.

Paula

now it is my turn to have been more clear! "naughty" was a euphemism - yes, it is the nature of the beast, yes, they do it as a matter of course, yes, we as people with parkinson's (it is a pain in the *** to write out “people with parkinson’s” rather than “patients,” but i am not going to continue to give in to the urge to let laziness - or difficulty typing - reduce me and everyone else with pd to being defined by pd - no criticism of anyone but me in that statement) are completely and utterly irrelevant to the machine, which hums along very nicely, thank you very much, as long as we all just shut up and take our medicine - and folks aren't doing that anymore. (no criticism meant toward any of our forebears, either, who might have believed the hype and or been too consumed with trying to keep their heads above water to be able to move on other fronts.)

and “putting profits first” was a gross over simplification – putting profits first can be much more complex and subtle than just not pursuing a therapy because it would not be as profitable as the status quo (see below for info on illegal activities on the parts of companies that make levodopa and its myriad adjuncts.)

We are of one mind on this, I believe.

But what do you mean when you say:

thank you, Paula
Boann

Illegal activities on the parts of companies that make levodopa/carbidopa products:

• Sandoz Pharmaceuticals Corporation, 115 F.T.C. 625 (1992) (consent order). The complaint charged that Sandoz unlawfully required those who purchased its schizophrenia drug, clozapine (the first new drug for the treatment of schizophrenia in more than 20 years), to also purchase distribution and patient-monitoring services from Sandoz. Blood monitoring of patients taking clozapine is required to detect a serious blood disorder caused by the drug in a small percentage of patients. The complaint alleged that this illegal "tying" arrangement raised the price of clozapine treatment and prevented others - such as private laboratories, the Veterans Administration, and state and local hospitals - from providing the related blood tests and necessary patient monitoring. The order prohibits Sandoz from requiring any purchaser of clozapine, or a patient taking clozapine, to buy other goods or services from Sandoz. [Sandoz is Novartis’ generic arm – in addition to making generic sinemet, together they make stalevo, bromocriptine, clozapine, amantadine, amitriptyline, nortriptyline, selegiline and comtan – all levodopa fixers] http://www.ftc.gov/bc/rxupdate021108...20to%20Compete

• FTC v. Mylan Laboratories et al., 62 F. Supp. 2d 25 (D.D.C. 1999) (FTC Commission Actions: November 29, 2000 (www.ftc.gov)). In a complaint seeking injunctive and other relief filed in U.S. District Court for the District of Columbia, the Commission charged Mylan Laboratories and three other companies, Profarmaco S.R.L., Cambrex Corporation, and Gyma Laboratories, with restraint of trade and conspiracy to monopolize the markets for two generic anti-anxiety drugs, lorazepam and clorazepate. The complaint also charged Mylan with monopolization and attempted monopolization of those markets.... On November 29, 2000, the Commission approved a proposed settlement, subject to approval by the federal district court, under which Mylan agreed to pay $100 million for distribution to injured consumers and state agencies. The defendants also agreed to an injunction barring them from entering into similar unlawful conduct in the future. [in addition to making generic sinemet, Mylan makes bromocriptine, clozapine, nortriptyline, amitriptyline, selegiline – all of which are used as levodopa fixers] http://www.ftc.gov/bc/rxupdate021108...20to%20Compete

• Bristol-Myers Squibb: On March 7, 2003, the Commission settled charges with Bristol-Myers Squibb Company (Bristol), one of the world's largest drug makers, that it engaged in a series of anticompetitive acts over the past decade to obstruct the entry of low-price generic competition for three of Bristol's widely-used pharmaceutical products: two anti-cancer drugs, Taxol and Platinol, and the anti-anxiety agent BuSpar. According to the FTC's complaint, Bristol's illegal conduct protected nearly $2 billion in annual sales at a high cost to cancer patients and other consumers who were denied access to lower-cost alternatives, and were forced to overpay by hundreds of millions of dollars for important and often life-saving medications. Under one of the provisions of the proposed consent order, Bristol will not be able to obtain a 30-month stay, as provided in the Hatch-Waxman Act, on later-listed patents. [BMS markets sinemet]

thank you for the summary, linda. there are, as they say, two sides to every story, and amgen is withholding its side, it seems.

questions i would like to ask or see asked include:

1) how do the risks of levodopa compare to the amgen-alleged risks of gdnf, even if the worst of those allegations were true, in terms of frequency of occurrence, in terms of impact on quality of life?
2) how do the benefits of levodopa compare to even the most conservative estimation of the benefits of gdnf, both in terms of symptomatifc benefit and neuronal regeneration or protection?
3) why have studies for the last god knows how many years on whether or not levodopa is toxic to DAa neurons been deemed "inconclusive" ad nauseum while this study was deemed negative after 12 months with enough improvement in enough people to cause this much of a furor in a community that has been swallowing hope to no avail in the form of experimental drugs for the last 40 years?
4) how far short of their endpoint of 25% improvement did they fall?
5) i thought the study was halted due to antibodies and lesions in primates? how can a study that was not completed fail to achieve its endpoint? (must re-read your post)
6) historically, what level of symptomatic improvement has been the endpoint for other experimental drugs, in particular, the various iterations of levodopa, and how close have they come to achieving them?
7) what motivation would amgen have for manufacturing a reason to halt the study?

i don't expect answers for all of these - not from folks here, i mean.

boann