licensee of amgen's gdnf-video

[lurkingforacure]

if you go to amt's website (amt is the licensee of amgen's gdnf), there is a fascinating video about viral vectors...very encouraging. AMT is a relatively young company (1998) but this is quite impressive, and hopeful. Of course, they have the benefit of knowing already that gdnf works, the only trick is how to get it to where it's needed...I think this is the link to the video:

http://www.amtbiopharma.com/mod.php?mod=userpage&page_id=74

[paula_w]

patent filed by Amgen in Jan. 2004 and published Sept. 9, 2004. This was for Amgen's GDNF gene.
Glial derived neurotrophic factor


Abstract A novel neurotrophic factor referred to as glial derived neurotrophic factor (GDNF) has been identified and isolated from serum free growth conditioned medium of B49 glioblastoma cells. Rat and human genes encoding GDNF have been cloned and sequenced. A gene encoding GDNF has been subcloned into a vector, and the vector has been used to transform a host cell in order to produce biologically active GDNF in a recombinant DNA process.
Inventors: Lin, Leu-Fen H.; (Boulder, CO) ; Collins, Franklin D.; (Agoura Hills, CA) ; Doherty, Daniel H.; (Boulder, CO) ; Lile, Jack; (Nederland, CO) ; Bektesh, Susan; (Boulder, CO) Correspondence Name and Address: AMGEN INCORPORATED
MAIL STOP 27-4-A
ONE AMGEN CENTER DRIVE
THOUSAND OAKS
CA
91320-1799
US
Assignee Name and Adress: Amgen Inc.


Assignee Name and Adress: Amgen Inc.

Serial No.: 758622 Series Code: 10 Filed: January 14, 2004
http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=3&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=150&f=G&l=50&co1=AND&d=PG01&s1=gdnf&s2=amgen&OS=gdnf+AND+amgen&RS=gdnf+AND+amgen



"FIELD OF THE INVENTION

[0001] The present invention relates to neurotrophic factors and glial derived neurotrophic factor (GDNF) in particular. Also included within this invention are processes for purification of GDNF from natural sources and processes for cloning rat and human genes encoding GDNF, as well as the nucleic acid sequence of the rat and human genes that encode GDNF. The GDNF gene has been subcloned into an expression vector, and the vector used to express biologically active GDNF. In addition, this invention includes the use of GDNF for preventing and treating nerve damage and nerve related diseases such as Parkinson's disease.

[0002] Antibodies to GDNF are disclosed, as well as methods for identifying members of the GDNF family of neurotrophic factors. And finally, methods are described for preventing or treating nerve damage by implanting into patients cells that secrete GDNF. "

[caldeerster]

If the AMT delivery system for GDNF involves stereotactic injections, or is it a small molecule system, where the cell is programmed to cross the blood brain barrier?

I watched the video and I'm still unclear as to their delivery mechanism.

[paula_w]

oops big goof - below is not the gene therapy study that the thread is about. This is armagen, not AMT, sorry for the big mistake....AMT is a different company and study.

Having said that - this one sounds real good!!

Project Description:

In this project, the GDNF will be delivered to the target region via transport across the BBB, following a non-invasive intravenous administration. To enable transport across the BBB, the GDNF is re-engineered with the molecular Trojan horse technology. The GDNF is fused to a genetically engineered monoclonal antibody, which crosses the BBB via endogenous transport systems. The antibody acts as a molecular Trojan horse, and ferries the attached GDNF across the BBB, from blood, to the target site in brain. The GDNF-antibody combination is a combination molecule, also called a fusion protein. Following manufacture of the new drug, the efficacy of intravenous GDNF-fusion protein in a primate model of PD will be evaluated. In parallel, the potential toxicity of intravenous GDNF-fusion protein will be tested in primates.

read abstract:
http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_3.cfm?ID=440


If the AMT delivery system for GDNF involves stereotactic injections, or is it a small molecule system, where the cell is programmed to cross the blood brain barrier?

I watched the video and I'm still unclear as to their delivery mechanism.

[lurkingforacure]

Thanks! And by "in parallel", does that mean at the same time? That would speed things up further, for sure.

[paula_w]

One definition of parallel defined as the 'computer' definition, speaks of two operations at the same time and distinguishes it from serial. I thought I copied it but didn't. I'd venture to say yes.

Arma gen - Amgen
"Non-program-specific Funding", 2008, MJFF
I suspect Andy Grove is involved here - but have no reason to say so - lol, so don't quote me.
UCLA

paula


Thanks! And by "in parallel", does that mean at the same time? That would speed things up further, for sure.

[paula_w]

What a mess. I found the armagen study in the list of all funding for neurotrophic factors here at the bottom of page:

http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_2.cfm?Search=Yes&ProgramID=&Keyword1=45&Keyword2=&Country=&State=&Last_Name=&Institution=&Grant_Funded_Year=&search.x=37&search.y=10

Then by clicking on that bottom abstract I found the armagen study:

http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_3.cfm?ID=440

The AMT study, which caldersteer was inquiring about is here and also linked on the home page:

http://www.michaeljfox.org/newsEvents_parkinsonsInTheNews_article.cfm?ID=401

geez I should just go copy this onto the clognition thread.
:o paula

[bryn]

There is also some good background on MJFF on trophic factors in the third link (not been here long enough to post a URL!) Explained a few things for me!

Bryn

[caldeerster]

Thanks for clearing that up Paula! :)

So, basically, that video I watched at the link has nothing to do with this Amgen/Amsterdam licensing agreement. And the Amsterdam delivery mechanism is a trojan horse system, whereby the GDNF will be delivered and ferried to the appropriate part of the brain via a non invasive intravenous mechanism.

Do I have that right?

If so, yes, it sounds remarkably promising.

Caldeerster

[aftermathman]

the method of delivery of the AAV virus however it has / is being used in various forms by Neurologix, Ceregene and Oxford Biomedica in existing gene therapy studies.

I believe in these other studies it is delivered via stereotactic injection in the brain, a procedure not without its risks as Carolyn can evidence. Still a small price to pay if the results are good.

No reason to assume the AMT study will not work in the same way.

AAV was reviewed last year by the FDA when a gene therapy trialist died (not a PD trial) however it was found to be safe and not connected to the death.

Neil.

[caldeerster]

Thanks, Neil. That was my original question. The Amsterdam procedure is unclear, but if like the others it may well be stereotactic delivery.

The link Paula provided is regarding work by ArmaGen, who apparently DO have a trojan horse mechanism to deliver GDNF intravenously.

http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_3.cfm?ID=440

So, I guess my question is - has Amgen licensed the gene to both Amsterdam and ArmaGen? Or is the upcoming ArmaGen trials using a different or non propietary version of GDNF?

I'm still a bit confused.

Caldeerster




the method of delivery of the AAV virus however it has / is being used in various forms by Neurologix, Ceregene and Oxford Biomedica in existing gene therapy studies.

I believe in these other studies it is delivered via stereotactic injection in the brain, a procedure not without its risks as Carolyn can evidence. Still a small price to pay if the results are good.

No reason to assume the AMT study will not work in the same way.

AAV was reviewed last year by the FDA when a gene therapy trialist died (not a PD trial) however it was found to be safe and not connected to the death.

Neil.

[paula_w]

I'm not sure - here it says:

The combination of this gene with AMT's proprietary adeno-associated virus (AAV) gene therapy platform could potentially allow the development of an effective, long-term treatment for this progressive and crippling disease.

and again further down:

AMT will combine this gene with its own proprietary technology to develop a gene therapy treatment that aims to protect and enhance the function of the nerve cells that produce dopamine.
http://www.michaeljfox.org/newsEvents_parkinsonsInTheNews_article.cfm?ID=401

This is what the video is explaining is it not?
http://www.amtbiopharma.com/mod.php?mod=userpage&page_id=74

My first question is what kind of cells are they using? It looks like the video is describing AMT - Amsterdam gene therapy technology using Amgen's GDNF gene. How did it become a gene?

??
paula

[paula_w]

We posted at the same time. I don't know where the armagen GDNF came from, but calling it armagen grabs your attention. Here we are back to calling it a protein.

http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_3.cfm?ID=440

paula

Thanks, Neil. That was my original question. The Amsterdam procedure is unclear, but if like the others it may well be stereotactic delivery.

The link Paula provided is regarding work by ArmaGen, who apparently DO have a trojan horse mechanism to deliver GDNF intravenously.

http://www.michaeljfox.org/research_MJFFfundingPortfolio_searchableAwardedGra nts_3.cfm?ID=440

So, I guess my question is - has Amgen licensed the gene to both Amsterdam and ArmaGen? Or is the upcoming ArmaGen trials using a different or non propietary version of GDNF?

I'm still a bit confused.

Caldeerster

[paula_w]

An article by ArmaGen researchers was published in Biotechnology and Bioengineering in Jan. 2008.
GDNF Fusion Protein for Targeted-Drug Delivery Across the Human Blood–Brain Barrier
Ruben J. Boado,1,2 Yun Zhang,1,2 Yufeng Zhang,1 Yuntao Wang,2 William M. Pardridge21
ArmaGen Technologies, Inc., Santa Monica, California
2Department of Medicine, UCLA, Warren Hall 13-164, 900 Veteran Ave., Los Angeles,
California 90024; telephone: 310-825-8858; fax: 310-206-5163;
e-mail: wpardridge@mednet.ucla.edu


Very technical article. I can provide a copy thru pm if you would like to see it.
Appears they genetically engineered their own formulation of GDNF that can go thru the blood-brain barrier. This was cloned from"human GDNF." It doesn't say where the human GDNF came from.
from the article:
"The present studies described the genetic engineering of a fusion protein of the chimeric HIRMAb and human GDNF.

Cloning of GDNF cDNA
The human prepro GDNF cDNA (GenBank P39905) corresponding to amino acids Met 1-Ile211 was cloned by the polymerase chain reaction (PCR) using the oligodexoynucleotides (ODNs) described in Table I and cDNA derived from reverse transcription of polyAþRNA isolated from human U87 glial cells."



paula

[aftermathman]

good bit of detective work.

As I see it (and I may be making this up):

i) AMT have a license from Amgen to use their GDNF gene, the GDNF gene contains the information for protein production.
ii) AMT have "production ready" facilities to produce AAV based gene therapies.
iii) AMT's approach will need injection into the brain.
iv) Armagen have a delivery mechanism that crosses the BBB (no injection needed).
v) Armagen have a product for PD, AGT-190, a protein that is comprised of a human neurotrophin that causes neuroprotection in the brain.
vi) I don't believe AGT-190 has any link to Amgen's GDNF.
vii) I can't find any timescales behind either company's products.
viii) AGT-190 sounds a lot like Ceregene's CERE-120 to me.
ix) What do Amgen get out of this relationship with AMT ?
x) Who is managing the AMT product, Amgen or AMT, who funds the trials and who picks up the revenue if it works ?

At least something is happening, the original delivery mechanism, though effective, was never going to have "commercial legs" IMO.

Take care,
Neil.

[paula_w]

Received this from another pipeliner in email this morning.

The patent - notice tabs on top to navigate the content

http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2007044323&F=0&QPN=WO2007044323

paula

[LindaH]

I’ve been following the GDNF saga for the last 4 years for the Parkinson Pipeline Project and I agree with most of Aftermathman’s conclusions.

also, Amgen holds a number of patents for both producing recombinant GDNF (the protein itself) and also for cloning the gene that encodes for GDNF. In the Bristol UK and Un. of Kentucky clinical trials, Amgen's GDNF was delivered into the brain through a pump catheter system (infusion delivery). After Amgen halted these trials in sept 2004, they would not release their GDNF to other researchers or companies who wanted to continue the research. You can buy other formulations of GDNF on the Internet, but Amgen’s was the only one that was FDA approved for use in human clinical trials.

It seems that ArmaGen has now produced their own version of GDNF (AGT 190) and developed a method of getting the protein through the blood-brain barrier. I also think this is not related to Amgen’s GDNF (but Amgen... ArmaGen - hard to believe its just a coincidence !)

Last week Amgen licensed their cloned GDNF gene to Amsterdam Molecular Therapeutics – a small biotech in the Netherlands. Instead of delivering the protein itself into the brain, this gene would be delivered into targeted areas of the brain through a virus vector (AVV), and the gene would hopefully transform brain cells into GDNF producing cells. The research is at the preclinical level

This approach is similar to Ceregene’s neurturin gene therapy treatment (CERE-120) currently in phase II trials. The gene is also delivered into the brain by a surgically implanted virus.
I’ve heard more than one researcher, in reply to questions, state that they would have preferred to use the gene for GDNF instead of neurturin. Neurturin is closely related the GDNF, and promising results were obtained in the phase I Ceregene trial (phase II results are expected soon), but GDNF seems to be recognized as the gold standard in neurotrophic factors.

However, AMT will now be able to use the GDNF gene and yes it is good news that Amgen has finally allowed another company to further research on GDNF for Parkinson’s. But this too is at the preclinical level.

Aftermathman, you ask important questions about Amgen’s future involvement.

“ix) What do Amgen get out of this relationship with AMT ?
x) Who is managing the AMT product, Amgen or AMT, who funds the trials and who picks up the revenue if it works “

If the development proceeds well, AMT will probably need to find a larger company to sponsor phase II and III trials. Hopefully it will it not be Amgen, who has a history of giving up on GDNF.

The one statement I don’t agree with is that “the original delivery mechanism, though effective, was never going to have "commercial legs"

Maybe not, but as an interim therapy, infused GDNF could have helped many PWP who are running out of options, possibly provided neuroprotection and regeneration until a more targeted delivery system treatment makes it through the pipeline in the future. And might have helped to advance the research. Other delivery methods do seem promising, but the clock has been set back for years.

There is a good summary on the MJFF website of various trophic factor delivery methods in development, as of April 2007 (maybe it will be updated?) at
http://www.michaeljfox.org/research_viewpoints_researcherAreaPositionPapers_t rophic.cfm


Finally I think we should recognize the GDNF trial participants in the US and the UK and the trial doctors who supported efforts to reinstate their treatments. Amgen’s phase II trial design and their resulting statistics and safety issues have all been challenged. I think the voices of the patients about the real life benefits of GDNF that they experienced were ultimately heard and they have helped to keep GDNF research alive.
Linda

[aftermathman]

What a shame Amgen didn't involve a partner with the resources to take a product to market, I expect they are concerned anyone big enough to do this will be real competition to them so went for a "lower league" player.

I have heard at a meeting of the Royal Medical Society that Neurosurgeon Stephen Gill at Frenchay (Bristol UK), one of the pioneers of the original GDNF trials, has developed his own delivery mechanism and is close to an agreement with Amgen to trial.

Anyone know any more about this ?

Neil.

[paula_w]

That's a possibility based on what I've heard in the past, but have no updated information. Gill disapproved the halt, but stayed out of the fray, not wanting to alienate Amgen, and kept working to improve the delivery.

Best case scenario: continue at phase II with a new delivery. I don't think that will happen tho, not in the U.S. anyway. Everything new must have clinical trials and FDA approval.

That's been our argument all along. When they think something better is coming along, they sacrifice entire generations of patients that could be treated with what they have now.

paula

What a shame Amgen didn't involve a partner with the resources to take a product to market, I expect they are concerned anyone big enough to do this will be real competition to them so went for a "lower league" player.

I have heard at a meeting of the Royal Medical Society that Neurosurgeon Stephen Gill at Frenchay (Bristol UK), one of the pioneers of the original GDNF trials, has developed his own delivery mechanism and is close to an agreement with Amgen to trial.

Anyone know any more about this ?

Neil.

[lurkingforacure]

What was that delivery method Gill used with his phase I trial participants? Sorry that I don't know, but am very curious. Thanks!

[CTenaLouise]

What was that delivery method Gill used with his phase I trial participants? Sorry that I don't know, but am very curious. Thanks!


if you can find an email or phone number - call them...
:)

[paula_w]

Good thing you did ask lfac. Gill didn't use his own pump, he was forced to use a medtronic. In spite of all my time spent on this subject, I don't think I ever realized that Gill never got to use his pump. It wasn't used in Bristol because Amgen was leary for already trying GDNF with injection and had already halted it once before in the 90's. Amgen wouldn't use Gill's for phase II either because it wasn't FDA approved. Here's a link to the GDNF summary on pipeline - clinical trials section includes the different delivery systems.

http://pdpipeline.org/advocacy/gdnf_overview.htm#monkeys

Monkeys in the Middle [ch 11 and 15] explains the difference in the pumps designed by Gill and another designed at the University of Kentucky. To attempt to put it simply, Gill and the un of K scientists felt that the pump should have some pressure behind it [convection enhanced] to shoot it into the putamen. The pumps they were required to use did not "push" it out and they worried that it would congregate around or reflux back up into the catheter - one explanation for why it worked for some and not others.

Amgen chose a different pump/catheter for phase II, causing one prominent researcher to quit. It was larger, more invasive.

paula

[LindaH]

Hi paula,
I checked one of the articles Gill and his colleagues wrote about the phase I study and he did use a Medtronic pump, but he designed the catheter.

" Intraputamenal Infusion of Glial Cell Line–Derived Neurotrophic Factor in PD:

A Two-Year Outcome Study"

Nikunj K. Patel, FRCS,1 Martin Bunnage, MPsych,1

Puneet Plaha, FRCS,1 Clive N. Svendsen, PhD,2

Peter Heywood, FRCP,1 and Steven S. Gill, FRCS1

In Ann Neurol 2005;57:298–302

"Patients and Methods

Five patients with idiopathic PD underwent stereotactic implantation of intraparenchymal catheters (in-house investigational device) into the posterodorsal putamen, which then were connected to SynchroMed pumps (Medtronic, Minneapolis, MN) implanted in the abdominal wall as described."

You're right on about the phase II trial -- Amgen chose to use a different, larger catheter for phase II, causing one prominent researcher to quit.

Also the dosage and method of delivery was different between the phase I and II trials.
This was summarized in "Crossroads in GDNF Therapy for Parkinson’s Disease" (Todd Sherer et al) in Movement Disorders, Vol. 21, No. 2, 2006, pp. 136–141 and discussed further in subsequent artciles by Bristol and Un. of Kentucky researchers, and others. Further research was recommended.

See: http://www.pdpipeline.org/advocacy/gdnf_research_history.htm

From the Movement Disorders article - Comparison of studies:
Dosage:
Bristol: Not standardized; different patients were dosed differently; range from 14.4 to
42.4
g/day and back
Kenrucky: 3
g/day for 2 months, 10
g/day for 2 months, 30
g/day for 2
months; 1-month washout
Amgen :15
g/putamen/day

Delivery
Bristol: Catheter may have provided convection enhanced delivery, but was not FDA approved

Kentucky: Medtronic multiport catheter; idle phase of delivery followed by
pulses every 6 hours

Amgen: Single-port Medtronic catheter (larger than Bristol catheter)

[paula_w]

Thanks Linda! I didn't think about them being separate and was wondering about why I could have sworn Gill used his own.

Neil, I'm throwing your question back to you. Was something said at a meeting recently about Gill and Amgen? I know he was definitely trying to use their GDNF again but it's been awhile.

paula