Objective/Rationale:
Glial cell-derived neurotrophic factor (GDNF) has been shown in various pre-clinical models of Parkinson's disease (PD) to restore damaged nerve cells, including dopamine-producing cells, and to protect them from ongoing injury. This seemed to translate into marked improvements in the first small studies in patients. Unfortunately, a subsequent larger study failed to confirm the previously observed benefits. The grantees believe that this failure was caused by flawed delivery of the drug to its target in the brain, the putamen.
Project Description:
Researchers have developed a novel approach to delivering GDNF to the putamen by a process called convection-enhanced delivery (CED). This approach is aimed to optimize drug distribution within the putamen while minimizing exposure to drug in other areas of the brain. The approach integrates the use of four distinct components: a customized, implantable catheter system for convenient repeat treatment at the neurologist's office; a specialized surgical planning software for optimized catheter placement; magnetic resonance imaging (MRI) technology to visualize the actual drug distribution in the putamen; and a new intermittent dosing scheme for optimized delivery of GDNF.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
Based on pre-clinical evidence, GDNF has the potential to show symptoms & side effects benefit and, unlike any currently approved treatment, to slow the progression of PD. Therefore, chronic intermittent bilateral intraputamenal treatment with GDNF, although invasive, holds great promise as a disease-modifying approach for those with PD.
Anticipated Outcome:
This first study in patients with Parkinson's disease is designed to generate proof of concept for chronic intermittent bilateral intraputamenal treatment with GDNF by showing clinical benefit. If successful, this study will be followed by two larger studies to confirm the effectiveness and safety of the product, before filing for drug approval with the FDA and other relevant health authorities.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation's Partnering Program.
Final Outcome
This MJFF grant partially supported several projects in order to enable re-activation of the GDNF clinical development program, specifically including:
- Scale-up and establishment of comparability with previous (Amgen) GDNF
- A pilot toxicology study
- A good lab practice (GLP) toxicology study
- An investigator-initiated Phase II clinical trial
Comparability Study
Transfer of the manufacturing process for GDNF from Amgen to MedGenesis was accomplished. New material suitable for use in human volunteers was produced to specifications. Health authorities confirmed that the new material was comparable to previous Amgen material.
Pilot Toxicology Study
This study involved treating pre-clinical models with GDNF for five weeks. The results showed that GDNF could be successfully delivered into a small region of the brain. The use of the drug in the study was found to be safe.
GLP Toxicology Study
This study involved 20 pre-clinical models. Treatment consisted of four weekly infusions of GDNF or placebo into a small region in both sides of the brain and lasted for 40 weeks; some were further observed for another 12 weeks. The results showed that GDNF was safe and not toxic at the dose tested. Certain laboratory data from the study are still pending.
Phase II Trial
This study involved 41 participants with Parkinson’s disease. It was conducted by the North Bristol NHS Trust at Southmead Hospital (Bristol, UK). All participants underwent surgery for implantation of a purpose-built delivery device. Treatment consisted of four weekly infusions into a small region in both sides of the brain and lasted for 40 weeks. Participants received either GDNF or placebo, but they did not know which treatment they were taking. Initial data suggest that the treatment was safe but that there was no significant difference between participants who received GDNF compared to those who received placebo.
October 2016