Part I: Introduction

To a mind diseased: Biotechnology's struggle to heal neurological ills

"Canst thou not minister to a mind diseas'd . . .?"

By Joan O'C. Hamilton
Signals Editor

A decade ago a "brainstorm" swept through biotechnology. Venture capitalists were raiding neurology labs and scrambling to set up companies around prominent neuroscientists. Some predicted they'd have Alzheimer's drugs in clinical trials by the early 1990s. At the time, one of biotechnology's best known Wall Street supporters confided worriedly, "These big VCs are all standing in a circle, seeing each other and calling it credibility. The fact is there have been no fundamental breakthroughs in the technology." At the risk of being branded a heretic, this banker asked not to be quoted by name.

Ten years later no one who's seen the devastating damage of neurological ills such as Alzheimer's disease or stroke takes any pleasure that history has confirmed the heretic's prediction. There's been a short list of modest gains from biotechnology projects aimed at neurological disease, including drugs from Biogen and Chiron to battle the recurring complications of multiple sclerosis, and a secondary stroke indication for Genentech's heart attack drug, TPA. Notably, neither came from a dedicated neuroscience company. "What became evident," says John Groom, chief executive of Athena Neurosciences, which was acquired by Ireland's Elan for $600 million in 1996, "was that this was just one hell of a tough area. The reality was that a decade is a blink of the eye in terms of taking on a neurological disease."

John Groom, CEO, Athena Neurosciences, Inc.

But despite the odds, despite the complexity, despite the frustration, many first generation neuroscience companies, including Athena, Neurogen, Synaptic, Cephalon, Alkermes, Neurex, and Cambridge Neuroscience, have persevered. Some have changed course, licensed-in existing products to sell, or weathered storms; but most are still pursuing important therapeutics. Meanwhile, more companies, both venerable and brand new, have joined in trying to tease out the monstrously complex biology of the brain and come up with viable new agents. Amgen, for example, and has increased investments across a broad range of CNS projects. Two year-old NeuralStem Pharmaceuticals of College Park, Md., meanwhile, hopes to be in the clinic with a novel new Parkinson's cell therapy approach based on replacing damaged neurons with fetal stem-cell derived dopaminergic neurons within a year to 18 months.

In addition to the original "holy grail" indications such as Alzheimer's, Parkinson's and multiple sclerosis, a long list of other problems are now under the microscope: migraine, chronic pain, anxiety, obesity, sleep disorders, schizophrenia and depression. In company after company, executives and scientists acknowledge that biotech has lost its arrogance when it comes to the brain. Yet, the activity is still intense. In Part I of this three-part series, Signals takes a look at the difficult road neuroscience companies have traveled in the past decade. In Part II, we'll look in-depth at the complex world of Alzheimer's Disease, where soon there should be answers to several fundamental scientific questions that could launch that field in a new direction. And in Part III, we'll look at the controversial arena of agents aimed at emotional and personality disorders, such as depression, anxiety and compulsive behavior.

Biology is destiny

When things take longer than expected in biotechnology, it's invariably safe to blame it on the biology.

For years, the brain was the human body's equivalent of the airplane black box -- it held many secrets, but was designed to be nearly impenetrable. Not only was it surrounded by tightly packed capillaries comprising the so-called blood-brain barrier, but even when scientists took a look directly at brain tissue, it yielded few clues. "For research in organ systems like the kidneys or liver, you can look at the cells and tissues and pretty much figure out what they do. Different cell types look different. The hard thing (about central nervous system or CNS disorders) is that you can't understand the function of cells by looking at brain cells. It's all a big gamish," explains industry consultant Cynthia Robbins-Roth, Ph.D., who's tracked neuroscience companies for years.

But in the mid-1980s, neuroscientists started using the tools of biochemistry. And soon, scientists were identifying neuronal cell receptor sub-types, or folded protein sections of receptors. Receptor sub-types helped explain the cell's function, offered potential drug targets, and began elucidating the mechanisms of disease. Explains Robbins-Roth: "Neurologists went nuts when they started to see this, because all of a sudden you had a mechanism to affect the specific cell types. It became exciting."

Among the most important neuronal cell receptor categories are the dopamine receptors, which are linked to Parkinson's disease and emotional behavior, gamma aminobutyric acid or GABA receptors, which are involved in anxiety, insomnia and migraine, neuropeptide Y whose subtypes are linked to metabolism and appetite, serotonin receptors, which are linked to depression, mood and other behavioral problems, and corticotropin releasing factor receptors which play a role in the body's overall response to stress.

Richard F.Pops, CEO, Alkermes, Inc.

With the receptor sub-types in hand, neuroscientists went fishing for proteins, and "a number of proteins were discovered that seemed to have the potential to regenerate neurons," recalls Richard Pops, chief executive of Alkermes Inc., one of the early neuroscience companies. And so venture capitalists started launching companies: "The idea was replicating the Amgen model for CNS," Pops says. Largely on the strength of that ambition, Wall Street funded the companies generously, too. During the 40-company-strong "IPO Class of 1991," for example, 17.5% of the companies going public were CNS-dedicated companies. They collected a whopping 23% of the $1.3 billion raised that year.

Some forget it was CNS that first inspired an earlier version of the dilemma that biotech executives debate endlessly to this day: Is it best to organize around a fundamental technology platform with broad application, or do you collect available technology and point all of it toward a single disease area where you can leverage your biological understanding of disease mechanism? You couldn't prove the wisdom of the latter strategy by the CNS companies' progress. "The trouble was what always happens in complicated areas like this," notes Robbins-Roth. "Everybody assumes the newest thing they've done must be the hardest thing they had to do," and that real pay-off is imminent.

'You can't swallow mice'

Indeed, there were bitter disappointments from those early projects. Researchers were learning more about disease mechanisms, but in terms of product development that primarily translated to explanations for why products weren't working. The biggest heartbreaks: Early projects such as Synergen's and Regeneron's human ciliary neurotrophic factors and Regeneron's brain-derived neurotrophic factor aimed at ALS. Despite tens of millions in investment, they just didn't pan out. And since it was only large proteins that needed special technology to penetrate the blood-brain barrier (small chemical molecules do pass through), an early burst of work in that realm died down as the big proteins looked less promising. Alkermes, for example, has shifted most of its efforts to drug delivery across a broad spectrum of disease, not just conquering the blood-brain barrier. Even big advances, such as Athena's development of a mouse model for Alzheimer's, "were a long way from a product. You can't swallow mice and use them as a drug," notes Groom.

Biotechnology's attack on neuroscience is still a work in progress, a tale of relative baby steps compared to the big promises of the mid-1980s. Yet much of the work is quite exciting: On February 16, Neurocrine Biosciences, Inc. of San Diego announced that its scientists have used small organic "drug like" molecules to elevate levels of the body's own insulin-like growth factors (IGFs) by inhibiting binding of this growth factor to IGF binding proteins. In the February 17th issue of "Proceedings of the National Academy of Sciences," scientists from Neurocrine demonstrated that displacement of IGF from their binding proteins seems to protect neurons in a stroke model. It also may have broader applications for the treatment of other neurodegenerative disorders as well as brain trauma and spinal cord injury. "The advantage of this approach is that small molecules have the ability to cross the blood-brain barrier, which is essential in the treatment of central nervous system diseases such as stroke. In addition, therapeutic agents can be designed to be active via oral or intravenous (I.V.) administration to treat chronic and acute indications such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, diabetes and Peripheral neuropathies," stated Errol B. De Souza, Ph.D Executive Vice President of Research and Development of Neurocrine Biosciences.

Industry leader Amgen currently has three neurotrophic factors in early clinical development including brain-derived neurotrophic factor (BDNF) for the treatment of ALS, glial-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease and ALS, and neurotrophin - 3 (NT-3) for treatment of nerve damage caused by chemotherapy and diabetes. It's also invested heavily in other neuroscience and neuroendocrine research, such as in obesity, and it's signed several collaborations with Guilford and others in CNS. Neurex of Menlo Park, Calif. has overcome lots of disappointments and strategic shifts, but has announced very promising progress in clinical trial with its novel pain drug, SNX-II, derived from shellfish. And despite some slow going, GABA sub-type receptor work, to name just one subtype research area, still represents top priority projects for a slew of companies, including Neurogen, CoCensys and Neurosearch.

Dr. Frank Baldino, President and CEO, Cephalon, Inc.

It's more evidence that the biotechnology industry's uncanny ability to adjust, partner and reboot R&D in the face of setbacks has not been lost on neuroscience companies. Cephalon, Inc., headquartered in West Chester, PA, is developing products for the treatment of ALS, narcolepsy, peripheral neuropathies, Alzheimer's disease, head and spinal injury, and stroke. Cephalon Inc.'s frustrations in trying to get Myotrophin, its recombinant insulin-like growth factor, approved for ALS are legend, yet CEO Frank Baldino, a high-energy, feisty optimist, maintains that despite the challenges, the future remains bright. After a devastating setback in May of 1997 when a Food & Drug Administration advisory committee issued a recommendation not to approve Myotrophin against ALS, Cephalon has since regrouped. The company is hopeful the FDA will look more favorably on additional data it submitted in November

"When we started the concept was: Can you develop drugs that slow the progress of neuro-degenerative disease," notes Baldino. "We all went after that. In Parkinson's, Alzheimer's, ALS, cells are dying. So the question was: Can it be done? Yes, it has been done," he adds, noting Myotrophin "is the only drug ever to demonstrate slowing" of nerve degeneration in man.

Now, the field is moving in some even more exciting directions. Baldino speaks somewhat for the old school when he maintains, "Once neurons are dead, they don't come back. I can't bring neurons back in the next 50 years, that's just not going to happen. So, what we want to do is stop (disease progression) in its tracks." At start-up Ontogeny, however, scientists are using developmental biology and specifically insights from the infamous "sonic hedgehog" protein to check the body's early circuitry for clues on how to reactivate it to repair damage later in life from disease or injury. "The joke used to be neurologists can diagnose everything and they can't treat anything, and the dogma was that the CNS doesn't repair. Well, guess what?" asks CEO Doros Platika, a developmental neurobiologist. "The circuitry is still there." Cambridge, Mass.-based Ontogeny, which is partnering with neighbor Biogen, hopes to enter human trials with a circuit reactivator sometime in 1998 against Parkinson's disease.

On the west coast, Signal Pharmaceuticals in San Diego, CA, has licensed a human neuronal cell line to Roche to explore in pain and urinary tract disorders, but Chief Executive Alan Lewis says the company isn't stopping there; CNS "is going to be a phenomenal area for us. We want to do something big, not just a program," he says. Neuroscience has been hindered by an inability to grow stable human neuronal cells for study; so far, researchers have used either non-human cells or neuronal receptors cloned into non-neuronal cells as discovery tools. Signal's hope is that these neuronal cell lines will be used in combination with genomic and other technologies to identify the underlying mechanisms of neurological disorders and to screen for new classes of drugs with improved pharmacological effects. "The knowledge is only really starting to emerge," says Lewis, but he feels Signal's cell line could offer insights on a number of pathways, including serotonin, epilepsy and Alzheimer's.

Start-up NeuralStem, meanwhile, has the technology to "grow up every kind of neuron," says an excited Richard Garr, CEO. "The history of the attempts to get stem cells and neuronal cell lines is littered with failures," he acknowledges, but says his company, working with technology licensed out of the National Institutes of Health, has made huge progress in isolating and propagating a broad array of CNS cell types. And at Layton Biosciences in Atherton, Calif., CEO Gary Snable says the company is optimistic about studies showing that neuronal cells it has managed to grow from an unusual type of cancer cell called a teratocarcinoma, could restore both physical and cognitive function in stroke victims. Layton hopes to begin testing in people soon.

Are we on the verge of important new therapies, or still in the tangled jungle of brain biology, always assuming the last river forded or tree climbed finally puts us on the path toward home? Cautious optimism is the only option for those who've seen the mysteries of the brain elude science for the last decade. Ten years ago, venture capitalists and entrepreneurs were mesmerized by the size of the proverbial "unmet medical need" in neurology, but they were also sadly deficient in having the technology, drugs and delivery systems to meet those needs. The good news for the rest of us, though, is that the companies didn't give up.