By Cynthia Robbins-Roth

BioWorld Today Columnist

As I head into my mid-50s, I have daily reminders that neurodegenerative diseases are huge problems. In addition to my own memory lapses, my family and my friends' families are affected by head trauma, Alzheimer's, ALS, multiple sclerosis and Parkinson's. Millions around the world lose the ability to function in society from those ailments.

It's only been in the past two decades that we've had any hints about the molecular underpinnings of neurodegeneration. A grab bag of relevant genetic mutations and cell interactions have been identified, but we still really don't know what is causing the gradual loss of nerve function or how to stop it.

Back in the late 1980s and 1990s, when protein replacement was biotech's primary strategy, Amgen, Chiron, Regeneron, Cephalon and others embarked on quests to use neuronal growth factors to treat neurodegenerative diseases. The idea was to slow and maybe repair the damage, regardless of underlying cause.

Unfortunately, all of those programs were dropped, in some cases after running several Phase III trials. Nobody could deliver enough of the factors in a selective way to the correct location to drive reproducible, significant clinical improvement. Some unexpected toxicity showed up - probably because of delivery problems.

Amazingly, neuronal growth factors are back in the clinic with big bucks behind them. The key to the rebirth? A new approach that more closely mimics natural delivery of those factors.

Ceregene was launched in 2001 as a subsidiary of Cell Genesys, getting a nice dowry of $10 million plus IP. Cell Genesys CEO Steve Sherwin and his team saw an opportunity to keep an internal focus on cancer therapies, while pursuing CNS gene therapy in a focused way. (Sherwin's team likes spinouts as a mechanism for generating value. They spun out Abgenix with its human monoclonal antibody technology in 1996. Abgenix went public in 1998 and was bought for $2.2 billion by Amgen in 2006. )

Another important ingredient was Neurological Gene Therapeutics (NGT), a virtual start-up founded by Mark Tuszynski and Armin Blesch of University of California - San Diego, and Jeffrey Kordower of the Research Center for Brain Repair at Rush Presbytarian in Chicago.

Tuszynski was trying to figure out how to get nerve growth factor (NGF) into cholinergic nerves in the desired brain region in Alzheimer's patients. His UC-SD team used ex vivo NGF gene therapy and reimplantation to reverse age-related neuronal atrophy in monkeys, restoring normal numbers and activity of axons.

Ceregene in-licensed that technology, and in 2001, Tuszynski treated skin cells from Parkinson's patients ex vivo with the NGF gene therapy and reimplanted them in the damaged brain region with stereotactic injection. Responding patients had a 50 percent reduction in the rate of decline and enhanced brain activity, measured by PET-glucose metabolism. Two years later, those patients still showed improvement.

But the 1990s convinced many that ex vivo cell therapy was a scary business model. The new Ceregene team created an AAV vector carrying the NGF gene, delivered by a proprietary in vivo procedure. A 2001 Phase I study in six patients showed promising results in line with the ex vivo treatment.

CEO Jeff Ostrove said Ceregene wants a partner to help support the Phase II trial - 50 patients, double-blind, 24 months duration, $5 million. Ostrove said they would love to team up with someone other than a conventional corporate partner and retain the product rights. (Hey, Symphony Capital, are you listening?)

But even more promising were rat studies showing that a single treatment in vivo with an adeno-associated virus (AAV) vector carrying the glial-derived neurotrophic factor (GDNF) gene was able to restore nerve function in a rodent model of Parkinson's.

Parkinson's Program

Amgen, owner of the GDNF patents and pursuing it until 2005, didn't want to license the gene to Ceregene, so the team switched to neurturin, a cousin of GDNF, delivered by needle directly into the brain site affected by Parkinson's.

Unlike previous methods - infusion into ventricles or a canula in the striatum - Ceregene's delivery is designed to mimic natural expression in the striatum. The AAV vector, which expresses no viral proteins, requires only 80 microliters, vs. the milliliters used in ventricle delivery approaches. The company believes that with less volume and less viral particles, there is less concern for immune reaction. Bonus point - you need only 10,000 square feet of manufacturing to make enough drug for the entire Parkinson's market.

The preclinical studies showed that approach to be lacking the adverse effects seen with ventricle delivery. Neurturin expression starts in 2 days, peaks at day 28 and persists at least 24 months.

In an open-label single-treatment Phase I, 12 patients showed a 40 percent (p<0.001) reduction in symptoms. Ceregene began Phase II early this year that will treat 51 patients for 12 months, with a crossover for another 24 months to look for persistence of treatment effects. The Michael J. Fox Foundation providing partial financial support for both trials.

A New Route Of Delivery

Ceregene's delivery approach is easily extended to other neurodegenerative diseases. After Cephalon and Chiron gave up on IGF-1 for ALS in 1998, Fred Gage's mouse studies at Salk suggested that retrograde transport of the AAV construct up peripheral nerves might be a more successful route of delivery. Ceregene licensed the technology and Project ALS, the ALS Association, the Robert Packard Foundation and NIH are funding the program. Ceregene has some early programs in Huntington's disease and retinal disorders, both based on preserving neural cell function.

Ostrove said that Ceregene is a development company, working with well-established factors that were discovered and cloned by others, and in-licensed by Ceregene. The novel twist is finding a solution to the delivery challenges that stymied earlier programs.

That appealed to Alta, MPM, California Technology Ventures and Hamilton BioVentures, who put in another $32 million in 2004. Cell Genesys retained a 25 percent stake in Ceregene. A series C round is in the works.

Will Ceregene succeed where others failed after expending significant time, energy and resources? For the sake of those patients, we certainly hope so.

Robbins-Roth, PhD, founding partner of BioVenture Consultants, can be reached at Her opinions do not necessarily reflect those of BioWorld Today.

BioWorld Today  March 12, 2007