The Unblinding: Has Lilly Solved the Alzheimer’s Puzzle? — An Epilogue

Late last winter, Lilly announced the results of a milestone clinical trial. Where does the company go from here?

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Publication note: Indianapolis Monthly published a feature story in November 2016 about Eli Lilly and Company’s $3 billion, three-decades-long pursuit of the world’s first effective drug to attack Alzheimer’s. That article can be found here. What follows is writer Adam Wren’s follow-up story to the pharmaceutical firm’s finding that the drug’s trial had failed.

On the east side of the Eli Lilly campus, near the entrance to Building 98, just off Delaware Street, an Indiana limestone sculpture offers a quote: “There is no medicine like hope, no tonic so powerful as expectation of something better tomorrow.” Indeed, around Lilly last year, the company’s 140th anniversary, it was hard to miss the sense of hope that surrounded solanezumab—“sola”—a potential Alzheimer’s cure.

But on the day of the “unblinding,” when milestone clinical results would be revealed, for Hong Liu-Seifert, who had arrived at the campus’s “Cave”—a secure, secretive room for crunching drug data—at 4 p.m, that wave of hope would soon recede. The Unblinding occurred earlier than anyone expected, thanks to her crack team of nearly half a dozen statisticians. Liu-Seifert sank into a sea of numbers for the next eight hours. But she didn’t need that long to see the result.

That same afternoon, scientist Ron DeMattos was at home, catching up on email. Once again, just like during a 2012 unblinding of earlier trial results, his wife was hounding him to get out of town, put his work behind him, and relax that holiday week. They had mulled a trip back home to Michigan for the holiday. But DeMattos thought better of it this time. He wasn’t about to be away from Indianapolis during a week that promised to render a verdict on what had been, up to this point, his life’s work. At 4 p.m., an email pinged his inbox, letting him know there was an all-hands meeting in the Cave scheduled for the next day.

Lilly’s Phyllis Ferrell was at an airport, traveling back from Lausanne, Switzerland, when a text came from Russ Barton, the chief operating officer for the company’s Alzheimer’s group. The Cave was full of statisticians, he told Ferrell. Ferrell inquired about their mood. Barton couldn’t quite get a read on the room. All of the statisticians had their poker faces on. Ferrell told him to buy them pizza. Barton ordered Bazbeaux, and they kept crunching data, losing track of time and working well past midnight.

By the next morning, DeMattos couldn’t think about anything else. He arrived on Lilly’s campus and raced to the door. I’ll know within 30 seconds whether this thing worked, he thought.

Researcher Eric Siemers was among the first to get result from the unblinding, on account of his medical background. The drug-in-waiting hit its target, but had only a marginal effect on subjects. The trial had failed. “We went through a lot of Kleenex that day,” Siemers recalls.

Inside the Cave, a feeling of numbness spread. This can’t be happening, thought Ferrell, now back in Indianapolis. That Monday night, Ferrell, Siemers, and Liu-Seifert had planned to work late and stay at the JW Marriott. They stared vacantly at each other over dinner.

On Tuesday night, Ferrell went home. Her 10-year-old son, Jack, raced to greet her, wrenching her out of the car. “Mom,” he said, “you have to see this.” On the kitchen counter, he had created a marketing and branding plan for sola. The drug should be called Purplexys. Purple is the official color of the Alzheimer’s Association—and the letters “X,” “Y,” or “Z” are necessary in any drug name, the boy astutely observed. Ferrell was amused but also heartbroken. Later, alone with her husband, she decompressed, cried into his shoulder.

The next day, a little after 7 a.m., Lilly sent out a press release announcing that “patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline treated with a placebo.”

“The results of the solanezumab EXPEDITION3 trial were not what we had hoped for and we are disappointed for the millions of people waiting for a potential disease-modifying treatment for Alzheimer’s disease,” wrote Lilly chairman, president, and chief executive officer John C. Lechleiter in the press release. “We will evaluate the impact of these results on the development plans for solanezumab and our other Alzheimer’s pipeline assets.”

Eli Lilly shares dropped 10 percent that day. Lilly would eventually lay off at least 500 sales officials in the wake of the news, though company officials familiar with the decision-making process say some of those layoffs were the result of a reorganization, and not all could be attributed to the phase-three failure. That morning, Ferrell broke the news to her son. “Oh, it’s okay, Mommy,” he responded. “You’ll do better next time.”

But the next time a Lilly Alzheimer’s drug enters an unblinding process likely won’t be until 2019 or 2020, company officials say. And though press coverage in the wake of the sola failure seemed bleak, the company is still testing the drug in partnership with the NIH, in younger populations. In fact, that may be the signature finding of EXPEDITION3: The disease may develop earlier in the brain than anyone previously thought. One leading hypothesis is that sola didn’t prove to be effective because it was introduced in patients where the disease had already progressed beyond the point where it would be responsive to therapy.

One patient in the trial has vented that he wasted the last two years of his life on the experimental drug. “It’s not a waste for the patients, it’s not a waste for any of us,” Siemers says, “because I really believe we moved the science forward. This is where you have to put on your analytical scientist hat. For me, this is the only way I can deal with it, or at least the best way I can deal with it … Even though we didn’t achieve the goals of the study in a way that you could present to the FDA, there was a little signal there. It just wasn’t as much as we expected it to be. From a scientific standpoint, that has some huge ramifications.”

Now, the company is charging ahead. Including sola, it still has eight other Alzheimer’s molecules in its drug development pipeline. It already has two phase-three trials underway.

“I’m convinced that we’re going to get this disease,” Ferrell says.

 

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