And this was not the only sobering GDNF news presented October 5, 2004, by clinical researchers at the annual meeting of the American Neurological Association in Toronto. Tony Lang of Toronto Western Hospital also discussed publicly for the first time the fact that scientists at Amgen, sponsors of the GDNF trials, have found cerebellar cell loss in a nonhuman primate study of the GDNF infusion method.

Last year, great excitement greeted an Amgen trial that was designed to confirm results reported earlier in an open-label study of a small number of patients. In that study, Gill and colleagues appeared to have licked the problems that plagued earlier approaches—the apparent failure of the drug to diffuse all the way into the nigrostriatal pathway, as well as the significant side effects associated with the cerebroventricular approach. The successful strategy was to infuse GDNF directly into the striatum, as opposed to the cerebral ventricles (see ARF related news story).

With this approach, Gill and colleagues had found motor improvements during the six-month open-label trial, as well as PET evidence of enhanced dopamine levels in the striatum. Amgen’s subsequent trial looked for the same results in a double-blind, placebo-controlled trial of 34 patients, again over six months.

Anticipation gave way to disappointment. Earlier this year, the company issued a press release indicating that they had not replicated the pilot data, and in Toronto Lang unveiled the details for the first time. There was no significant benefit of GDNF therapy on the primary trial endpoint—changes from baseline on the motor portion of the UPDRS (a battery of tests used to assess Parkinson disease severity) during the "off" phase, when symptoms are not controlled by drugs. There was also no benefit seen on the various secondary indices, such as on-phase motor scores, UPDRS non-motor scores, patient diaries, dyskinesia, or quality of life indices. In agreement with PET data from the open-label trial, there was significantly greater 18F-dopa influx into the posterior putamen in the GDNF-treated patients, but Lang cautioned that there was no significant association between this finding and any improvements experienced by patients.

Indeed, there appears to have been a noticeable placebo effect, especially among the patients with milder symptoms at the outset of the trial. All of which, Lang noted, emphasizes the limitations of open-label trials, not to mention the apparent shortcomings of the neurotoxic lesion models of PD—remember that it was the promising recovery seen in substantia nigra-lesioned monkeys that spurred human clinical trials of GDNF. As Lang suggested, these animal models may be useful for studying the effects of losing substantia nigra neurons, but their particular pathology may have less relevance to rescuing cells in PD.

Beyond the lack of clinical response to GDNF, there are now safety issues to consider. In a letter sent to clinical investigators in the trial in early September, Amgen announced that they were halting the open-label extension of the six-month double-blind placebo-controlled phase for two safety concerns. First, pathology results from a study of GDNF in nonhuman primates revealed that Purkinje cells and granular cells were being lost in the cerebellum of GDNF-treated animals. There is, as yet, no obvious explanation for this effect. Second, four of the human patients receiving GDNF in the open-label extension developed antibodies to GDNF. According to Lang, the antibodies in three of these patients are neutralizing, as opposed to merely persistent. The Amgen letter to investigators points out that such antibodies might reduce endogenous GDNF, as well as the synthetic variety.

Asked whether the amount infused—15 microgram/putamen/day—might have been insufficient to benefit neurons, Lang said that the investigators did not think this was the case. Did the GDNF perhaps not penetrate far enough beyond the tip of the infusion catheter? This was a possibility worth considering, Lang suggested, but if getting GDNF to the right places is the issue, he now is more interested in the promise of other approaches such as viral delivery.—Hakon Heimer.