[girija]

From Medscape Medical News > Neurology
Neurotrophic Factor Promising for PD in Early Phase - Again

April 26, 2011 (Honolulu, Hawaii) — A change in dosing paradigm has a gene therapy approach to treating Parkinson's disease (PD) back on track to a phase 2b trial.

The therapy injects an adenoassociated virus vector carrying the gene for neurturin, a neurotrophic factor that enhances the function and survival of dopaminergic neurons (CERE-120, Ceregene Inc; www.ceregene.com), directly into the brains of PD patients during stereotactic brain surgery. An earlier approach directed injections only to the putamen, which in the end did not sufficiently reduce clinical symptoms, specifically on the primary endpoint of United Parkinson's Disease Rating Scale motor subscore "off of medications," in a phase 2a trial.

Injection to the putamen in animal studies had shown biological activity, lead study author Joao Siffert, MD, vice president and chief medical officer at Ceregene, told Medscape Medical News. However, he said, it came "somewhat as a surprise" that it wasn't enough in patients. The expectation was that the vector and protein would be transported from the putamen into the substantia nigra via the nerve cells, but in fact this wasn't efficient in patients.

"This is more and more acknowledged and reported in the literature — but it's not something that's widespread knowledge — that in fact there is a problem with transport of proteins along the axons in Parkinson's," Dr. Siffert noted.

Now, they are addressing this issue by injecting both the putamen and substantia nigra. However, he added, "In order to ultimately do the testing that we're now conducting, we had to go back and test whether it was feasible and safe in patients, and that's the phase 1 trial I reported."

The new results were presented during a late-breaking science session at the American Academy of Neurology 63rd Annual Meeting.

Open-Label Study

In this open-label study, 2 dose cohorts included 3 patients each; patients all had chronic idiopathic PD and a robust response to levodopa, although with motor complications, such as dyskinesia or severe wearing off.
Dr. Joao Siffert

Both cohorts received injections of 2.0 x 1011vg into each substantia nigra. The putaminal dose in cohort 1 was 2.7 x 1011vg, the same dose used in the previous phase 2 study; subjects enrolled in cohort 2 received a much higher dose of 10 x 1011vg. Patients were dosed once between December 2009 and June 2010.

The primary endpoint was the safety and tolerability of the procedure. Follow-up is now at 9 to 12 months. During that time, there have been no serious adverse events reported in this small number of patients, Dr. Siffert said. There have been no surgical complications or prolonged hospitalizations.

"All the adverse events are mild to moderate and expected, namely, headache and some swelling," he said. "Some patients had transient increase in 'on' state dyskinesias, most of which have resolved."

Importantly, there was no weight loss, he noted. "There were 2 reports in animals, , saying this was risky and could lead to inexorable weight loss, and this has not been shown either in our own animal studies under therapeutic doses or in this clinical study." Magnetic resonance imaging findings have also shown no complications.

"Going forward, we're doing a very rigorous, multicenter, well-controlled trial, comparing CERE-120 delivered through 3 injections in the putamen and 1 into the substantia nigra, on both sides of the brain, with half the patients receiving placebo surgery, Dr. Siffert said in an interview.

Patients will continue taking their usual medications and be evaluated every 3 months.

"We think by the end of the summer we'll complete enrollment, and it will be a year and a half, give or take, until the results," he said. "We're also following patients longer, in part because of the previous study — it may take longer to see an effect and also, I guess, to overcome the period where people are very enthusiastic because the placebo effect can be pretty high in patients with PD."

In the first phase 2 trial, reported at that time by Medscape Medical News and published in The Lancet Neurology in 2010, they did see "modest but significant" benefits on several endpoints, including the primary outcome in a subgroup of patients assessed at 18 months, suggesting that a longer follow-up might be necessary for the neurturin to provide clinical benefit.

Earlier Intervention

Session comoderator Walter A. Rocca, MD, professor of neurology and epidemiology at the Mayo Clinic, Rochester, Minnesota, asked Dr. Siffert what he sees as the future of this therapy. "Which patient do you think will ever benefit from this and what is your agenda?"

Dr. Siffert said from the ethical standpoint they have had so far to limit their enrollment to those in whom current therapy has failed and are experiencing motor complications, although they are trying to avoid those patients who are so far progressed that a neurotrophic approach would not be expected to make a difference.

"But I don't think it's a far leap to believe that if there's efficacy demonstrated for this in phase 2, and it's replicated in future studies, that ultimately this will be an approach that would be adopted earlier in the disease to really try to preserve the function of these cells before they've further degenerated," he said. "But that's for the future."

The study was supported by Ceregene Inc and the Michael J. Fox Foundation for Parkinson's Research. Dr. Siffert is an employee of Ceregene. Disclosure information for coauthors appear in the abstract. Dr. Rocca has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 63rd Annual Meeting: Abstract LBS.003. Presented April 13, 2011.
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Authors and Disclosures
Journalist
Susan Jeffrey

Susan Jeffrey is the news editor for Medscape Neurology & Neurosurgery. Susan has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor for thekidney.org and also wrote for theheart.org; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians. She can be contacted at SJeffrey@webmd.net.

[sim00]

Ceregene Completes Enrollment of Second Phase 2...

http://www.marketwatch.com/story/cer...ase-2011-12-01

[Conductor71]

Originally Posted by sim00

Ceregene Completes Enrollment of Second Phase 2...

http://www.marketwatch.com/story/cer...ase-2011-12-01

Unfortunately, I missed the boat on this one. I was screened on the telephone for participation, so I decided to ask the researcher a few questions. We know that GDNF is a growth factor, but how is that patients show clinical improvement? He answered that it looks not all cells are dying but rather thwarted or malfunctioning and the treatment is restoring function. Not his exact words but that was gist. I wonder if they have a cancellation list...if someone finks out early.

Laura

[lurkingforacure]

Originally Posted by Conductor71

Unfortunately, I missed the boat on this one. I was screened on the telephone for participation, so I decided to ask the researcher a few questions. We know that GDNF is a growth factor, but how is that patients show clinical improvement? He answered that it looks not all cells are dying but rather thwarted or malfunctioning and the treatment is restoring function. Not his exact words but that was gist. I wonder if they have a cancellation list...if someone finks out early.

Laura

Yes, this has been one of the things I have never been able to confirm for a fact. Everyone throws out that the cells die in PD but some very few folks have been brave enough to disagree. This seems to confirm that the vast majority who have supported the cell-death theory are incorrect, and this would make sense with Dr. Jannetta's lady who recovered from PD the day after her surgery for another condition. There is no way, if all those cells had died (she'd had PD for 9 years, I think), that they could have regrown overnight. Instead, I think what happens is that the cells are atrophied, compromised, sick, weak, whatever you want to call it, and when they start getting what they need (in Jannetta's case/theory, blood blow and everything that it brings to a cell), they become normal again and can function properly.

It's interesting how research can end up contributing to establishing things that were probably not part of the original hypothesis.

[Conductor71]

Funny how things become established as fact when indeed nearly everything about this disease that we think we know is theoretical. Funny too how it is always the worst case scenario. I have had some experience lately with the power of suggestion and wonder that if our prognosis and treatment were approached from giving equal consideration to positive things we can do. I am starting to have anxiety attacks when I visit the neuro because we area always so focused on decline.

Good points on why they most likely not all dying. I always had a hard time with the idea of us losing our urons in one big hit and then go on for 10-20 years before motor symptoms emerge? That is some extraordinary compensatory system. I think key to all this is the statement above by Dr. Sifferxt:


"This is more and more acknowledged and reported in the literature — but it's not something that's widespread knowledge — that in fact there is a problem with transport of proteins along the axons in Parkinson's,"

From The Role of Axonopathy in PD

This goes right along with what we are saying. Don't we always hear how when motor symptoms appear that we have lost 70% or more of our cells?Well the scientist who has been misquoted since 1973 that we lose 70-80% of our axonal Dopamine in the striata and 50% of nigral Dopa cells. A little more is involved than what we commonly hear.

Not only does this point to new, earlier treatment strategies, it points out how very late in the disease we get aggregation of alpha-synuclein. By that time the damage has really been done which begs the question. Should we be spending so much time on targeting Alpha-Synuclein for treatment and spend more on establishing more ways to prevent the loss or damage to our axons?
I
n reading that article the main things we all share in common (genetic,sporadic,environmental) is the axonal damage and misfolded protein. Why still do they cling to Lewy Bodies as disease hallmark when upon autopsy they are present in other conditions and are not always present in the PD brain. We have here another example of theory as fact.

It just goes to show that a little knowledge can be a dangerous thing. This sort of theory as fact spills over into can shape decades of research. When do we start looking and at the anomalies for answers? Why do other seemingly healthy brained people have Lewy Bodies? for starters. I know this is attributed to Einstein and is supposedly his definition of insanity. That is a bit harsh; the words need no further explanation: "If you keep doing the same thing repeatedly, how can you expect to see different results?"