Neurotrophic Factor for Treatment of Advanced Parkinson's Disease
Neurotrophic Factor for Treatment of Advanced Parkinson's Disease
Abstract & Commentary
By Claire Henchcliffe, MD, DPhil, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.
Synopsis: A randomized trial of glial-derived neurotrophic factor directly placed into the putamen did not show a statistically significant improvement or the signs and symptoms of PD.
Source: Lang AE, et al. Randomized Controlled Trial of Intraputamenal Glial Cell Line-Derived Neurotrophic Factor Infusion in Parkinson's Disease. Ann Neurol. 2006:59;459-466.
This phase .5, multicenter, double-blind, placebo-controlled study randomized 34 patients with advanced Parkinson's disease (PD) to continuous, bilateral, intraputamenal (Ipu) infusion of either recombinant human GDNF (liatermin, 15 microgram/putamen/day) or placebo. Eligible patients had a stable Unified Parkinson Disease Rating Scale (UPDRS) off-motor score of 30 points during the 60-days pre-procedure, on constant PD therapy. Each had 30% improvement in this score after an L-dopa challenge. The 2 treatment groups were well matched for age, gender, UPDRS motor score off and on, L-dopa response, time since diagnosis, and age at diagnosis, but not matched for L-dopa equivalents (median dose: liatermin: 752 mg/day; placebo: 1,250 mg/day). Intraparenchymal infusion catheter tips were targeted stereotactically to the posterior dorsal putamen. Placement was verified in postoperative MRIs by blinded radiologists. Lang and colleagues found a non-significant change at 6 months in mean percentage in UPDRS off motor score of -10.0% and -4.5% in the liatermin and placebo groups, respectively (P = 0.56, 95% CI -23 to 12). The 2 groups did not differ in the clinical secondary end points, including Mentation/Behavior, Activities of Daily Living, and Complications of Dopaminergic Therapy UPDRS subscores, UPDRS motor scores in the on condition, timed motor tests, PD diary ratings, Dyskinesia Rating Scale, PD Questionnaire (PDQ- 39), and the Short Form (SF)-36 health survey. 18F-dopa PET-imaging was performed in 9 liatermin and 12 placebo patients, demonstrating a 32.5% treatment difference in mean 18F-dopa influx constant, favoring liatermin at 6 months. Serious device-related complications occurred in 24%, all treated and well tolerated. In the liatermin treated group, the most common drug-related adverse events were paresthesias (65% liatermin vs 18% placebo), headache (29% vs 6%), and upper respiratory tract infections (24% vs 6%). Three patients developed neutralizing antibodies to liatermin (one in the study and 2 in the open-label extension).
Commentary
The present data is yet another blow to hopes that we may be on the verge of offering restorative therapy in PD by making use of the well-described effects of neurotrophic factors in diverse disease models. Based on carefully conducted animal experiments, Ipu infusion of liatermin is thought to increase sprouting of distal nerve terminals of remaining mesencephalic dopaminergic neurons acting on postsynaptic putamenal neurons. Now, after encouraging results of 2 open-label trials of GDNF in PD, Lang et al's 6-month results from this rigorous trial are intriguing, but do not demonstrate a statistically significant effect on a range of PD motor/non-motor measures, or in QOL scores. First, the randomized, placebo-controlled study design controls for placebo responses (well-described in prior PD medication and transplant trials). Second, many factors in this trial differed from prior open-label trials (intervention along the course of PD, baseline PD medications, length of follow-up, catheter tip location, catheter design, drug dose infused). However, it is unclear why improved 18F-dopa uptake observed in PET scans of a subset of subjects did not translate into significant clinical improvement. Finally, there are major safety concerns. Neutralizing anti-liatermin antibodies developed in 3 patients. Although they remained asymptomatic, the long-term implications are unknown. Longer periods may also be required to investigate other potential toxicities: segmental loss of Purkinje and granular cells was observed in a 6-month trial in 4 of 15 monkeys treated with 100 micrograms liatermin daily.1 While efforts, including gene therapy, continue in the research community to address the potential clinical use of neurotrophic factors in PD, we clearly have much to learn before this could be added to our therapeutic armamentarium.
Reference
1. Chebrolu H, et al. MRI Volumetric and Intensity Analysis of the Cerebellum in Parkinson's Disease Patients Infused with Glial-Derived Neurotrophic Factor (GDNF). Exp Neurol. 2006 Jan 30; [Epub ahead of print].
A randomized trial of glial-derived neurotrophic factor directly placed into the putamen did not show a statistically significant improvement or the signs and symptoms of PD.Subscribe Now for Access
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