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striking down parkinsons (signals magazine)




Pope John Paul II, Muhammad Ali, former U.S. Attorney General Janet Reno, and Michael J. Fox may have put a public face on Parkinson's disease, but they are hardly alone in their suffering. This debilitating neurodegenerative disease afflicts about 1 million Americans and 4 million individuals worldwide. The exact cause is not known, but genetics and environment have both been implicated. And, while the disease generally affects older people, it can strike earlier, before the age of 40. There is no known cure and treatments are focused on relieving the symptoms - but even available therapies, which replenish the neurotransmitter dopamine, are far from ideal. That leaves the field wide open for the many biotech and pharma companies that are devising what they hope will be more effective treatments for Parkinson's - or perhaps slow its progression. We'll explore several different approaches - including receptor agonists and antagonists, signal inhibition and nerve growth promoters.




Neuroscientists have been trying to crack the safe that holds the secrets to the human brain's inner workings for decades - and in the mid-1980s, they thought they had found the right combination when they began to identify the various receptors and receptor sub-types that reside on nerve cells. The receptors themselves would no doubt serve as great drug targets, the thinking went, and understanding how they functioned would also provide key insights into disease mechanisms.

It was an exciting time for all - and venture capitalists, caught up in the rush, started funding one CNS-based company after another. Wall Street caught the fever, too: Of the 40 companies that comprised the IPO Class of 1991, seven were neuroscience firms. Some of those - including Cephalon Inc. and Alkermes Inc. - are still around (even though Alkermes has changed its focus). However, most of the early batch of neuroscience companies (including the private ones) were assimilated or fell by the wayside.

In short, that's because the science has proved a lot tougher than anyone thought it would be. While biotech and pharmaceutical companies have managed to concoct a small number of therapies for various CNS diseases and disorders, they have yet to find any bona fide cures.

That's certainly not for lack of trying. Indeed, as technological innovations have continued to provide a steady stream of new tools for the molecular biologist's kit, researchers have made some significant strides in unraveling the mysteries of the brain - especially in neurodegenerative diseases. And they've founded one new company after another to capitalize on the advances that are sure to come.


Neurodegenerative diseases - Alzheimer's, Parkinson's, Huntington's, ALS, and others - are progressive disorders accompanied by the loss of neurons in the brain. Unfortunately, much of the damage has already occurred before a patient is actually diagnosed with one of these diseases: In Parkinson's, for instance, it's thought that 70-80 percent of the neurons in the affected area of the brain are already dead before symptoms appear.

To date, medicines for treating such patients aim at replacing the neurotransmitters that are lost through cell death. The ultimate goal, of course, is to prevent cell death in the first place. But that requires a clearer picture of the underlying biochemical, genetic and environmental factors that cause the phenomenon in the first place.

"Our understanding of the causes of [neurodegenerative diseases] is just now beginning to explode," explained Dale Schenk, SVP of research at Elan Corp. plc. Speaking on a neurodegenerative disease panel at the BIO Emerging Company Investor Forum (BECIF) in San Francisco last month, Schenk mentioned advances in understanding the role of amyloid plaques and neurofibrillary tangles in Alzheimer's; the part that cell trafficking plays in multiple sclerosis; and the contribution of genetic factors in Parkinson's.

But challenges remain to this day. For one thing, getting drugs into the central nervous system is problematic, since many can't squeeze past the blood-brain barrier. For another, conducting clinical trials is made more difficult because the endpoints are "soft."

Plus, although there are now a thousand or more speculative targets for drug development, "the next step to the actual target is very tough," according to Franz Hefti, who also participated on the panel at BECIF. Hefti, the EVP of drug development at startup Rinat Neuroscience Corp., said that companies used to identify targets with a reasonable chance of success and then figure out if they worked in the clinic. This approach, he believes, is flawed. "We have to work on disease mechanisms."

That, also, can be difficult, since not every disease has a good animal model to rely on. Fortunately, the animal models for Parkinson's are fairly good, and they have helped researchers in this field to come up with some promising therapeutic approaches.

Selected Therapies Under Development For Parkinson's Disease

Company
Product
Mechanism Of Action (Known Or Proposed)
Status

ACADIA Pharmaceuticals
ACP-103
Blocks activity of the 5-HT2A receptor (inverse agonist)
Phase II

Aderis Pharmaceuticals;
Schwarz Pharma
Neupro
(rotigotine transdermal system)
Dopamine receptor D2 agonist
NDA submitted

Amgen
GDNF
(glial cell line-derived neurotrophic factor)
Promotes growth, regeneration and protection of neurons that secrete dopamine
Phase II trial failed; product did not achieve primary endpoint of clinical improvement

Arena Pharmaceuticals
Inverse agonist to GPCR
(G protein-coupled receptor)
Orphan receptor that is expressed and co-localized with dopamine receptor D2; inverse agonist may amplify dopamine function
Early-stage research

Avigen
AV201
(gene therapy)
Delivery of human gene AADC (which enables more efficient use of L-Dopa) into the striatum of the brain
Phase I/II

Cephalon;
H. Lundbeck
CEP-1347;
mixed lineage kinase (MLK) inhibitor
Prevents death of neurons that produce dopamine by inhibiting key signaling mechanism
Phase II/III



Parkinson's disease, originally called "the shaking palsy" by the English MD James Parkinson in 1817, is, indeed, characterized by a tremor in the hands, arms, legs, jaw and face, stiff limbs and difficulty in movement and balance. As the disease progresses, patients may find it hard to walk, talk or perform simple tasks of daily living.

These symptoms are caused by degeneration of the neurons in the area of the brain called the substantia nigra, which produces the neurotransmitter dopamine that is required for smooth, coordinated movement. The standard therapy for Parkinson's is levodopa (L-dopa), which is converted in the brain to dopamine. However, while L-dopa does diminish disease symptoms, it cannot halt disease progression. Moreover, it becomes less effective the farther the disease progresses, meaning patients must take increasingly larger doses. Sadly, that's not a solution either, for large doses induce side effects such as involuntary movements, tics, rigidity and even hallucinations. Thus, even though L-dopa works well early on, due to its serious, dose-limiting effects in late-stage disease, the quest for new therapies is compelling.


In many cases, that means devising ways to replace lost dopamine by introducing a dopamine agonist, which interacts with the dopamine D2 receptors and thus mimics the actions of dopamine.

That's the idea behind Aderis Pharmaceuticals Inc.'s transdermal patch to treat Parkinson's. The patch, called Neupro, contains the non-ergot dopamine agonist rotigotine. Importantly, the once-daily patch provides sustained delivery of therapeutic levels of drug, thus avoiding the side effects and changes in efficacy that accompany fluctuating levels of orally delivered medications. "Most patients take 9-19 pills a day," explained Kenneth Rice, Aderis' VP, CFO and chief commercial officer. "If they are under-medicated, they are rigid. If they are over-medicated, they have uncontrollable movements."

But the patch is intended to alleviate this problem. It took the firm 12 years to develop the final version of the drug/patch combination, he said, and "we can scale up the dose by the size of the patch."

Aderis' partner Schwarz Pharma AG has tested the patch in two pivotal Phase III trials in Parkinson's patients with early-stage disease and submitted an NDA in September 2004. The German pharma is also conducting Phase III trials in patients with late-stage disease, and predicts that it will file for marketing approval in this indication in the first quarter of 2006. Already, the company has presented results demonstrating that Neupro, when used in combination with L-dopa, showed statistically significant and clinically relevant reduction in "off" time (when patients are experiencing symptoms, such as when medication wears off) without an increase in involuntary movements (dyskinesia) in patients with advanced Parkinson's.

Selected Therapies Under Development For Parkinson's Disease

Company
Product
Mechanism Of Action (Known Or Proposed)
Status

Ceregene
Gene therapy
Delivery of GDNF gene into the striatum to prevent degeneration of dopamine-producing neurons
Early-stage research

Curis;
Wyeth Pharmaceuticals
Hedgehog proteins and small molecule hedgehog pathway agonists
Promotes healing of nerve tissues
Preclinical

Guilford Pharmaceuticals
GPI 1485;
neuroimmunophilin ligand
Induces growth in damaged nerves
Phase II

Kyowa Hakko
KW-6002
(istradefylline);
adenosine A2A receptor antagonist
Acts as a dopamine receptor D2 agonist
Phase II

Neurocrine Biosciences
Adenosine A2A receptor antagonist
(in-licensed from Almirall Prodesfarma)
Acts as a dopamine receptor D2 agonist
Preclinical

Neurologix
NLX-P101;
gene therapy
Delivery of GAD gene (which makes the inhibitory neurotransmitter GABA) into the subthalmic nucleus in the brain
Phase I



Another approach is to target a G protein-coupled receptor (GPCR) that is expressed and co-localized with the dopamine receptor D2. Although not a priority program at this time, Arena Pharmaceuticals Inc. has identified such a receptor and the intracellular second messenger (cAMP) that this receptor activates. The company believes that inverse agonists to this orphan receptor GPCR 19X may be able to amplify dopamine function.

According to Dominic Behan, Arena's SVP and CSO, both the D2 receptor and the orphan receptor 19X are stimulated by cAMP. But in Parkinson's disease, the D2 receptor is overstimulated. "If we could tone down cAMP [expression] in these neurons, we may have a novel approach to treating the disease." Company researchers have "found some small molecules to that receptor that appear to moderate signaling activity, but they haven't been evaluated in animals."

While Aderis' compound acts directly as a dopamine D2 receptor agonist, and Arena's approach involves an inverse agonist, another sort of small molecule - known as an adenosine A2A receptor antagonist - ends up serving the same purpose. (Adenosine is a neurotransmitter that also plays a role in the control of movement.) The A2A and D2 receptors are co-localized in the brain, and an agonist to one of them will counteract an agonist to the other, according to Alan Foster, senior director of neuroscience at Neurocrine Biosciences Inc. Thus, "an A2A antagonist would be similar to a D2 agonist," he said.

Selected Therapies Under Development For Parkinson's Disease

Company
Product
Mechanism Of Action (Known Or Proposed)
Status

NeuroSearch;
Boehringer Ingelheim
NS2330;
monoamine re-uptake inhibitor
Increases existing dopamine levels
Phase II

Newron Pharmaceuticals
Safinamide
Multiple mechanisms of action, including inhibition of dopamine uptake and MAO-B
Phase III

Nura
GPCR-based small molecule therapies
Drugs that act through GPCRs on dopamine-producing cells; drugs that target GPCRs that modulate movement control
Discovery

Teva Neuroscience;
Eisai
Agilect (rasagiline mesylate);
second-generation MAO-B inhibitor
Blocks breakdown of dopamine
NDA submitted

Titan Pharmaceuticals;
Schering AG
Spheramine;
Human retinal pigment epithelial (RPE) cells on microcarriers
RPE cells produce dopamine
Phase II

Vernalis;
Biogen Idec
V2006;
adenosine A2A receptor antagonist
Acts as a dopamine receptor D2 agonist
Phase I



There's a lot of hope for this approach, too. Preclinical and clinical studies have already shown that selective A2A receptor antagonists are able to relieve Parkinson's symptoms when used as a monotherapy and can also enhance the effects of L-dopa.

For instance, two Phase II trials of Japanese pharmaceutical company Kyowa Hakko Co. Ltd.'s adenosine A2A receptor antagonist KW-6002, which were published in August 2003, demonstrated "an increase in L-dopa efficacy" in one trial and, when used as a monotherapy, "improvement in movement" in the other, Foster said.

Those results, plus the fact that there are good animal models for Parkinson's disease (both rodents and non-human primates), were enough to convince Neurocrine Biosciences to start its own Parkinson's research program - and earlier this month, it licensed the rights to preclinical, selective small molecule A2A receptor antagonists from the Spanish pharmaceutical company Almirall Prodesfarma S.A.

As well, there is some evidence from A2A "knockout" animal studies that the antagonists may be neuroprotective, Foster added. "If this translates into Parkinson's disease, the antagonists may also have a disease-modifying aspect."


Indeed, if a compound was able to enhance the survival of dopamine-producing neurons, it should be possible to delay the progression of Parkinson's disease. That's certainly the goal of Cephalon's experimental drug CEP-1347, which it is developing through a partnership with H. Lundbeck A/S. The compound is currently in placebo-controlled Phase II/III trials in patients with early-stage Parkinson's disease, where it is being tested as a monotherapy. The idea is to "delay the use of L-dopa therapy," explained Paul Blake, Cephalon's SVP of clinical research and regulatory affairs.

These multinational trials are being conducted by the Parkinson Study Group, and with a final enrollment of 809 patients, are some of the largest ongoing studies at the moment. "The first patients have already been on the drug for two years," Blake said. Once the last patient reaches that point, which should be in mid-2006, then the results will be analyzed.

CEP-1347 acts by inhibiting members of the mixed lineage kinase (MLK) family, which are part of the stress-activated protein kinase pathway. It's known that triggering this pathway is one of the first events in apoptosis. By inhibiting the MLKs, then, it should be possible to halt cell death, enhance neuronal survival, and inhibit or delay the progression of neurodegenerative diseases such as Parkinson's. That's proved out in non-human primate models of the disease, and hopefully will translate in the clinic.

Cephalon's been interested in therapies for neurodegenerative diseases right from the beginning, explained Jeffry Vaught, SVP and president, R&D. At the time (1987) "we set out to understand the signaling mechanisms by which neurons stay alive and the processes that cause cell death," he explained.

Cephalon researchers developed the MLK inhibitor in-house, but the program sprang from an early-stage in-licensing deal on receptor tyrosine kinase inhibitors that the biotech firm signed with Kyowa Hakko in 1992. Under this collaboration, the parties worked on a series of small molecules with various activities, and some of them enhanced survival in cultured neurons, Vaught said. "We discovered CEP-1347 in 1994. It had a robust effect on survival and broad biological activity in multiple models in vivo." But company scientists didn't discover that MLKs were the target until 1996. According to Vaught, MLKs didn't even exist as a target until then.

And they now know that "CEP-1347 prevents cell death by intercepting a key signaling mechanism in the cell," he added. The company chose to develop the molecule in Parkinson's (rather than Alzheimer's) because "the animal models are better, there is greater consensus on the mode of cell death, and the MLK pathway is engaged in that."


The other way to enhance the survival of neurons is to repair and regenerate damaged cells, which Guilford Pharmaceuticals Inc. has set out to do with its small molecule compound GPI 1485, a neuroimmunophilin ligand. In preclinical experiments, Guilford scientists showed that this compound was able to repair and regenerate damaged nerves without affecting normal ones. But the original research goes back to 1990, when researchers in the lab of Guilford co-founder Solomon Snyder, the director of the department of neuroscience at Johns Hopkins Medical School, discovered that the immunosuppressive drug FK-506 was able to induce nerve growth in vitro and in vivo.

"FK-binding proteins had just been discovered," explained Craig Smith, Guilford's chairman, president and CEO. The scientists found out that not only did the brain contain this new class of proteins, but also that it was "highly enriched" for them, especially in the growing tips of nerve axons, he said. That was encouraging, because "very little other than nerve growth factor can stimulate the growth of nerves," but the drug FK-506 also suppressed the immune system. So, Guilford researchers designed a series of compounds based on FK-506 that retained the nerve growth properties without those associated with immunosuppression.

The resulting drug candidate, GPI 1485, is currently in two Phase II clinical trials: one is testing the drug in patients with mild to moderate disease who are taking anti-Parkinson's drugs (but not L-dopa); the other is being tried in newly diagnosed patients who are not taking L-dopa or dopamine agonists.

Interestingly, Guilford isn't even paying for these trials. One is being conducted and funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the other is under the aegis of Symphony Neuro Development Company, a special purpose entity (SPE) that Guilford formed in June 2004 to carry forward the development of GPI 1485 in four indications, including Parkinson's. Symphony's investors poured about $43 million into the SPE, which will use the bulk of that to shepherd the product through the clinic via RRD International LLC, a contract research organization. Symphony's investors also received warrants for Guilford's stock, and Guilford has the option to acquire all of Symphony's equity in the future at a price that rises over time.

The business world hasn't seen too many SPEs since the Enron and Elan debacles, but Guilford's Smith felt it was the right way to go in this case. Plus, he's made sure that the set-up is transparent, and will consolidate Symphony's financial activity with Guilford's financial statements. "We are fully reporting and accounting for the activities," he said.


Receptor agonists, antagonists, and inverse agonists to increase dopamine levels; inhibiting the key signaling mechanism that triggers cell death; or promoting the growth of damaged nerves are just a few of the approaches being tried in the quest to find new treatments or even cures for Parkinson's disease. Others include gene and cell therapy, even surgery. But none has yet to prove out - and the disease is still far from being understood. "There's a lot we don't know about the mechanism by which neurons die in Parkinson's disease, or even the disease itself," Guilford's Smith said. "A lot of research still needs to be done in both areas."








Copyright © 2004. Signals (www.signalsmag.com) is an online magazine of analysis for biotechnology executives. To contact the Signals editorial department, send e-mail to [e-mail]. Signals is published by: Recombinant Capital, 2033 N Main Street, Suite 1050 , Walnut Creek, California 94596-3722, Phone: [phone]