A Parkinson's therapy makes its way through the "valley of death"

Andrew West is pursuing a compound to inhibit LRRK2, an enzyme that appears to be a central enabler
of the brain cell death seen in Parkinson's disease.

In its long journey from the petri dish to the first human patient, every new drug has to cross a wasteland called the "valley of death." Therapeutic programs enter, but most don’t come out the other side.

"The government is good at funding basic research to identify drug targets, and Big Pharma is good at taking drugs and putting them through clinical trials," says Andrew West, Ph.D., John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB. "But all of the in-between work, the pre-clinical and drug development components, is called the 'valley of death' for research, because nobody funds it, nobody pays attention to it. That's a big part of the lack of new drugs."

In fact, less than 10 percent of drugs that make it into preclinical testing will end up getting FDA approval, according to the agency's figures. But West is part of a new approach to the drug-discovery process designed to upend those odds: a partnership between UAB and Birmingham-based Southern Research Institute known as the Alabama Drug Discovery Alliance (ADDA).


The partnership is built around the strengths of each institution. UAB labs identify molecular targets that play a key role in disease. In West's case, that's the enzyme LRRK2 (pronounced "lark two"), which appears to be a central enabler of the brain cell death seen in Parkinson's disease.

Southern Research has decades of experience in drug discovery and testing. It employs a host of researchers who are adept at the chemical tweaking needed to make a drug work in humans. Southern Research scientists are also experts at proving a drug's safety and efficacy to the FDA and to large pharmaceutical companies. Big Pharma is often willing to step in and fund new drug projects—but only after they have demonstrated initial success.

Thanks to several years of work, "we're most of the way through the valley of death now," West says. "We have dozens of compounds that are fantastic drugs. We just have a little bit left to go—sometimes the last mile of the marathon can be the most painful."

On the Move

In June 2014, West's lab published a new study in the Proceedings of the National Academy of Sciences that suggests LRRK2 inhibitors could play a wide role in slowing the progression of Parkinson's disease, or even preventing it altogether.

"This is a critical first step showing that inhibition of LRRK2 may be beneficial to protect against the cell loss and degeneration that occurs in Parkinson's disease," says West. It's another sign that the team's approach is taking it in the right direction across the valley of death—and a welcome oasis to recharge their efforts.

Robotic systems at Southern Research Institute allow UAB investigators such as Andrew West
to screen hundreds of thousands of potential compounds to find the best candidates for new therapeutics.

Screen Team

The LRRK2 project's first step was high-throughput screening—using the advanced robotic testing machines at Southern Research to analyze hundreds of thousands of potential compounds and find candidates capable of slowing down LRRK2.

They emerged with hundreds of potential compounds. Further analysis has whittled that down to the best candidates. What makes a "drug great in a tissue culture dish may not be a great thing for a preclinical candidate," West says. "We want to know how well it crosses the blood-brain barrier, if it interacts with any other protein besides LRRK2, how fast it metabolizes, if it collects anywhere abnormally in the body, and if it causes toxicity."

Medicinal chemists at Southern Research specialize in taking promising chemicals and tweaking them to make them even better. "We make very small changes," says West. "We'll put a nitrogen here, a carbon there, and look at the effects in a hypothesis-driven way."

The collective knowledge of the Southern Research scientists is an extremely valuable resource, West emphasizes. "Most of the time you only see these people at big pharmaceutical companies. The relationship between UAB and Southern Research in the ADDA is unique. I haven't seen it built anywhere else in the country, where we get a high-throughput group, drug development group, and biologists sitting at the same table every two weeks discussing the issues."

Getting Close

In the next few months, West's lab will evaluate each remaining compound in its animal models of Parkinson's disease. The best ones will then move into toxicology studies, "and hopefully next year we'll begin first-in-man studies," West says.

The team has already come very close. "We had a great candidate last year that passed all of the key measures," West says. "It went to the brain perfectly, had good potency, seemed to only interact with LRRK2, no side effects, no toxicity." But when the drug got to living models, "we discovered that the metabolism was way off the charts," says West. "It only survived 15-20 minutes in the body before it was destroyed by the liver. We were close—if we could just have slowed what the liver did by a little bit, we'd be in humans now. But it turns out that was not the right molecular scaffold."

The good news, says West, is that "we have two or three other series that are getting to that same point now." Even more important, he says, "we have a clear pipeline to go to a phase 1 clinical trial," the first evaluation of a potential new drug in humans.

Strong Local Support

It's important to note that these advances have been accelerated significantly "through local philanthropic support," says West. "There are many people in this area who are disappointed to see that the government doesn't fund a lot of research into Parkinson's disease cures. I think patients are frustrated. You get a diagnosis of Parkinson's disease and there is nothing you can do to stop it. The best advance we have, L-dopa, was developed 50 years ago. There’s really been no breakthrough like that since."

But West is convinced that is about to change. "As soon as I found during post-doctoral work in 2006 that all mutations we know about that cause Parkinson's disease increase LRRK2 activity, the next step in my career was finding somewhere I could do something about that," he says. "And the only place I found in the country was Birmingham, so I moved here immediately."

Now, eight years later, the end may be in sight. "We have to take these drugs to the next level and make them suitable for use in humans," West says. "It's a formidable trek, but I think we have some really good compounds, and more important, the right people that will get us there."

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