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 It is believed that lesions were seen only in monkeys that had been abruptly withdrawn from very high doses of GDNF.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