In Alzheimer's, hope, hype and disappointment as biopharma goes all in on amyloid

There is a scene in the documentary I'll Be Me in which musician Glen Campbell, the movie's subject, watches grainy old home videos alongside his wife, puzzling over what's in front of him and constantly asking just who all these people are. That's Billy. That's your second wife; you were married for 16 years. That's you, honey.

The movie chronicles Campbell's experience with Alzheimer's disease, a memory-robbing ailment that is gradually eroding his ability to perform simple tasks, recognize his family and play his music. We see Campbell, seated gamely at the Mayo Clinic, listening as Dr. Ronald Petersen points to an MR scan of his brain, showing that his hippocampus, vital to memory, is simply disappearing. And we see Campbell embark on a farewell tour, determined to get out in front of his audience for a final time after a 50-year career despite the worsening of his symptoms. With each performance his fingers a little clumsier on his guitar, the lyrics a little slower to his lips. Eventually he will need to move to an around-the-clock treatment facility, as the disease will have left him incapable of caring for himself.

Campbell's experience is broadly shared by about 5.3 million Americans, a number that could more than triple by 2050, according to the Alzheimer's Association. Deaths from Alzheimer's increased about 71% from 2000 to 2013, according to the group, and the disease is alone among the top 10 causes of mortality in that it cannot be prevented, cured or even slowed.

Then there's the economics: By 2050, all living baby boomers will be over 85, and half of them will have Alzheimer's, according to a new report from the Lewin Center for Aging and Disability Policy. That phenomenon will come to account for nearly 25% of all Medicare spending, the group figures, up from an estimated 2% in 2020.

Dr. Dean Hartley

"It's a tsunami that's going to break the healthcare system," said Dr. Dean Hartley, director of science initiatives for the Alzheimer's Association.

And the prognosis has been similarly grim on the research side. Reviewing clinical trial data from 2002 to 2012, Cleveland Clinic researchers calculated a 99.6% failure rate for all would-be Alzheimer's treatments, including promising early technologies that proved toxic and high-profile breakthroughs that ultimately fizzled in the final stages of testing.

Further confounding matters, no one knows for sure how exactly Alzheimer's comes about, a fact that has divided the brightest minds in neuroscience and occasionally led to bitter public debate. That's in part because basic research into the disease has been underfunded for years, Hartley said. In the U.S., cancer and heart disease garner between $2 billion and $6 billion in federal research support each year, he said, while Alzheimer's projects get just $600 million.

As a result, scientists have a much less sophisticated understanding of Alzheimer's relative to other diseases. For instance, it has long been known that cancer is not a monolithic ailment but a diverse collection of malignancies, giving rise to generations of targeted therapies that have extended and saved lives. Similarly, cardiologists know that treating a patient with high cholesterol is much different than caring for one who has already had a stroke. But Alzheimer's has remained something of a black box, difficult to diagnose and impossible to treat.

The beta amyloid renaissance

However, thanks to some recent clinical advances, physicians and scientists--convening in Washington, DC, this week for the Alzheimer's Association International Conference (AAIC)--have some new hope that blasting away some misshapen proteins in the brain called beta amyloids could be a path to finally reversing years of developmental futility.

The approach, like everything else in Alzheimer's, has already racked up a slew of failures--and an insider trading scandal--but a handful of projects suggest that getting to patients early and with the right treatment could forestall the disease's effects.

Eli Lilly's Dr. Eric Siemers

"The amyloid hypothesis has been a bit of a roller coaster," said Eli Lilly's Dr. Eric Siemers, medical director of the company's Alzheimer's team. But he, like many in the field, is optimistic researchers are beginning to turn a corner.

And at AAIC this week, a pair of treatments, from Lilly ($LLY) and Biogen ($BIIB), typified just what it's like to ride that roller coaster.

Each is an antibody designed to degrade amyloid proteins, which build up in the brain and lead to the formation of toxic plaques thought by many to contribute to Alzheimer's gradual assault on the brain. One, a once-failed reclamation project, has stoked hopes that it can finally succeed if administered in the right setting. The other, a headline-grabbing new entity, has shifted the R&D landscape in Alzheimer's thanks to some promising early data, convincing its inventors to lay out billions of dollars in hopes of replicating that signal in larger trials. Each, if eventually approved, could generate peak sales in the neighborhood of $10 billion a year, analysts have said.

And the drugs' fortunes at AAIC provide a fitting illustration of just how little is understood about Alzheimer's disease and why developing treatments for it is among the biopharma industry's most maddening pursuits.

Solanezumab's second chance

Lilly's antibody, called solanezumab, managed to effectively reduce amyloid buildups in a pair of Phase III trials back in 2012, but the treatment failed to beat placebo at actually improving the cognition and function of Alzheimer's patients, missing its primary goals and dealing its maker a costly blow.

However, poring over the data from those studies, Lilly noted that solanezumab did chart a significant cognitive effect on subjects with mild forms of the disease. And so the company devised a plan for the future: In what investigators call a delayed-start trial, Lilly took the roughly 1,300 mild patients from its previous studies--including those from the placebo arm--and started dosing them with solanezumab, giving the group already taking the antibody a roughly 18-month head start on the patients previously on placebo.

The goal of the study was two-pronged, looking to establish both solanezumab's effect on the root cause of Alzheimer's and the wisdom of getting to patients early. On the former score, if solanezumab modulates only the symptoms of Alzheimer's and not the disease itself, then late-starting patients should be able to catch up to the other group within months of initiating therapy. So, Lilly measured success in part by whether the difference in cognitive ability between the two groups at the start of the study was roughly preserved throughout its entirety, which would mean solanezumab is actually altering the course of the disease, the company figured. On the second aspect, if the early adopters perform measurably better after a year, Lilly will have demonstrated that initiating therapy early leads to better outcomes.

And it worked. In results presented Wednesday, Lilly disclosed that the late starters' cognition and function didn't catch up to the early group after 28 weeks, and that the treatment difference between the two arms stayed significant through a year of study. That said, the all-solanezumab group didn't come through with a statistically significant improvement in two measures of cognition and function, which "warrants some caution in drawing firm conclusions from these analyses," the study's investigators wrote.

The overall results don't negate solanezumab's earlier failures, and Lilly won't be running to the FDA with its new data. But the study does bode well for a Phase III solanezumab trial currently underway, one that has enrolled only the mild patients seen to benefit in previous studies. Results from that effort are expected late next year, and if they're positive, Lilly can finally make the case for an approval for its long-delayed treatment.

Aducanumab's return to Earth

But most of the buzz at AAIC centered on a different amyloid-blocking antibody. Biogen's aducanumab turned heads around the industry in March when the Big Biotech unveiled Phase Ib results in which the antibody demonstrated a dose-dependent, placebo-beating effect on cognition after one year, an industry first. The results--early-stage and from just 166 patients--were widely viewed as the best-ever clinical affirmation of the amyloid hypothesis, sending Biogen's share value to an all-time high.

But there was a caveat. Biogen began by administering three doses of aducanumab: 1 mg per kilogram of a patient's weight, 3 mg and 10 mg. Only the latter two doses led to a statistically significant reduction in the rate of cognitive decline, and only the 10 mg injection hit that threshold for improving function compared with placebo. The problem is that higher doses of aducanumab are linked with ARIA, or amyloid-related imaging abnormalities, which can result in dangerous brain swelling and spelled the most common reason for discontinuation in the study. After running into spikes in ARIA with the 10 mg dose, Biogen enrolled 30 more patients and gave them 6 mg of the antibody, hoping to find a happy medium that could achieve similar effects on cognition and function but present a better safety profile. And because that group got off to a later start, Biogen had to hold off on presenting data from the 6 mg arm until AAIC.

With all that prologue, the eventual letdown was that much more dramatic. On Wednesday morning, Biogen revealed that not only did the 6 mg injection fail to come through as the "Goldilocks dose" it had hoped for, but it failed to measure up to even the 3 mg group. Aducanumab at 6 mg per kilogram didn't lead to a statistically significant improvement over placebo on two measures of cognition and function, effectively poking a hole in that dose-dependent efficacy response that stirred up excitement in March.

Biogen was quick to point out that the results, from such a small group of patients, were by no means a definitive portrait of aducanumab's potential. Furthermore, while investigators kept tabs on cognition and function, the study was in fact powered to measure the antibody's effect on amyloid, and by that measure, the 6 mg dose came through with the statistically significant result Biogen sought. The company, now enrolling thousands of patients for a global Phase III trial, is not altering its overall strategy based on the new data.

The most common takeaway from analysts was that the latest aducanumab results are disappointing but not a sign the sky is falling in amyloid. Now, all eyes turn to the ongoing solanezumab study, as Biogen is unlikely to have new efficacy data on aducanumab until some time in 2018.

Eyeing the finish line

With all of the parsing and hand-wringing over solanezumab and aducanumab, AAIC felt much like a referendum on the amyloid hypothesis. Each treatment demonstrated its effect on brain plaques, but remaining elusive is definitive proof that doing so can actually alter the course of Alzheimer's.

For Hartley, the latest results are a sign "that the path is looking clearer as we go forward."

"What you've seen is a maturation of the field," he said. "(But) we've seen so many trials turn out not to be successful in Phase III. We're not there until we cross that finish line of two FDA-approved trials that are successful."

Siemers, who of course has a vested interest, shared the same cautious optimism. Looking at data from Biogen's treatment and a pair of similar drugs from Roche ($RHHBY), Siemers sees a through-line of promise in the amyloid field. And, due mostly to the severity of the unmet need in Alzheimer's, Lilly and its rivals occasionally collaborate on precompetitive pursuits like methodology and trial design, hoping to bend the curves of risk in favor of clinical success.

"When you start to see that many different compounds point in the same direction, that's what gives you some hope that this is the correct approach," Siemers said. "We don't have proof yet, but I would say that we're probably in a place where we've never been before in terms of getting close to getting the first disease-modifying treatment across finish line."

But if the scientists are going to finally clear that hurdle, it's going to take more than a handful of candidates targeting amyloid, Hartley said. The field needs more clinical endeavors, more exploration of potential targets and more funding for basic research in order to build on the past decade's breakthroughs in the disease, he said.

"We now know the disease may start some 15 to 20 years prior to clinical symptoms," Hartley said. "That set us along the pathway of thinking of Alzheimer's as a continuum. … Now we need more shots on goal, in other words more drugs coming into those clinical trials."

-- Damian Garde (email | Twitter)