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cientists at Eli Lilly are racing to wrap up a clinical trial on a drug that could be the first major advance in treating Alzheimer’s in more than a decade — or a crushing reminder of why the memory-destroying disease has bedeviled researchers for so long.

This is the third time Lilly has tested the drug in large-scale trials. The first two tests flopped. But the company, which has spent about $3 billion on Alzheimer’s research over 25 years, believes it has finally identified the patients most likely to benefit from its therapy.

Lilly is testing the drug, solanezumab, on more than 2,000 patients with early-stage Alzheimer’s. If the treatment succeeds, it will mark the first time a drug has delayed cognitive damage rather than just treating the disease’s symptoms, creating a multibillion-dollar opportunity for Lilly and giving hope to millions of patients. Success would also validate a key hypothesis about how Alzheimer’s works and would likely buoy several rival drug companies at work on related therapies.

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This is a field, however, where roughly 99 percent of experimental treatments have failed in clinical trials.

“I hate having to tell people every day that we don’t have anything that can truly arrest the disease at this point,” said Dr. David Knopman, a Mayo Clinic neurologist not involved in Lilly’s trial. “So, the field — and the world — is extremely anxious to see if we can finally break the ice and have a drug that genuinely is beneficial.”

An injection to sweep away plaques in the brain

The primary goal of Lilly’s study is to beat placebo in slowing cognitive decline in patients with mild Alzheimer’s. The therapy, injected monthly, is an antibody that aims to sweep away plaques called beta-amyloids, which build up in the brains of patients with Alzheimer’s. Many scientists believe these clumps of proteins are to blame for the destruction of neurons that marks the disease.

The treatment is by no means a cure for Alzheimer’s.

At best, patients treated with the drug would perform about 35 percent better on cognitive tests than those on placebo, researchers said. Such a result would suggest that Lilly’s treatment had delayed degradation of brain function. It’s likely to work, if it works at all, only in the roughly one-third of Alzheimer’s patients who have a mild form of the disease.

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But even that would be a major advance. Analysts at Jefferies say Lilly’s treatment could bring in peak sales of more than $3 billion a year around the world if it’s approved. And researchers say a late-stage success for the antibody would go a long way in validating the idea that amyloid plaques are integral to disease progression, bolstering the odds of success for Biogen, Merck, Roche, and others working in the same field.

Researchers say the ideal future of Alzheimer’s treatment will feature not one stellar drug but a battery of combinations that can be tailored to each patient, as is the current standard in cancer and diabetes. But the first step in testing combinations is to come up with an effective foundational drug, and that hasn’t yet emerged.

In a best-case scenario, solanezumab could be that foundation, and its approval could usher in a wave of new drug approvals and combination therapy trials. That would create what would likely be “the largest pharmaceutical market in history,” said Dr. Howard Fillit, chief science officer at the Alzheimer’s Drug Discovery Foundation.

Lilly’s solanezumab team is planning to work through Thanksgiving analyzing the trial data, and if the results are positive, they’ll plow through Christmas to prepare a filing for the Food and Drug Administration.

“It’s like having a baby,” said Phyllis Ferrell, vice president of Lilly’s Alzheimer’s division. “That baby’s coming whether you’re ready or not.”

If all goes well, solanezumab could win approval as soon as late 2017.

Failure could have chilling effect

A complete late-stage failure — which would be solanezumab’s third — would likely spell the end of the line for the antibody, Lilly executives acknowledged. “I don’t know what the precedent is for submitting three negative studies” to the FDA, Ferrell said in a deadpan tone.

And it would have a chilling effect on other drug developers targeting amyloid plaques to treat Alzheimer’s. Late-stage studies are long and costly affairs in Alzheimer’s, and while the potential for blockbuster success has led some companies to accept the risks, many have curtailed their investments in recent years.

“Other companies are watching this,” said Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development. “One thing about this industry, one failure in one company has ripple effects in other companies. They may start to think, ‘Well, maybe we’re going in the wrong direction, as well.’”

But failure wouldn’t necessarily spell the end for the “amyloid hypothesis” that has animated so much Alzheimer’s research.

For decades, drug developers have largely focused on trying to rid the brain of those amyloid plaques. And thus scientists have now developed multiple ways of targeting amyloid, so a failure for Lilly might just rule out one approach, not imperil the whole concept.

“We always thought that solanezumab was essentially the weakest horse in this field,” said Dr. Dennis Selkoe, co-director of the Center for Neurologic Diseases in the Department of Neurology at Brigham and Women’s Hospital.

“It’s entirely possible that the biology of Alzheimer’s is so complex and perverse that even though this amyloid is accumulating, removing it doesn’t have anything to do with the clinical outcome,” said Knopman, the Mayo Clinic neurologist. “But if you had therapies for it, wouldn’t you want to test them before you just went off onto other things?”

Inside a healthy brain, proteins called beta amyloids are destroyed; in the brains of people with Alzheimer's disease, they are not and accumulate to form sticky plaques. Dom Smith /STAT

In a post-solanezumab world, the Alzheimer’s community would turn its attention first to Merck, which is slated to present results in June on a drug that takes an upstream approach to amyloid. Merck’s treatment, called verubecestat, targets an enzyme called BACE, which plays a role in the body’s production of amyloid plaques. Block BACE, the theory goes, and you can stem the flow of toxic proteins at the source.

Then, in 2018, Biogen is expected to disclose late-stage data on an amyloid antibody that scientists and Wall Street analysts say could be the most promising treatment in its class.

In a small study, Biogen’s treatment led to a significant reduction in cognitive decline compared with placebo in early-stage patients, a tentative but promising ray of hope that has created big expectations for the larger study now underway.

And Lilly won’t be giving up if solanezumab flops. The company has its own BACE inhibitor, which is now in late-stage development in partnership with AstraZeneca, plus a handful of early-stage therapies aimed at other Alzheimer’s targets.

No matter what happens, it’s crucial that patients and caregivers not lose hope, said Dr. Eric Siemers, senior medical director of Lilly’s Alzheimer’s group.

“I always try to come back to the point, whether the study’s positive or negative, still the most important thing for patients to do is to get into clinical trials,” Siemers said.

Bracing for a muddled outcome

But what if solanezumab either just ekes out a cognitive benefit over placebo or narrowly misses on its primary goal? Analysts at Cowen, citing conversations with neurologists, say that’s a likely outcome. And though Lilly has declined to discuss particular scenarios, the company hasn’t ruled out filing for FDA approval with mixed results.

That could put the FDA in a tough spot. Alzheimer’s patients are desperate for anything that might forestall the disease’s devastating effects, and even a moderate benefit could change people’s lives. But if the agency grants approval only to find that solanezumab’s benefits don’t hold up in long-term studies, it would be an embarrassment for an agency that has come under increasing public scrutiny over the past few years.

One possibility: The FDA could grant Lilly a conditional OK, said Kaitin of Tufts, allowing the company to market solanezumab but reserving the right to rescind its approval if the antibody’s positive effects fade over time.

“I think the mantra of the FDA is, ‘We have mothers and fathers too — we’re people too,’” said Fillit, of the Alzheimer’s Drug Discovery Foundation. “Show us a drug that’s safe and efficacious, and we’ll approve it.”

A middling result for solanezumab, regardless of whether it results in approval, would still have a positive read-through for other projects in Alzheimer’s, Selkoe said, with “any partial good news” encouraging researchers “to keep our fingers crossed for Merck’s BACE inhibitor.”

Back at Lilly, the mood is hopeful, if impatient. Solanezumab has been in clinical development since 2004, and its late-stage program, fittingly named Expedition, began in 2012. Whatever happens, it’ll mark the end of a long, expensive journey for the company.

“Personally, at this point, I’m just anxious to open up the envelope,” Siemers said. “One way or another, I just want to get the answer.”

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  • How long will there be a legal drug for the people to use how do get on a testing clinic we live in Mobile , Al , my home email is harley4me@bellsouth.net if can send information to harley4me@bellsouth.net is there a new drug he can take now I know got something for dementia but besides that they sad on TV news they had something new. HELP Thank you Ramona & Charles Simmons

  • This is a good, balanced article.

    The dominant thinking in regards to Alzheimer’s disease–that it is the result of beta amyloid and tau tangles–has limited the development of effective treatments against Alzheimer’s disease. Both the first cut in the amyloid precursor protein (the beta secretase cut) and the cleavage of tau are regulated by the enzyme caspase-3 and caspase-3 is upregulated by peroxynitrite (ONOO-) in Alzheimer’s disease. The second cut in the c-terminal fragment (the one leading to amyloid oligomers) and the hyperphosphorylation of tau are due to the release of intracellular calcium. Peroxynitrite mediates the formation of amyloid plaques and tau tangles via nitration.

    http://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

    http://www.genome.jp/kegg-bin/show_pathway?hsa05010

    The c-terminal fragment of the amyloid precursor protein and amyloid oligomers both contribute to peroxynitrite formation through increasing g protein signalling, but they are one of many factors that do so. So inhibiting their formation at best only slows down the onset and early progression of the disease. On the other hand, peroxynitrite scavengers not only stop the negative effects of beta amyloid, they also partially reverse Alzheimer’s disease.

    https://www.ncbi.nlm.nih.gov/pubmed/11432978

    https://www.ncbi.nlm.nih.gov/pubmed/17420060

    https://www.ncbi.nlm.nih.gov/pubmed/19298205

    https://www.ncbi.nlm.nih.gov/pubmed/22780999

  • It’s quite troubling that so many people are still clinging to this treatment option when a better alternative exists. Dr. William Frey of HelathPartners in MSP is doing revolutionary work with intranasal insulin delivered to the brain and has shown amazing results. If you or a loved one is affected or worried about Alzheimers, please investigate:

    http://startribune.com/minnesota-researcher-brainstorms-a-new-approach-to-treating-alzheimer-s/375770341/

  • I have undergone extensive testing which demonstrated that I have little or no amyloid plaques. I am 80 years old, and would like to know whether there are studies being done on individuals like me, to determine why I am plaque free.

    • Your question is puzzling. Do you assume that being plaque free at 80 is abnormal? What prompted the extensive investigations that demonstrated you are plaque free? What methods were used on you?

    • How long will there be a legal drug for the people to use how do get on a testing clinic we live in Mobile , Al , my home email is harley4me@bellsouth.net if can send information to harley4me@bellsouth.net is there a new drug he can take now I know got something for dementia but besides that they sad on TV news they had something new. HELP Thank you Ramona & Charles Simmons

  • My educated bet is:

    not going to work

    But I am nobody. While, there are scores of mighty emeritus professors, brilliant MDs, stellar principal scientists saying otherwise and getting funded billions for their “solid” research and theories.

    • Your uneducated guess is quite educated with regard to actual efficacy. The drug has already failed two large trials. On top of that, the amyloid hypothesis has a weak scientific foundation. Without a solid, viable indication of what leads to amyloid accumulation (and neurofibrillary tangles, and other cellular detritus), this is a wild goose chase. However, as indicated in the article, the FDA nowadays is far more receptive to political and public pressure than to scientific arguments. They seem to have given up on any pretense of integrity and scientific due process. So from an approval perspective, all bets are off.

    • Dear Wen,
      when I say educated, I mean, I have a PhD in neuroscience and worked in the field years ago. And when I say nobody, I mean, I cant get a job as I am considered a lost cause. While a company like Denali Ther., among others, raises 217 million $ in financing for pursuing the same fallacious target

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