The Search

IN LATE 2016, Alan Palkowitz, PhD, was waiting. Over three decades, he helped push countless medicines through Eli Lilly’s pipeline, rising to become head of discovery chemistry. Along the way, Palkowitz’s career paralleled an audacious bid by the Indianapolis-based drugmaker: thwarting the cognitive decline caused by Alzheimer’s disease.

By then, Lilly had poured $3 billion into its quest to develop solanezumab, which had shown promise in sweeping out the hallmark amyloid plaque from the brain. While the drug had failed in two earlier trials, the pharmaceutical giant found it affected patients with milder symptoms.

So, Lilly launched another trial, focusing on 2,100 patients with mild dementia. “We were hoping some of the findings suggested by that earlier trial would materialize,” Palkowitz said. “Unfortunately, the data didn’t turn out that way.”

Every clinical trial comes with a degree of secrecy and confidentiality. Data is tightly held, vetted and then released. With solanezumab, the news came the day before Thanksgiving. Palkowitz learned the outcome in the same manner as patients, families, and shareholders. It landed with a thud: patients treated with the drug did not show a slowing of their cognitive decline.

“I read about it in a press release,” Palkowitz recalled.

FOUR YEARS LATER, IU School of Medicine has taken up a task that has chastened biomedical companies and prompted soul searching from many scientists—the quest for new, effective Alzheimer’s drugs.

With Palkowitz now a senior research professor and a co-leader in the effort, the School has launched the Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) Center, including Purdue University as a key partner, using $36 million from the National Institute of Aging.

Over the next five years, the center’s faculty will cull a list of 100 potential targets amassed by government, private industry, and non-profit organizations. Ideally, it will assemble a package containing the structure, chemistry, and pre-clinical data that shows promise.

“There was really an appreciation that we needed to reinvigorate the pipeline,” said Bruce Lamb, PhD, executive director of the Stark Neurosciences Research Institute, who co-leads the center with Palkowitz. “Get more drug targets and more ideas moving toward clinical trials.”

IU’s experts in bioinformatics, computational biology, animal modeling, and medicinal chemistry are focused on how the brain’s immune system and neuroinflammation play a role. It’s among this archipelago of lightly explored targets that a potential drug might await.

The challenge isn’t modest. The last drug for Alzheimer’s won approval in 2003. The failure rate of 99 percent is sobering. As failures have mounted, prominent players in the pharmaceutical industry have scaled back investment, and some, such as AstraZeneca, abandoned their efforts.

Meanwhile, the role of amyloid, once seen as the key to finding a treatment, has come under scrutiny. As the scrap heap of failed drugs grew, it helped shape a more nuanced understanding of Alzheimer’s memory-robbing pathology. In all likelihood, the disease has been at work long before symptoms emerge and amyloid plaque shows up on brain scans.

Today, Alzheimer’s is viewed as a complex and tragic cascade. Within the brain, immune cells called microglia do more than snuff out pathogens. They help support neurons, rush to repair lesions and break up soluble forms of amyloid. They also summon proteins called cytokines to help with the clean-up.

Sometimes, though, this process goes haywire. A genetic mutation can make it hard to switch off microglia, creating a feedback loop of inflammation. Over time, debris from the amyloid plaques, the presence of cytokines, and an uptick in oxidizing agents start harming the very neurons they were programmed to protect.

Now, Alzheimer’s researchers are asking whether the build-up of amyloid starts this sequence. Or is the system already going awry, making it easier for amyloid to glom on to neurons? At IU, those questions are pivotal because the targets scientists are attempting to profile are intimately involved.

“A lot of them, we know nothing about,” Lamb said. “It might be a protein, and there’s only two obscure publications about it. So, what do you do with that?”

THE SCHOOL OF Medicine doesn’t lack facilities or expertise. Lamb, the Roberts Family Professor of Alzheimer’s Disease Research, leads an NIH-backed consortium generating more accurate mouse models. Andrew Saykin, PsyD, is a leading authority on neuroimaging. And Tatiana Foroud, PhD, oversees a national biobank at IU housing more than 500,000 tissue samples from Alzheimer’s patients.

It falls on Palkowitz, who joined the Precision Health Initiative in 2018, to align IU’s assets. At Lilly, the structure and culture are one of tight control given its mission. Every task is hitched to a deadline and a link in a chain pulling a new small molecule from the lab to clinical trials and, lastly, to market.

At IU, which is like any academic setting, Palkowitz’s curiosity can roam. He’s free to walk into a scientist’s office, plop down and begin firing off questions. “There are no rules,” he said. “Everybody wants to talk with you about how you can work together.”

Still, the School of Medicine is a place where faculty can orient their labs around a particular focus, score grants, go deep and carve out a comfortable niche. Knowledge is the commodity. If it happens to have commercial potential, all the better. “That’s not what drug discovery is—at all,” Lamb said. “You don’t stew or overanalyze. Not every academic researcher is built that way.”

The starting point is usually a few scraps of genetic data on a target. Before anything else, experts in bioinformatics and computational biology pore over it to answer a crucial question: Is the target actually involved in Alzheimer’s? If so, a group of biophysicists study its chemical structure, looking for a place where a molecule could gain a foothold.

That sends a core of researchers, including those from Purdue University’s Institute for Drug Discovery, to the drawing board. Their tasks range from figuring out how to get a molecule into the brain, where it will attach, and how to hit the target accurately.

At the same time, Lamb’s modeling consortium might be tasked with engineering an animal for pre-clinical testing. Created in 2016, the group has already manufactured 50 different animals. In many cases, they might already have one ready.

“The challenge is to integrate all those capabilities into an overall workflow,” said Palkowitz, who is also president and CEO of the Indiana Biosciences Research Institute.

The drug discovery center focuses on a pair of options each year, and it started with two proteins that are relatively well-known in Alzheimer’s research circles. In one case, existing data showed it plays a role in activating microglia. Whether it can be drugged is another matter.

Fortunately, Purdue’s experts had already done some work on a molecule for a similar protein. “We strategically chose targets and models in which we can already bring considerable expertise and resources to the table,” Lamb said.

AND WHAT IF IU unearths a viable target? Palkowitz and Lamb are unabashed in their belief the school could partner with a company and serve as a base for safety and dosing trials. But this assumes a pharmaceutical group is willing to take the plunge.

Today, the sticker price for developing a new Alzheimer’s drug is an estimated $5.6 billion, including $1.65 billion before clinical testing ever begins. Only the final stage of clinical testing costs more. “Half of the cost of a new drug is incurred with the decision to make a Phase 3 trial,” said George Telthorst, director for the Center for the Business of Life Sciences at Kelley School of Business.

Over the past decade, the industry’s Goliaths have hunted for smaller start-ups with narrow expertise or sought to partner with academic institutions. There are now more than 40 drug discovery centers focused on neurodegenerative disorders.

“The appeal is expanding the supply of ideas,” Telthorst said. “With the right areas of focus, there might be some companies that find what IU is doing very appealing.”

Frequently, companies are searching for promising immunotherapy treatments, especially for hard-to-treat cancers. There’s still keen interest in Alzheimer’s, but even if IU offers up an alluring option, the tradeoffs are still complex. For example, a company may have a drug whose patent is expiring and need another drug to replace that revenue stream quickly.

“Depending on future cash flows, they may decide they can’t invest in Alzheimer’s,” Telthorst said. “It’s a long shot.”

For his part, Palkowitz downplays talk about how the mechanics of a potential partnership might operate. The drug discovery work is in its early days. And there’s no guarantee that the targets it investigates will yield a therapy.

“No matter what we do, we’ll always be faced with a leap of faith,” he said. “That’s the nature of high-risk research, but it’s how we find new therapies.”