PAN GDNF Conference Calls
The Parkinson's Action Network (PAN) recently held two conference calls to update the Parkinson's community about Amgen's halt of its phase II GDNF trials, the future of GDNF research related to PD, and recent meetings at the FDA focused on safety concerns and possible "compassionate use" of GDNF for trial participants. The calls included PAN staff and grassroots State and Congressional Coordinators, representatives from the Michael J Fox Foundation, GDNF trial participants and their families, and researchers who were involved in Phase I and II GDNF trials.
Following are notes from these conference calls written by Parkinson Pipeline Project members and reviewed for accuracy and edited by the main presenters. We are sharing these with the Parkinson's community so we all can be informed about these important developments.
Notes on Call with
Katie Hood and Dr. Todd Sherer
Michael J Fox Foundation, January 4, 2005
Reported on GDNF Scientific Summit held in Oct. 2004. Summit was to examine differences between Phase I and II trials, reach consensus on what we know and don’t know, and open dialog between stakeholders --Amgen and scientific community.
Who attended: about 30 scientists, Amgen researchers, clinical trial doctors such as Drs. Gill, Gerhardt, Gash and Lang, and other experts. No patients were included, however Amy Comstock from PAN attended as an advocacy representative.
Why were there different results? What research should be done in the future? What are the safety concerns?
1. All 3 trials – Bristol, UK, University of Kentucky and Amgen used different delivery systems.
Bristol - very small catheter – operated like a faucet.
University Of Kentucky - larger catheter – delivered to only one side of the brain. Multi - ports.
Amgen - used largest catheter. Single port.
2. Dose of GDNF and rate of delivery different for each study.
Bristol – dose elevation and reduction protocol. Pulse delivery. Each subject received a different dose.
University of Kentucky: Used unilateral infusion and a dose escalation protocol.
Amgen – constant delivery. Received the initial effective dose from the Bristol trial. There was no dose escalation in Amgen study.
Believe differences in catheter design and doses may be responsible for differing results.
Differences that were noted were: 1) size of catheters; 2) rate of infusion.
Flurodopa imaging showed 30% increase., however PET scan results did not always correlate with clinical improvement.
3. Placebo effect was discussed as something thought to have effect in PD patients and something which could play a role in any trial. Bristol subjects showed improvement over 3 years, and questions were asked as to whether the placebo effect could last that long.
4. Safety concerns:
Neutralizing antibodies – could interfere with natural GDNF. But not enough known about either the antibodies or the role of naturally-occurring GDNF.
So far no clinical effects seen.
Cerebellum pathology : loss of neurons in monkeys who received the highest doses. (100 mg).
Further research needed to answer safety concerns.
5. Future GDNF studies:
Systematic comparison of catheters in primates.
Compare effects of recombinant GDNF and natural form – to be funded by Fox Foundation and Kinetics.
Any long –term effects in patients from earlier GDNF trial (Un. Of Oregon)?
Alternative delivery methods – gene therapy; encapsulated cell technology – Fox Foundation is funding research.
Amgen stated it did not believe this form of GDNF in this particular pump delivery system should be used clinically. Fox Foundation is expecting to work with Amgen and other scientists on future studies to better understand GDNF and delivery.
Few questions asked due to technical problems with un-muting of participants’ phones.
Dr. Hutchinson and Kristen Suthers stated they believed there were errors in Amgen’s results – wrong type of statistical test was used. If recalculated using correct measures – efficacy was shown. Other researchers attending the summit did not agree with Dr. Hutchinson’s analysis of the Amgen data.
Next Conference call will be Wed. Jan. 12 at 4 PM with Dr. Greg Gerhardt – Un. Of Kentucky - who will talk about GDNF and the meeting with the FDA for continued access for the study participants.
Dr. Greg Gerhardt was one of the primary investigators for the University Of Kentucky (a Udall Center) Phase I GDNF trial. His colleague Dr. Gash attended the FDA meeting held yesterday.
There were 2 main issues discussed:
(1) Could GDNF be reinstated for the Phase I and II trial participants
(2) Possibility of a new GDNF trial in the future to test efficacy in advanced stage patients.
He reported the meeting was a “positive experience,” but must wait for an official report or other communication from FDA before discussing further details or next steps. Expected this communication would be forthcoming in the next few weeks. Documents from FDA are also needed by NINDS to make funding decisions.
There was a discussion of what kind of report to expect from FDA. Perry Cohen stated that the transcript of the meeting was the record of what was said and that was not likely to be available because of the confidentiality of the meeting. Amy Comstock indicated that the FOI act may allow public access to the transcript. Dr. Gerhardt indicated a need for Official FDA approval in order to continue grant funding that had been suspended while the fate of GDNF is unknown. He indicated that he had put in a request to Dave Banks of the FDA for a response and awaited a call back. Perry stated that he could help get information from FDA on their response and will be following up with the Office of Special Health Initiatives (OSHI).
Also discussed the safety issues stated by Amgen to be the reasons for halting the trial.
1. Antibody formation in a few patients that might potentially neutralize naturally occurring GDNF. But there have been no autoimmune or anti body clinical effects reported to date. It is not uncommon for foreign bodies to produce antibodies – e.g. insulin.
Possibility of this safety issue must be included in any future informed consent documents and should be investigated in any trials.
2. In some of the non- human primates, there was evidence of toxicity to cerebellum at very high doses.
But Amgen stated at summit meeting that if Phase II had shown more efficacy they would have moved forward with the research.
If Amgen won’t develop GDNF further – they should allow another company to do so. One cited problem was the death last year of Amgen exec. (Dr. Michael Traub) who had directed the GDNF project.
Dr. Gerhardt talked about the strong effect that patient groups and advocates have had. He thought in September the research was over. We have made “great strides.” Letters have made a difference. Some Congress reps. are now involved ( such as Lane Evans) Advocacy efforts will be important as the doctors continue to negotiate with Amgen.
The other doctors he works with are also committed to their patients, who were doing so well, and want to see them get their treatments back.
Future discussions will focus on
Will schedule another conference call in a few weeks after they receive the documentation needed from the FDA.
Thank you Dr. Gerhardt!