For Eli Lilly’s head scientist, Alzheimer’s results cap a 25-year scientific quest

If you flip to the 1,031st page of the May 1998 edition of the Journal of Cell Biology, you’ll find the first scientific byline for Daniel Skovronsky, then a young trainee at the University of Pennsylvania, on an article describing how beta-amyloid, a vexing molecule thought to play a role in Alzheimer’s disease, was more complicated than the field understood.

“I’ve been pursuing the same enemy for 25 years,” Skovronsky, now head of research at Eli Lilly, said at the STAT Breakthrough Summit in San Francisco on Wednesday.

Skovronsky and his employer, which has spent decades trying and failing to treat Alzheimer’s, notched a victory against that mutual enemy this week. Donanemab, Lilly’s amyloid-targeting therapy, met its goals in a pivotal trial, slowing the cognitive decline of Alzheimer’s relative to placebo in a study that will likely lead to Food and Drug Administration approval.


“I wish more people could have this kind of experience, of working on something really hard for a long period of time,” Skovronsky said. “I was just a kid, essentially, when I started at this. And then seeing it come to some meaningful fruition is just a hugely rewarding experience.”

Donanemab’s success in clinical trials doesn’t guarantee it will become a mainstay medicine, and the drug’s pronounced but modest benefits hardly offer a cure for Alzheimer’s. Instead, it’s an affirmation that the drug industry is building marginally better mousetraps in the form of amyloid-targeting medicines, said Ronald Petersen, a neurologist and Alzheimer’s researcher at the Mayo Clinic. It started with Biogen’s debatably effective drug Aduhelm and continued with Eisai’s better-received therapy, Leqembi.


“And now with donanemab you get more corroboration that these drugs do, biologically, what they’re supposed to do, and there’s a clinical accompaniment to it,” Petersen said. “It’s not huge. It’s modest. But it’s probably clinically meaningful, and that’s good for patients.”

For Skovronsky, donanemab’s success, however incremental, is a major milestone in the decades-long pursuit of amyloid that led him to his perch at Lilly.

Daniel Skovronsky, head of research at Eli Lilly, speaks at the 2023 STAT Breakthrough Summit.

After getting his M.D. and Ph.D. from Penn, Skovronsky started a company called Avid Radiopharmaceuticals in 2004. The idea was to come up with ways to reliably detect amyloid and a related protein called tau in the brains of patients with Alzheimer’s, bringing modern medical tools to a disease that was often haphazardly diagnosed. Avid’s imaging techniques eventually became the state of the art in Alzheimer’s, and Lilly bought the company in 2010 for $300 million in cash. The company kept Skovronsky on board, betting that his more precise approach to diagnosing the disease would lead to better trials and more effective medicines.

It would not be a quick fix. Lilly put all of Avid’s imaging know-how into a do-over study of solanezumab, an amyloid-targeting agent that had previously failed in a less rigorous test. In 2016, it failed anyway, wiping billions of dollars from Lilly’s valuation and marking a nadir for the idea that targeting amyloid could ever lead to an effective medicine. Major drug companies began curtailing or outright ending their work in neuroscience, as Pfizer, AstraZeneca, and Amgen successively pulled the plug on would-be treatments for Alzheimer’s.

“Sometimes disease areas become popular, and sometimes they fall out of fashion,” Skovronsky said. “For the last 10 years or so, Alzheimer’s was way out of fashion. The strategic thing to do was to stop working in neuroscience. That shows what a great leader you are. We resisted that.”

Instead, Lilly embarked on “Alzheimer’s 2.0,” he said, a plot to “pick up the pieces” of solanezumab’s costly failure. The company would focus only on projects that had ironclad supporting evidence from human genetics, and it would target only what could be reliably measured in the brain. Drugs would have to “hit their targets hard” to advance the next stage of development, Skovronsky said. And perhaps most importantly, Lilly would actually conduct Phase 2 trials, bucking an industry trend of skipping the middle step of clinical development in hopes of quickly finding effective Alzheimer’s medicines.

That led to donanemab, a medicine with more potent effects on amyloid than anything Lilly had previously invented; it also led to the Trailblazer clinical trials, which built on Avid’s insights by screening specifically for patients with levels of amyloid and tau that made them ideal candidates for therapy. Trailblazer 1, a Phase 2 study, met its goals in 2021, at which point Lilly was already enrolling Trailblazer 2, an upsized effort to replicate those results and gather enough evidence to win FDA approval.

Skovronsky was at home when he got the call from Lilly’s statisticians: Trailblazer 2 was a success. Alzheimer’s 2.0 had paid off.

“All of this work,” he said, “building up to this moment where we could have a Phase 3 result for a drug that has such a potent effect on removing amyloid plaques — probably any words I use to describe my emotions at seeing this data will understate it.”

For the field, the successive clinical victories of Leqembi and donanemab “really confirms we’re on the right track” with amyloid, said Reisa Sperling, a Harvard University neurologist who leads Alzheimer’s clinical trials.

“But I want us to do even better,” she said. “I want 100% slowing. That’s why I think both Leqembi data and donanemab data are consistent in saying you need to be very aggressive about plaque removal and you need to do it as early as possible.”

The news sent Lilly’s share price up about 6% on Wednesday, burnishing the reputation of what has become Wall Street’s favorite pharmaceutical giant. “Given that investors generally gave [the study] a 50/50 chance of success, today’s news is a clear plus for Lilly,” TD Cowen analyst Steve Scala wrote in a note to clients. Analysts expect donanemab to bring in about $10 billion a year at its commercial peak.

But Lilly has more work ahead. The company plans to present detailed Trailblazer 2 data at a conference this summer, where it is sure to field questions about donanemab’s safety and efficacy. Two patients in the study died from ARIA, a type of brain swelling caused by amyloid-clearing drugs, raising concerns about just which patients should be candidates for the therapy. Lilly also needs to win over the FDA, which declined to grant donanemab an accelerated approval earlier this year and will now review the latest data for full approval. And even if donanemab is approved, Lilly can’t hope to recoup its investment unless Medicare reverses a restrictive policy that all but forbids reimbursing for any amyloid-targeting medicine.

Hearing of donanemab’s success, Skovronsky had pivoted to those issues almost as soon as he hung up the phone.

“I probably have a pathological inability to celebrate accomplishments,” he said, grinning. “I’m always moving on to the next problem.”

Source: STAT