The quest to treat Alzheimer's disease is heating up as drugmakers Eli Lilly, Biogen and Roche blaze new trails. But there are speed bumps up ahead — and they've recently rocked Eli Lilly.
Eli Lilly's Alzheimer's treatment, donanemab, suffered a setback early this month when the Food and Drug Administration said it would hold an advisory committee meeting to discuss the drug.
The FDA had been expected to make its approval decision in the first quarter. The delay was bad news for Eli Lilly whose stock slipped the day the delay was announced. Analysts say the delay will give Biogen and its partner, Eisai, more time to further entrench their already approved drug, Leqembi, as the standard of care. Shares of the two companies rallied.
Race For Alzheimer's Disease Cure
Eli Lilly faces other challenges.
Biogen and Eisai, as well as Swiss pharma behemoth Roche, are working on under-the-skin shots for Alzheimer's treatment. These updated formulas could offer an easier proposition for Alzheimer's patients. Many patients are older and struggle to travel long distances to infusion centers. Lilly is also testing a next-generation shot, but is farther behind Biogen and Eisai.
Meanwhile, new competitors are eying the market, including Alnylam Pharmaceuticals, Alector Therapeutics and Novo Nordisk.
The next round of Alzheimer's treatments could prove more effective and individualized. Experts say companies are shifting their focus, taking an oncologylike tact to the neurodegenerative disease. New drugs will use a precision medicine lens to treat each patient's own unique biology.
Exciting Time In Fight Against Alzheimer's Disease
That's why, despite the expected regulatory and other hurdles, experts say it's an exciting time to be in the Alzheimer's treatment space.
Heather M. Snyder, vice president of medical and scientific relations for the Alzheimer's Association, says there is "unprecedented diversity in Phase 3 clinical trials" for Alzheimer's treatments.
"Eventually, this will mean more treatment options that provide more time with their memory and thinking skills intact," she said in an email to Investor's Business Daily. "That means more time for independence, family and friends, and fully participating in daily life."
But all of this comes as Eli Lilly faces its second high-profile setback for donanemab in about a year.
Comparing Alzheimer's Disease Treatments
Leqembi and donanemab target a hallmark of Alzheimer's disease: built-up plaque in the brain called amyloid beta.
Over 18 months, patients who received donanemab had a 29% slower decline in cognition than those who received a placebo. On the same scale, Leqembi slowed cognitive decline by 27%.
But Eli Lilly's donanemab targets a different form of the protein. As a result, the drug clears amyloid beta at a faster clip than Leqembi.
But this increases the risk of swelling in the brain known as amyloid-related imaging abnormalities, or ARIA. It also means Lilly has had to propose stopping donanemab dosing after patients' brains are clear of beta amyloid. Leqembi, on the other hand, is a chronic treatment.
ARIA typically doesn't cause symptoms and passes. But it can be serious or deadly for some people. In an Eli Lilly study pitting donanemab against a placebo, three people who received the Alzheimer's treatment died. There were no deaths in Biogen and Eisai's placebo-controlled study of Leqembi. In a later study, three people died. All patients in that study received the drug.
Different Dosing For Donanemab
The FDA will likely ask its advisors to consider the ARIA risks and different dosing schedule for Eli Lilly's donanemab, Piper Sandler analyst Christopher Raymond said in a report. He noted the FDA originally rejected an accelerated approval for donanemab, saying not enough patients in the Phase 2 study had received the drug long enough.
"Bottom line — given FDA's struggles with donanemab's long-term safety and meaningfully higher ARIA rates, we are not surprised FDA wants to take a closer look at this drug before approving, but believe — ultimately — it will be approved."
The FDA has yet to set a date for the advisory committee meeting. Anne White, Lilly's executive vice president and president of Lilly Neuroscience remained confident in the "very meaningful benefits" that donanemab could have for people with early, symptomatic Alzheimer's disease.
"It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process, but we look forward to the opportunity to further present the TRAILBLAZER-ALZ 2 results and put donanemab's strong efficacy in the context of safety," she said in a statement.
TRAILBLAZER-ALZ 2 was the final-phase study of donanemab.
A $13.7 Billion Market By 2030
Analysts aren't giving any of the companies much credit for their Alzheimer's treatments.
The Street projects just $136 million in Leqembi sales for Biogen this year, according to FactSet. In 2029, they expect sales to hit $2.35 billion. Likewise, analysts expect donanemab to generate $185 million in sales for Lilly this year. By 2029, they project $2.17 billion in donanemab sales.
Still, that would account for a handsome chunk of the overall Alzheimer's treatment market. Grand View Research expects the market to be worth $15.19 billion by 2030. That will come as new companies make their moves into the market with approaches beyond amyloid beta-targeting drugs.
The amyloid beta-targeting drugs are a marked advancement for the Alzheimer's treatment space, says Prothena Chief Executive Gene Kinney. These are the first drugs to target an underlying cause of Alzheimer's disease, rather than merely seeking to improve the symptoms.
There are many genes associated with Alzheimer's disease, but the only causal genes are related to the amyloid beta pathway, he told IBD.
"Amyloid beta has a critical role," he said. "Is it the only target in Alzheimer's disease? No. Of course not. That's where additional research is needed to really elucidate the relative contributions of these different systems."
Alzheimer's Treatments Beyond Amyloid Beta
Prothena is working on several Alzheimer's treatments.
One targets amyloid beta. Another in partnership with Bristol Myers Squibb focuses on tau, a second protein tied to Alzheimer's disease. The FDA has also given Prothena the go-ahead to begin testing a vaccine that would block both amyloid beta and tau.
Eventually, CEO Kinney says the future of Alzheimer's treatment will look more like cancer. There will be more precise, targeted drugs. Patients will receive treatment in earlier and earlier stages, before they've started developing symptoms. There will be combination approaches that take into account each patient's own biology and genetics.
The question of whether amyloid beta has an impact on Alzheimer's disease is settled.
"I think the question that remains now is how do we move the field forward and do even better?" he said.
6.5 Million People In The U.S.
But there are 6.5 million people in the U.S. with Alzheimer's disease and north of 50 million people globally have dementia.
So the odds of one drug class working equally for everyone is relatively low. And the risk of ARIA could be too high for some patients. Patients with a specific mutation in the APOE4 gene and those taking certain medicines, for example, have a higher risk of swelling in the brain with amyloid beta-targeting drugs.
Other approaches will focus on inflammation, gene-editing and new proteins like tau, says Snyder, of the Alzheimer's Association.
INmune Bio, for example, is testing an Alzheimer's treatment that acts on TNF, the same inflammatory cytokine targeted by anti-inflammatory drugs like AbbVie's Humira. Unlike arthritis and Crohn's disease, INmune is looking at TNF in the brain.
Weight-Loss Drugs In Alzheimer's?
Novo Nordisk is also testing its weight-loss drug in Alzheimer's disease. The thinking there is that obesity causes widespread inflammation that could be tied to the neurodegenerative condition.
Alector Therapeutics believes targeting a protein called PGRN could offer another avenue for treating Alzheimer's and Parkinson's diseases. High levels of PGRN have proven effective in animal testing to protect against these conditions, the company says on its website. Alector is partnered with GSK on this effort.
And Alnylam and Biogen are working on a gene-silencing approaches to the condition. The former is under a partnership with Regeneron Pharmaceuticals.
These approaches "could represent the next wave of innovation in the space along with others in the field," William Blair analyst Myles Minter said in a recent report.
Follow Allison Gatlin on X, the platform formerly known as Twitter, at @IBD_AGatlin.
