Over the course of the nearly two years since Amgen halted its phase II trial of infusion delivery of GDNF, there has been no scientific evidence released that proves any harm to humans from this drug. The Question is -- just how much harm is going to come from GDNF being withheld? When compared to risks of living with Parkinson's, trial participants say, "a lot".
Many of us have met Steve Kaufman and seen the benefits he realized from GDNF with our own eyes. We have read about Richard Hembrough in the UK who after 31 years with PD and 2 1/2 years of GDNF treatment, no longer requires levodopa. We've listened to Robert Suthers on 60 Minutes describe his improvements and subsequent decline after the trial halt. Statistics cannot obscure what these patients have experienced. They know and we know these were not placebo effects.
When Amgen initially halted the GDNF trial they cited three reasons:
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 issues -- the trial design, the statistics, and the safety issues -- have since been challenged in peer-reviewed journals.
The safety issues have been much publicized by Amgen's press releases.
Brain lesions found in monkey brains of experimental primates were the initial cause to halt the trial in August 2004. On the request of several study doctors 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. But Amgen has not released these data. Requests for release of their monkey toxicology data has yielded nothing. Amgen claims they are preparing it for publication (now 2 years later!).
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. "Unilateral administration of GDNF results in significant, sustained bilateral benefits… Safety concerns with GDNF therapy can be closely monitored and managed.” (Slevin )
Related investigations 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." (Chebrolu )
Indeed, “no clinically significant adverse effects were ever seen in patients from either phase, some of whom took GDNF for 3 years.” (Penn)
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. These antibodies may have occurred only in patients whose catheters became dislodged during the course of treatment - a problem that could be easily remedied. Some researchers believe these patients
were not getting the GDNF into the brain; instead it may have been pumped into other parts of the body. These findings have not been made available to the public by Amgen.
The statistical analysis and conclusions of the Amgen phase II study (Lang et al) have now also been challenged in the current issue of the Journal of Neuroscience Methods (Hutchinson, et al ).
“The study was found to be underpowered and thus incapable of ruling out a large effect of GDNF on Parkinson disease. It therefore does not contradict the large effects seen in previous open-label studies.”
In the Lang article itself inconsistencies were noted between the Phase I trials and the Amgen trial -- different GDNF dosages, catheters (diameter size, number of ports), and infusion methods (constant versus pulsed), which may have accounted for differing outcomes.
Given the overwhelmingly positive phase I trial results, and the inconclusive results of the phase II trial, the research should have been continued.
Infusion delivery of GDNF is our “bird-in-the-hand.” No other neurorestorative and neuroprotective treatments are so far along in development at this time. The trial participants and every PD patient has been denied a likely effective treatment, that could have been available in the near future – much sooner than the "5 - 10 years" often predicted for unproven delivery methods of GDNF, such as gene therapy.
Chebrolu, H. , Slevin J.T., Gash, D.A.., Gerhardt, GA, Young, B., Given C.A, Smith C.D.
MRI volumetric and intensity analysis of the cerebellum in Parkinson’s disease patients infused with glial-derived neurotrophic factor (GDNF) Experimental Neurology, 2006 Apr;198(2):450-6. Epub 2006 Feb 7.
Hutchinson M, Gurney S, Newson R. GDNF in Parkinson disease: An object lesson in the tyranny of type II. Journal of Neuroscience Methods. 2006 Jul 27; [Epub ahead of print]
Lang, A. et.al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrphic factor infusion in Parkinson’s Disease. Annals of Neurology, 2006, Vol. 59, Issue 3, 459-66.
Penn, Richard, et.al. GDNF in treatment of Parkinson’s Disease: response to editorial. The Lancet Neurology. March 2006, Vol.5
Slevin J.T., Gash, D.A., Gerhardt, GA, Smith, C.D., et al. Unilateral intraputaminal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year each of treatment and withdrawal. Neurosurgical Focus, 2006 May 15;20(5):E1.