Jordan Tang is not done with Alzheimer’s yet.
An Alzheimer’s drug. That was how the story was supposed to end. In 1999 and 2000, Dr. Jordan Tang and his team of researchers at the Oklahoma Medical Research Foundation made an extraordinary series of Alzheimer’s breakthroughs. First, they identified the enzyme believed responsible for the disease and cloned it. Then they developed an inhibitor that stymied the enzyme.
Understandably, the work created sky-high expectations. The reasoning went something like this: Here is a deadly, memory-robbing disease with no effective treatments, and Tang seems to have figured out a way to stop it. His fix worked in a test tube. But how long would it be until he transformed his work into an effective drug to treat people suffering from Alzheimer’s?
Stories ran everywhere from the Los Angeles Times to CNN. Tang even appeared on “The Early Show” on CBS. In 2001, OMRF’s then-president told a magazine, “These are monumental discoveries. I will be stunned if a decade from now, corner drugstores are not selling a drug to inhibit Alzheimer’s disease that came out of this foundation.” Well, that decade has passed. The Alzheimer’s treatment landscape looks about as bleak as it did ten years ago. The few available drugs are, at best, band-aids for a disease that cries out for much, much more in the way of treatment.
And what of a drug based on Tang’s discoveries? No, you can’t find it on the shelves of your local pharmacy. As is so often the case, reality proved far more complicated than first imagined. But the dream of an Alzheimer’s drug is far from dead.
Asking Tang about Alzheimer’s research feels a little bit like talking to Neil Armstrong about the moon landing. Or discussing Harry Potter with J.K. Rowling. Surely, his eyes say, there must be something else we can discuss. But as the state’s best-known Alzheimer’s researcher, he understands the role that’s been thrust upon him: educating the public about the disease that has defined the last 12 years of his scientific life.
“I know the magnitude of tragedy that’s involved when people find out their loved ones have this terrible disease,” says Tang. He speaks softly, his voice just above a whisper. “But when people turn to me for answers, I feel powerless, because we don’t yet have a treatment.”
He’s just come from a lunch where he’d given a talk about Alzheimer’s disease. With 5 million Americans, including 1 in 2 people over the age of 85, suffering from the illness, Tang receives frequent requests to speak on this topic. “I know how desperate the situation is. I have personal acquaintances with the disease. People in my lab—two of their parents had Alzheimer’s.” He grows quiet, his dark eyes seeming to search the room for a delicate way to express this next thought. “But you can’t get emotional about it. Because if you do, it will interfere with your work.”
Tang is an unlikely standard-bearer in the quest to stop Alzheimer’s. For more than four decades, his work had nothing to do with the human brain. Rather, he focused his research on a group of cutting enzymes known as proteases.
Proteases play roles in many different processes in the body. But their essential function is to act as a sort of biological scissors, breaking complex proteins down into simpler constituent parts. In his early work, Tang discovered a previously unknown protease in the stomach. He then spent the better part of a decade unlocking the chemical structure of a similar protease that plays an important role in the digestive process.
When scientists discovered that this stomach enzyme was quite similar to a protease that controls blood pressure, Tang moved his work into the field of hypertension as well. In particular, using techniques he’d developed when working with stomach proteases, he created an inhibitor he hoped could form the basis of a drug to lower blood pressure. He developed a molecule that acted as a sort of chemical chewing gum that stuck to the enzyme’s scissor-like blades, thus preventing their cutting mechanism. But while the inhibitor fared well in laboratory tests, the results did not play out in human clinical trials; the inhibitor proved too large and interfered with the cutting mechanisms of other vital enzymes in the body.
Tang’s work took an unexpected turn in the 1980s, when research revealed that the ability of the AIDS virus to replicate itself hinged on the action of a protease. For the next decade, tapping on the knowledge he’d acquired working with the proteases involved in digestion and regulating blood pressure, he laid the scientific groundwork for inhibitors that would stop the AIDS virus from replicating. These inhibitors became key ingredients in potent HIV-fighting therapeutics that have added years to the lives of people suffering from the disease.
In the late 1990s, scientists assembled the first rough sequences of the human genome. Dr. Gerald Koelsch, a researcher in Tang’s lab, suggested they search the data for new proteases. In 1999, Tang’s team discovered a previously unknown protease. The enzyme, which Tang named memapsin 2, was present in several organs throughout the body. Most puzzling of these sites was the brain.
“Why would there be a cutting enzyme in the brain?” Tang remembers asking himself at the time. “Is it possible this enzyme might play a role in Alzheimer’s disease?”
Researchers had known that the brains of Alzheimer’s patients contained an abundance of plaques, clumps of protein and cellular material that cannot dissolve and pile up like garbage. Using the expertise they’d developed in many years of working with proteases, Tang’s team synthesized memapsin 2 and “fed” larger brain proteins to the enzyme in a test tube. They found that this newly discovered protease sliced a particular protein and created the same fragments that, when clumped together, formed plaques in the brains of Alzheimer’s patients. These fragments, most experts agree, disrupt and destroy brain cells, leading to memory loss and dementia.
Tang’s team had, it appeared, discovered the culprit behind Alzheimer’s disease.
If the researchers could figure out a way to prevent the enzyme from cutting, they realized, they could halt the creation of fragments and the build-up of plaques. And if they could do that, they might be able to stop Alzheimer’s.
Within months of this breakthrough, Tang’s team took another major step forward. Working in collaboration with Dr. Arun Ghosh, a synthetic chemist then at the University of Illinois-Chicago, the researchers designed a chemical inhibitor that stopped memapsin 2’s cutting mechanism. “From our work in blood pressure and HIV, we knew a great deal about designing protease inhibitors,” says Tang. “That gave us a big advantage.”
In a test tube, the inhibitor acted as a sort of “chemical chewing gum,” says Tang. It enticed memapsin 2 to take a bite out of it, but when the protease chomped down, the inhibitor stuck to its scissor-like “jaws,” preventing it from making any further cuts. If the protease couldn’t slice, then plaques couldn’t form. And this, many researchers hypothesized, could delay or even prevent the progression of Alzheimer’s disease.
In other words, Tang’s inhibitor had all the hallmarks of a promising drug candidate for Alzheimer’s disease.
But the key word here is “candidate.” Although the inhibitor worked splendidly in a test tube, a test tube is not a human being. “What we had was potent, but it was nothing like a drug,” says Tang. “If you put it into the body, it wouldn’t get to the brain. It wouldn’t stick around long enough to do the job.”
Even if the molecule Tang and his collaborators had created could be transformed into a so-called biologic that would remain in the blood—rather than immediately being broken down by the body—and eventually penetrate the brain, that would not be the end of the story. Trials would then take place in lab animals to determine whether the drug was effective and safe in slowing or stopping the progression of Alzheimer’s-like conditions.
Success in these “pre-clinical” phases would open the door for filing an investigational new drug application with the US Food and Drug Administration. If the FDA okayed the application, this would initiate a new chapter: human clinical testing. This multi-phase process entails administering the drug to progressively larger groups of people to assess the drug’s safety and effectiveness. For a disease as prevalent as Alzheimer’s, the final phase of this process would involve thousands of patients at hospitals and clinical sites on multiple continents. Only after the drug had successfully completed all of these steps would its manufacturer seek final marketing approval from the FDA.
“Transforming a laboratory discovery into a drug that works in people is like trying to scale Mount Everest,” says OMRF President Stephen Prescott, who has worked extensively in the area of drug development. “The process involves incredible amounts of hard work, endurance and luck, and the odds of any discovery making it to the top are extremely slim.”
Indeed, the vast majority of promising drug candidates ultimately fail. According to a study from the Tufts Institute of Drug Development, of every 5,000 potential new drugs tested in animals, only five are promising enough to be tested in humans. Of those five that begin human testing, only one earns FDA approval for marketing. For those few drugs that do reach the market, the climb is long and expensive; the Tufts researchers found the process averages a dozen years and costs close to $1 billion.
Nonprofit research institutes like OMRF do not have $1 billion—or anything close to that amount. With limited resources, they must focus their efforts on limited areas. In OMRF’s case, that means discovery science.
“We take the first steps toward creating treatments,” says Prescott. “But then we have to find partners capable of helping shoulder our discoveries to the summit.” In the world of drug development, those partners are typically pharmaceutical companies.
When Tang published his early work in scientific journals, more than a dozen drug makers beat a path to OMRF’s door. “Their goal was to make as much money as they could,” says Tang. And they wanted to do the drug development without us.” Those aims, he says, “weren’t the ideas we had.”
“Our concern was not money. We simply wanted to get a treatment for Alzheimer’s to patients as fast as possible,” says Tang. Plus, he says, with a long track record of developing protease inhibitors, “we felt we had the knowledge and experience to help.” But Tang and OMRF recognized that drug development was so expensive that it couldn’t be funded through the typical channels available to a nonprofit research institute: competitive research grants from agencies and philanthropic support. So OMRF opted to go a different way. “We decided to form a company of our own to compete with big pharma,” says Tang.
OMRF started a company that it named Zapaq. “The name was short for ‘zap the plaques,’” says Tang with a little laugh. “Because that’s what the goal was”—preventing the accumulation of Alzheimer’s-causing plaques in the brain. The company would take the basic inhibitor designed by Tang and his collaborators and begin the time-consuming, expensive process of transforming it into a drug for people. As a for-profit business, Zapaq could attract capital in a way that a nonprofit like OMRF could not. And it did, drawing investments from the Oklahoma Life Science Fund and New York’s Institute for the Study of Aging. Still, with the investors’ total stake topping out at slightly over $1 million, Zapaq didn’t seem to stand a chance against behemoths like Merck and Pfizer, which had billions of dollars of cash on hand to bankroll such projects.
“With start-up companies, your initial goal is not to reach the summit,” says Prescott. “Your aim is simply to make as much scientific progress as possible. And, you hope, by the time you’ve exhausted that first round of funds, you’ve moved far enough down the path to attract more investment.” In other words, it’s a sort of pay-as-you-go proposition. As might be expected, such ventures are risky and come with a low probability of success. “That’s why,” he says, “investors in early-stage companies are known as ‘angels.’”
Zapaq shied away from big capital investments, rationing precious funds so as to focus on a pair of key scientific projects. First, a team of chemists synthesized new variations of the basic inhibitor pioneered at OMRF. Then researchers studied the biochemical and crystallographic properties of these newly created molecules.
“We made several hundred new compounds and evaluated them along the way,” says Tang, who acted as a scientific consultant to Zapaq in the company’s early stages. “It’s trial and error, and you’re constantly examining which direction you can move to build inhibitor structures that could create a more effective drug. The process is extremely complicated, because there are 10,000 different ways you can change an inhibitor.” The ideal candidate would have to be extremely small, allowing it to move from the bloodstream to the brain. It would also have to possess the proper shape to bind to its target. And it would have to disable only memapsin 2—not any of the many other proteases (like stomach enzymes) that perform vital functions in the human body.
Drawing on their experience in the realms of HIV and hypertension, the researchers developed scores of new inhibitors. Over time, the candidates they designed became more selective and potent. In other words, they zeroed in on the memapsin 2 protease, and they were growing more effective at disabling the cutting action of the enzyme. When Zapaq scientists tested them in test tubes and cell culture dishes, the newly synthesized compounds appeared much more “drug-like” than the basic inhibitor first engineered by Tang and Ghosh.
Still, Tang felt Zapaq could continue to refine its work and develop compounds that were even better. Then it would need to move to the next stage: studying those compounds in living organisms. That meant administering the inhibitors to laboratory rats and mice and assessing the animals’ reactions.
Those next steps carried a price tag that totaled millions of dollars. And Zapaq was running out of money.
Start-up companies are like zombies in horror movies. Just when you think they’re dead, they spring to life again.
In 2004, on the strength of the progress it had made designing its inhibitor, Zapaq received $6 million in financing from a pair of leading venture capital firms. With this infusion of capital, the company spent the next two years developing hundreds of new inhibitors. From those, it identified the most promising candidates and began testing them in mice genetically engineered to develop a condition resembling Alzheimer’s. By 2006, results from several of the compounds pointed to the next step: testing in humans. But clinical testing is expensive, especially for a small company with limited resources. So if Zapaq was going to move forward, it would have to put all its eggs in one basket; it would have to choose a single inhibitor to undergo human clinical trials.
To provide the company with the capital necessary to continue, the venture capitalists gave Zapaq another infusion of cash. This funding, known in finance circles as a “series B round,” once again shrunk OMRF’s ownership stake in the company, to the point that the foundation held only a tiny fraction of Zapaq’s stock. That, says Prescott, was exactly what OMRF had anticipated from the get-go.
“When we start a company, we never do it with the goal of making money. In fact, we know that for OMRF, there’s no pot of gold at the end of the rainbow. But to translate our discoveries into treatments for human disease, this is the only path available.” If those investments yield any proceeds, he says, “We pour them right back into disease research.”
With this new round of funding, the venture capitalists decided to merge Zapaq with another biopharmaceutical company they owned. The new, combined company would have a new name, CoMentis. It would also have a new management team and move its corporate headquarters to California. “The merger,” says Tang, “effectively weaned the company from OMRF.”
Although Tang did not have an active hand in CoMentis’ scientific operations, his legacy loomed large. When it came time to choose an initial lead compound, the company’s scientists selected one known as CTS 21166, an inhibitor based on Tang and Ghosh’s work. Then CoMentis filed an investigational new drug application with the US Food and Drug Administration and prepared to begin human clinical testing.
The initial round of testing, known as Phase I, would involve administering the drug to healthy volunteers and assessing its safety. In 2007, CoMentis began this phase with an intravenous form of the drug. The following year, when it developed a pill version of the drug, it initiated a second clinical trial.
This was no small feat. At the time, says Tang, many big pharmaceutical companies were working on similar drugs, known technically as beta secretase inhibitors. “But here was a company with less than 20 people initiating the first—and second—Phase I trials on its beta secretase inhibitor. The little guy had beaten a group of 800-pound gorillas!”
The trials proved a success. “As far as Phase I testing goes, we could not have expected better results,” says Tang. Both formulations of the drug showed no side effects in human subjects. Data also suggested that the drug would prove effective in keeping Alzheimer’s at bay when administered to patients suffering from the disease.
In 2008, Japanese pharmaceutical giant Astellas entered into an agreement with CoMentis. In exchange for an investment that could amount to as much as $760 million, Astellas would become partners with CoMentis in developing an Alzheimer’s drug. The funds would give this once-tiny company all the capital it would need to take an experimental drug all the way through clinical trials and, if successful, to market.
Since that time, CoMentis has not initiated any additional trials of CTS 21166. Tang is no longer involved in the company’s operations, so he is not privy to its inner workings or decision-making. Of course, he’d like nothing more than to see CTS 21166 or one of its sister compounds reach the market. “This is a terrible disease, and there’s so much need.”
That still may come. But, he says with a shrug of resignation, it’s something he’s learned to accept that he cannot control. “The job of scientists is to make discoveries and publish those findings. We’ve done that. We’ve done our job.” Now, he says, “It’s in the company’s hands.”
That might be the end of the story, at least as far as Tang and OMRF are concerned. The narrative arc would go something like this: Scientist makes groundbreaking discovery, hands it off to corporate partner, hopes for the best.
But Jordan Tang is no ordinary scientist.
For a half-century, he’d picked apart proteases. If they were at the heart of Alzheimer’s, there was no one better suited to solve this mystery than he. Besides, sitting still and leaving the work to others just isn’t a part of Jordan Tang’s DNA.
As CoMentis continued to evolve its inhibitors, Tang and his lab branched off to explore other facets of Alzheimer’s. In 2007, they uncovered a molecular mechanism that helped explain why individuals with a certain gene are at a higher risk for the disease. Later that year they showed that vaccinating mice bred to develop symptoms of Alzheimer’s with memapsin 2 could slow or even prevent the onset of disease. This work, says Tang, was “extremely exciting.” “What we saw is that the mice immunized with memapsin 2 developed fewer plaques than mice who didn’t receive the vaccine.
Those immunized mice also performed better than control mice in tests that assessed their cognitive function.”
Tang saw the work as a complement to his work on inhibitors. “Like cancer and heart disease, Alzheimer’s is a complicated, multi-faceted disease. It demands that we develop many different approaches to combat it, because what works in one patient will not necessarily work in another.” Despite promising early results, though, the vaccination project stalled following the mouse studies. “The next step”—progressing the research to the point that vaccines could be tested in humans—“required a lot of money. And no one wanted to pay for it.”
But Tang refused to be discouraged. Instead, he kept pushing ahead on other fronts. In particular, he focused his efforts on developing new inhibitors.
“Alzheimer’s is untested territory, and the odds for any single drug are not good,” he says. “So instead of sitting there and hoping one will be perfect, you have to have multiple tracks of attack.” In other words, you have to keep churning out new, more promising candidate compounds. And that’s exactly what he’s done.
Last year, in the scientific publication FASEB Journal, Tang published a study showing the effects of administering a new experimental compound to Alzheimer’s mice. Using mice genetically altered to exhibit Alzheimer’s-like symptoms, Tang’s lab treated some of the animals with another new inhibitor he and Ghosh had developed. The animals that received the compound developed 75 percent fewer disease-causing plaques than untreated Alzheimer’s mice. The treated mice also performed significantly better on memory tests. In those tests, where the animals had to remember the location of a platform in a pool full of opaque liquid, the mice who received the experimental compound performed nearly as well as healthy mice without the Alzheimer’s gene.
“Once again, these are remarkable results,” says Prescott. “Every time Dr. Tang makes a new insight, I think, ‘Fantastic, but surely he can’t take this any further.’ And then he does.”
At the moment, Tang is working with this compound and 30 or so other inhibitor candidates that he and Ghosh have developed. By continually improving, testing and refining these compounds, he believes they can develop a lead candidate for a next generation of inhibitors. That candidate would eventually become a new experimental Alzheimer’s drug that would go to human clinical trials. Which would require—cue the theme from Groundhog Day—lots of money.
So that means drug companies and commercial partners, right?
Tang lets out a deep breath and shifts in his chair. It’s almost palpable, the weight he feels in carrying the hopes and expectations of so many. “We won’t worry about those things until we get there.”
Then the edges of his mouth turn up, and with them the corners of his eyes. “But wouldn’t that be a nice problem to have?” He grins. Broadly. It’s the kind of smile that comes when you imagine what it’s like to reach the summit at last.
