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.
Questions discussed:
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.
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Bristol - very small catheter – operated like a faucet.
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University Of Kentucky - larger catheter – delivered to only one
side of the brain. Multi - ports.
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Amgen - used largest catheter. Single port.
2. Dose of GDNF and rate of delivery different for each study.
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Bristol – dose elevation and reduction protocol. Pulse delivery.
Each subject received a different dose.
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University of Kentucky: Used unilateral infusion and a dose
escalation protocol.
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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.
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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:
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Neutralizing antibodies – could interfere with natural GDNF. But
not enough known about either the antibodies or the role of
naturally-occurring GDNF.
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So far no clinical effects seen.
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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:
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Systematic comparison of catheters in primates.
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Compare effects of recombinant GDNF and natural form – to be
funded by Fox Foundation and Kinetics.
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Any long –term effects in patients from earlier GDNF trial (Un.
Of Oregon)?
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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! |
