A new trial coming for previously failed Parkinson's treatment

June 7, 2011 — 9:33am ET | By Howard Lovy



.. updates ...on efforts to try an experimental gene therapy using glial-derived neurotrophic factor (GDNF), a protein that helps keep neurons alive, against Parkinson's disease. A team led by Krystof Bankiewicz is in the final stages of gaining approval from the FDA in the hopes that this trial can address problems with the protein in previous tests.

There was some hope back in 1993 that GDNF could help dopamine-producing neurons survive rather than degenerate with the disease. Trials using various delivery methods, however, have been unsuccessful. So, what makes this time different? Better, and more precise, delivery, Bankiewicz tells Technology Review. "They all turned out to be negative, because the delivery was never controlled," Bankiewicz says.

This time around, researchers will deliver a gene encoded with GDNF in the the putamen, the area of the brain involved in Parkinson's. They'll do it with a virus brought to the brain through convection-enhanced delivery, which uses pressure to drive it deep into the regions that are targeted. And, as a chaser, they'll include an MRI contrast agent to track where the treatment is going...







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http://www.technologyreview.com/biomedicine/37708/

...Ronald Mandel, a neuroscientist at University of Florida, is also working on a GDNF gene therapy. He's optimistic that GDNF could help Parkinson's patients, but he believes it should be tested in patients at the early stages of the disease—before the dopamine-producing cells have become severely diseased and die off. Getting approval to test therapies in such patients, however, is very difficult...

The Daily Mail gives a case study:

"Doctors at Frenchay Hospital in Bristol implanted two pumps into Mr Nelson's abdomen which deliver a drug [GDNF] directly into the damaged part of his brain."

http://www.dailymail.co.uk/health/ar...gave-life.html

Not a "cure", but good news nevertheless.

John

I imagine getting early stage patients to sign up for clinical trial(s) involving experimental brain surgery with placebo will be equally difficult.

Jean

you said: "And, as a chaser, they'll include an MRI contrast agent to track where the treatment is going..."

Finally! It's about time this was added.
thanks, olsen
peg

how many variants are there of GDNF and delivery mechanisms.

We appear to have at least four delivery mechanisms:

i) Gene therapy (Olsen's initial post).
ii) Stephen Gill at Frenchay, (abdomen injections via catheter to brain).
iii) Lilly and Medtronic, (looks the same as (ii) to me).
iv) Armagen, (small molecule delivers GDNF to brain).

Gill appears to have a clinical trial running and Olsen's looks to be kicking off as well.

Is this all the same "GDNF" ? How is Amgen involved with regards rights to GDNF ? Is any advocate group monitoring the work done on GDNF ? Can anyone explain how Gill's mechanism works ?

Still with so much "noise in this space" I am quite excited.

Neil.

Neil, I know Amgen's GDNF was their patented synthetic GDNF named "Liatermin." That's the version that Amgen pulled so many years ago.

Jean

http://pdpipeline.org/2011/GDNF/tran...l_research.htm

Delivery Methods:
Pump infusion

“The infusion system, also known as “direct protein therapy,” involves placing a long thin tube (called a catheter) into the part of the brain affected by Parkinson’s disease. This tube is hooked up to a pump implanted under the skin that contains a reservoir of the GDNF protein. The protein slowly flows into the damaged area of the brain and can provide support to injured or dying cells” (MJFF website).

This delivery method was used in the early phase I trials at the University of Kentucky, at Bristol Hospital in the UK, and for the Amen-sponsored phase II trials. In 2004, Amgen terminated all further human research and clinical trials with their recombinant GDNF, claiming it didn’t work and possible safety issues based on their monkey studies, It wasn’t until 2010 that Amgen licensed another company (MedGenesis) to resume GDNF research in humans.

However in the ensuing years, many scientists and patients continued to believe in the promise of GDNF, and animal research continued on ways of improving the delivery system – making it more targeted and effective. By 2011, a few early clinical trials were starting and others were on the cusp of translating laboratory research into clinical treatments.

Examples of Pump Infusion delivery:

Dr. Steven Gill
Designed new infusion pump and catheter system.
Funded in part by Cure Parkinson’s Trust (UK).
Expected to enter clinical trials in 2011.

“Professor Gill plans to conduct a two year double blind, randomized, placebo-controlled phase 2 study of intermittent intraputamenal GDNF infusions for the treatment of Parkinson’s in 36 patients. CPT’s Research Committee has asked that brain imaging be included in the study to provide further evidence of the efficacy of GDNF in the brain, which in turn supports the development of other GDNF-related therapies using a range of delivery methods. “ (Cure Parkinson’s Trust)

MedGenesis Therapeutix
Partnered with Biovall until Nov 2010.

“On January 12, 2010, MedGenesis "announced that it has successfully entered into an agreement with Amgen Inc., granting MedGenesis an exclusive, worldwide license for glial cell line-derived neurotrophic factor (GDNF) protein in CNS and non-CNS indications"

“The MedGenesis approach is to "deliver a known therapeutic utilizing the MedGenesis cutting-edge CED platform to a well-defined local target inside the blood-brain-barrier
This is the first time, Amgen has allowed another company to research it's GDNF molecule in treating humans since the halt of Amgen's phase II clinical trial in Sept. 2004.

“... As part of the license agreement, Amgen now holds a small equity stake in MedGenesis.” (MedGenesis web site)

Dr. Gill, Dr. Howard Federoff and Dr. Bankiewicz (NINDS consortium) are scientific advisors to MedGenesis.
Eli Lilly/ Medtronic

Preclinical.

Lilly announced in April 2011 a new formulation of GDNF, delivering it to the brain through a catheter connected to a new implanted pump and drug reservoir supplied by Medtronic

Gene therapy

“ In gene therapy, the brain is genetically modified in order to produce the therapy itself within the brain tissue. This is achieved through the injection of a genetic vector in order to allow the brain to produce the trophic factor.” (mjff website)


Examples:
Parkinson's Disease Gene Therapy Study Group - a consortium of 7 research institutions throughout the U.S., funded by NINDS.

Phase I trial planned to begin in fall 2011.

Uses Convection Enhanced Delivery to distribute the genes efficiently to the targeted areas of the brain.An Adeno-associated virus (AAV2) encoding human GDNF is the vehicle for gene transfer to the central nervous system. This is the same viral vector used by Ceregene in its research on neurturin – a neural growth factor and a close relative of GDNF (currently in phase II clinical trial.)

Amsterdam Molecular Therapies (Netherlands)
Preclinical
“Amsterdam Molecular Therapeutics (AMT), announced in 2010 that it obtained a license from Amgen to use their GDNF gene together with AMT's proprietary adeno-associated virus (AAV) gene therapy platform for the development of a gene therapy treatment for Parkinson's disease.
(AMT website)

Encapsulated GDNF producing cells
Lead researcher: Olle Lindvall, Lund Un., Sweden

Funded in part by MJFF

“Pre -clinical research to develop a neuroprotective therapy based on the implantation of encapsulated cells that produce GDNF directly into the brain. "

Final outcome report in 2010, “Cell clones were developed that produced GDNF in vitro. Additionally, the encapsulated device was generated. However, cell clones did not produce sufficient GDNF when implanted into the brains of pre-clinical models. Though significant efforts were made, the team was unable to overcome the limitation of insufficient in vivo production of GDNF.” (MJFF website)

Intravenous GDNF Gene Therapy of Experimental PD (AGT 190)

Preclinical.
Lead researcher – William Pardridge
Sponsor UCLA and Armagen Technologies; also funded by MJFF

“Applied for FDA approval of phase I trial
Therapeutic gene encodes GDNF, and is engineered to restrict expression of the GDNF gene in only parts of the brain related to PD…This research provides a new approach to the selective targeting of a GDNF gene therapy in PD without the use of viruses or neurosurgery.” (MJFF Web site)
If phase I has no safety problems, new funding source needed to continue development, estimated at $15 million. (Vastag)


Oral delivery of GDNF

Cogane
Sponsor: Phytopharm.
“Cogane (PYM50028) arose from research into the activity of an Asian medicinal plant…. In pre-clinical models, Cogane™ reverses the changes in the area of the brain involved in Parkinson’s disease by inducing the body’s own production of proteins known as neurotrophic factors. In particular, one of these factors known as “GDNF” has been shown to be particularly effective in re-growing damaged nerves. Since GDNF is a protein it cannot be given orally (in pill or liquid form) because it is degraded in the stomach and intestine, and also does not readily cross the blood-brain barrier. ... Cogane™, which can be taken orally, readily crosses the blood-brain barrier and stimulates the release of GDNF in the brain…” (Pipeline Project Database)
Phase II clinical trials began in 2011: Randomised, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety and Tolerability of PYM50028 in Subjects With Early-stage Parkinson's Disease Administered Once Daily for 28 Weeks. (clinicaltrials.gov)
Completion expected Dec. 2012


References
Cure Parkinson’s Trust. GDNF appeal. 2011. Accessed online on 6/1/11. http://www.cureparkinsons.org.uk/document_1.aspx?id=0:60951&id=0:36727

Investigation of Cogane (PYM50028) in Early-stage Parkinson's Disease (CONFIDENT-PD). Clinicaltrials.gov. Accessed online 6/1/11 at: http://clinicaltrial
Applied for FDA approval of phase I trial
s.gov/ct2/show
/NCT01060878?term=cogane&rank=2

Michael j Fox Foundation. Our Research website and database. Accessed online on June 2, 2011 at: http://www.michaeljfox.org/research.cfm

Parkinson Pipeline Project. Therapy Development Database. Accessed online 6/1/11 at: http://apexutf.shellprompt.net/pls/apex/f?p=162:12:5997922620574622

Vastag, Brian. Biotechnology: Crossing the barrier. Published online 18 August 2010 | Nature 466, 916-918 (2010) Accessed June 1, 2011. http://www.nature.com/news/2010/1008...l/466916a.html

The NIH NINDS trial has not been FDA approved yet, so that's why it is unpublished. And after FDA approval it will be listed on clinical trials.gov.

At this point it is likely that stage 3 pwp will be eligible. And the NIH NINDS do hope to start the trial by the end of 2011.

They will use a convection-based delivery system.

Paula and-or Linda posted NIH contact info. I echo their praise for the folks at the NIH. They are very kind, informed, and helpful in every way.


Jean