We already know Eli Lilly’s big bet on Alzheimer’s disease didn’t work. But a deep dive into just how it failed has provided a bit of encouragement to Biogen and the many companies still hoping to succeed where their rival fell short.
Lilly’s treatment, solanezumab, had no significant effect on the buildup of toxic brain plaques believed by many to be responsible for Alzheimer’s neuron-destroying effects. The company had already disclosed that the treatment failed to improve patients’ cognition and function, but the new data, released Thursday night, shed some important light on the underlying biology.
Here’s why it matters: Lilly’s therapy is among many designed to treat Alzheimer’s by clearing away brain deposits of a protein called beta-amyloid. Doing so, the thinking goes, can at least delay the progression of the memory-robbing disease. Because Lilly’s failed treatment didn’t have a marked effect on those deposits, the so-called amyloid hypothesis lives to fight another day.
This is particularly important for Biogen, which is now in the midst of two huge studies testing an amyloid treatment of its own. In a small, early trial, Biogen’s therapy showed signs that it could improve cognition by blasting away amyloid proteins, and many in the Alzheimer’s field consider it the most promising drug in its class.
Furthermore, the two treatments are quite different. Biogen’s drug, aducanumab, targets plaques once they have already settled in patients’ brains, while Lilly’s was meant to attack the free-flowing proteins that eventually aggregate and form those sticky clumps. And Biogen is testing its therapy in patients in the very early stages of Alzheimer’s, while Lilly pursued those who already had mild dementia.
In data presented at the annual Clinical Trials Conference on Alzheimer’s Disease in San Diego, Lilly’s treatment had only glancing effects on amyloid levels in the brain, beating placebo by too narrow a margin to rule out random chance. But solanezumab did markedly reduce amyloids floating around in the cerebral spinal fluid, suggesting that the problem may have been that it didn’t go after the proteins already clumping in the brain.
“I think this is not a refutation of the amyloid hypothesis,” said Dr. Paul Aisen, a professor of neurology at the University of Southern California. “In fact, I think this is our strongest confirmation to date.”
Solanezumab’s lack of potency is also positive for Merck, which is in the final stage of trials with a pill that takes an upstream approach to the amyloid question. Called a BACE inhibitor, Merck’s drug targets an enzyme responsible for the production of amyloid, seeking to stem the flow of toxic materials at the source.
And, somewhat paradoxically, the news is good for Lilly, too. Solanezumab wasn’t the company’s only Alzheimer’s project. It has a BACE drug of its own, developed in partnership with AstraZeneca, and two more amyloid-targeting treatments in early trials.
Each contender is racing to commercialize the first-ever therapy that can modify the course of Alzheimer’s rather than just treat its symptoms.
The field has a daunting rate of failure, with more than 99 percent of therapies coming up short in the past decade. But the rapid growth of Alzheimer’s, which now affects an estimated 5 million Americans, has presented a multibillion-dollar market opportunity for whoever can finally beat the odds.
Trouble is, there’s no consensus that targeting amyloid will ever show an effect on the progression of Alzheimer’s disease. Many scientists are bitterly divided on the issue, and the drug industry is yet to come up with a molecule that can prove it once and for all.
The next big test of the amyloid hypothesis is still years away, as Biogen isn’t expected to have final data on its treatment until 2019 at the earliest.
The company got some incremental good news of its own at the CTAD conference, as an extension of its earlier trial on aducanumab found that patients who got gradually increasing doses of the treatment experienced similar benefits with fewer side effects compared with those who got one lump injection, according to data presented at the same conference. The results bode well for Biogen’s ongoing Phase 3 studies, analysts said, but with the caveat that it’s still too early to make any conclusions.
An experimental Alzheimer’s drug that had previously appeared to show promise in slowing the deterioration of thinking and memory has failed in a large Eli Lilly clinical trial, dealing a significant disappointment to patients hoping for a treatment that would alleviate their symptoms.
The failure of the drug, solanezumab, underscores the difficulty of treating people who show even mild dementia, and supports the idea that by that time, the damage in their brains may already be too extensive. And because the drug attacked the amyloid plaques that are the hallmark of Alzheimer’s, the trial results renew questions about a leading theory of the disease, which contends that it is largely caused by amyloid buildup.
No drug so far has been able to demonstrate that removing or preventing the accumulation of amyloid translates into a result that matters for patients: stalling or blocking some of the symptoms of dementia. “It’s not going to be disease-modifying therapy for mild patients, so that’s heartbreaking,” said Dave Ricks, the incoming president and chief executive of Eli Lilly.
There are clinical trials underway with several similar drugs made by other companies, and two large trials with solanezumab are in the works. Experts said on Wednesday that they still held out hope for those studies, noting that many involve people who are at high risk for Alzheimer’s but do not display symptoms.
Some Alzheimer’s experts not involved in trials testing anti-amyloid drugs said they were not surprised by Lilly’s results, saying they reflect an emerging scientific understanding of Alzheimer’s as a disease with a multipronged cascade of causes, including amyloid buildup.
“We’re much more really appreciative of how complex this disease is,” said Dr. Lon Schneider, director of the California Alzheimer’s Disease Centerat the University of Southern California. “There’s so much going on, and as the brain is failing or dying, it is dying on all levels.”
It has also become clear that Alzheimer’s pathology begins damaging the brain years before symptoms emerge, leading many experts to think a drug given to people with even mild dementia may have little chance of success.
“Once you see amyloid on a scan, it’s probably been there for decades,” said Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai Hospital.
The Eli Lilly and Company corporate headquarters in Indianapolis. A potential Alzheimer’s treatment, solanezumab, failed in another large clinical study, the company announced.
“I’m worried and have been worried that that’s just too late,” he said. “I think it has a better chance of working much earlier.”
But, he said, testing a drug before people have begun showing symptoms is challenging and costly. Such trials need to involve even larger numbers of patients to produce a useful result, and because the patients are healthy, without symptoms, the drugs cannot have side effects that might make them feel sick.
Solanezumab had previously failed in two large clinical trials involving patients with mild or moderate Alzheimer’s disease. But when Lilly reported the results of those trials in 2012, the company said the drug did have an effect in a subset of patients with mild symptoms. So it started another trial with 2,100 patients with mild dementia caused by Alzheimer’s.
In a news release on Wednesday, the company said that although some of the effects looked promising, “patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo.”
The company said it would evaluate future plans for solanezumab, but no longer planned to seek regulatory approval for use of the drug in treating symptomatic patients. Eli Lilly stock initially dropped after the news.
“This is very disappointing,” said Dr. Reisa Sperling, a neurologist who is recruiting patients for a trial testing whether solanezumab can help people with amyloid buildup who are about 10 years away from having symptoms. “But I have to be honest that I’ve always thought we needed to treat much earlier, because by the time people have mild dementia, they already have a lot of irreversible damage,” she said.
The trial she is leading, called Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4), which has funding from Lilly and the federal government, had hoped to reach its goal of about 1,150 patients by the middle of next year, said Dr. Sperling, who directs the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital.
“I have several patients within my practice who were hoping to take this drug,” she said. But she said it was at least encouraging that patients taking solanezumab in Lilly’s trial did show improvement, just not enough to be statistically significant, and she plans to evaluate the data to see if changes should be made to the design of the A4 trial.
“What does that mean for an earlier population?” Dr. Sperling said. “Do we need more people? Do we need a longer time? I just want to get a clear result.”
The other major solanezumab trial, the Dominantly Inherited Alzheimer Network Trials Unit, is also testing a Roche drug, gantenerumab, and is funded by industry, the federal government and the Alzheimer’s Association. It involves people who have not yet shown symptoms, but have a very high risk of an early-onset version of the disease because they have a genetic mutation that causes a small subset of cases.
Other trials are using anti-amyloid drugs that work in different ways, experts said. Solanezumab is a monoclonal antibody that removes amyloid by attaching itself to free-floating amyloid protein before the protein forms into plaques, while several other antibody drugs also attack amyloid fibrils that are part of the plaques.
Another class of anti-amyloid drugs are called BACE inhibitors, which block an enzyme that makes a protein needed for amyloid production.
“You can’t really say that the solanezumab results predict that a drug with a different mechanism will fail,” Dr. Schneider said.
Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute, is leading a prevention trial involving members of a large extended family in Colombia who do not have symptoms but have a genetic mutation that causes early Alzheimer’s. They are taking Genentech’s crenezumab.
Dr. Reiman said Wednesday’s results raised questions about whether Lilly’s dose was high enough, whether the researchers were “attacking the right form of amyloid,” and whether they were they treating patients too late in the disease process. The results may also support theories that the ultimate answer will be combinations of drugs addressing different aspects of Alzheimer’s.
He and other experts continue to believe that “the accumulation of amyloid serves as the kindling for other events” that ignite the fire of Alzheimer’s disease, he said, and “it would be a grave mistake to throw out the baby with the bathwater and not give the amyloid hypothesis its best real test.”
Still, “a win for Lilly would have been a win for the entire field,” Dr. Reiman said, and “would have opened up new opportunities for patients.”
Background: Recent studies have implicated specific assembly subtypes of β-amyloid (Aβ) peptide, specifically soluble oligomers (soAβ) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aβ assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Aβ assemblies including soAβ. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aβ antibodies to the clinical bioactivity of IVIg has been lacking.
Methods: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Aβ conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAβ levels using standard anti-soAβ antibodies.
Results: We provide evidence that NU4-type soAβ (NU4-soAβ) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aβ plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAβ and A11-soAβ but not OC-type fibrillar Aβ oligomers.
Conclusions: We propose that targeting of specific soAβ assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aβ antibody drugs.