It’s not often that drug company executives will sing the praises of a competitor’s drug. But at a recent neuroscience forum in Boston, nearly every suit on the dais had good things to say about aducanumab, an Alzheimer’s disease treatment being developed by Biogen.
The drug is an antibody that binds to amyloid-β, the protein that aggregates into the telltale plaques that coat the brains of people with Alzheimer’s. In a small study, it demonstrated something that to date has evaded the field: It showed that removing amyloid plaques from the brain could slow down progression of the disease.
5.3 million: Americans who have the disease
65%: Percent who are women
51: Number of drugs that have failed in Phase III trials
$226 billion: Direct cost of patient care in 2015
$1.1 trillion: Expected cost by 2050
$340 million: Write-down taken by Johnson & Johnson after failure of bapineuzumab
166: Number of people who were in Biogen’s Phase Ib trial for aducanumab.
SOURCE Alzheimer’s Association, InnoThink Center for Research in Biomedical Innovation, companies
In a field plagued by failures, the possibility of a winner is making the entire Alzheimer’s drug pipeline look better. Maybe the disease, the most common form of dementia, is not a dead end for drug developers after all. As important, success for aducanumab would prove the amyloid hypothesis—the long-standing theory that the protein is the main driver of the disease.
The data from the aducanumab study are a sign that “if you do things right, you appear to be able to move the dial,” says Luc Truyen, head of neuroscience external affairs at Janssen, the pharmaceutical arm of Johnson & Johnson. “That lifts everybody’s boat.”
The data come at a time when everyone could use a lift. Since 2002, 356 drugs have entered human tests to treat Alzheimer’s, according to Bernard Munos, founder of the InnoThink Center for Research in Biomedical Innovation. Of those, only seven—all of which offer only mild relief from the symptoms of the disease—have been approved. Most of the rest have flopped, including many in the later stages of development.
Those failures hang over the industry like a black cloud. It might then seem surprising that an early study could so thoroughly energize researchers. And, indeed, many who publicly proclaim excitement over Biogen’s data privately walk back their enthusiasm, noting the small patient group size and cautioning that the effect could disappear when a larger group is tested.
Still, there’s a sense among neuroscientists that this time is different for Alzheimer’s. They’ve learned from their mistakes with earlier drugs, they’re armed with better tools to detect and track the disease, and they’ve got compelling evidence from large genetic analyses that amyloid-β is in fact a major driver of the disease. If the amyloid hypothesis holds water, everyone agrees that the Biogen drug is the vessel in which to test it.
Moreover, their excitement extends beyond the possibility of getting an amyloid-β-targeted drug on the market. Researchers in industry and academia are making inroads with other therapeutic targets, most prominently tau, the disease’s other hallmark protein. If specific details of disease pathology remain blurry, researchers at least contend that the larger picture of Alzheimer’s progression is coming into focus.
“Ten years ago, we just didn’t know that amyloid was accumulating in the brain 15 years before symptoms,” says Harvard University neuroscientist Rudolph E. Tanzi. “We didn’t know that tau tangles spread once they form. We were shooting in the dark.”
Aducanumab might be providing excitement, but researchers have been burned before by early data. A low point came in 2012, when several high-profile Alzheimer’s therapies failed in quick succession. The drugs worked in various ways—some were antibodies that sequester amyloid-β itself or its aggregated form, others were small molecules that prevent amyloid-β from forming—but all had flaws.
The failures caused some critics to declare the amyloid hypothesis dead. Now, researchers understand that the trials were riddled with problems, not the least of which was that the drugs weren’t always being tested in people with Alzheimer’s. Because researchers at the time lacked good imaging tools and other biomarkers to detect the disease, people whose dementia had other causes were included in studies.
The earlier trials were further flawed because they included people whose disease was too far along to benefit from the drugs, which slow down Alzheimer’s but don’t reverse its course. Many of the people enrolled in the trials “couldn’t remember their spouse’s name,” Harvard neurologist Bradley T. Hyman explained at the Boston neuroscience event.
“When you look at those individuals by MRI or autopsy, they’ve lost something like a third of the substance of the brain,” Hyman said. “At that point, that’s really organ failure.”
Another cause of the disappointments is poor drug design. “You can’t test the amyloid hypothesis if you don’t reduce amyloid-β production or clear existing plaque,” says Michael L. Hutton, chief scientific officer for neurodegenerative diseases at Eli Lilly & Co. “You’ve really got to make sure—prior to Phase III—that your molecule is testing the hypothesis.”
Unfortunately, Hutton notes, some compounds that got far into the clinic before failing turned out to not actually hit their intended targets. Researchers point to Lilly’s small-molecule semagacestat and J&J’s antibody bapineuzumab as examples of failures in drug design.
“It’s not a mystery why things went so bad,” says Dennis J. Selkoe, a Harvard neurologist who was among the first to put forward the amyloid hypothesis in the early 1990s. “It all makes perfect sense in the area of human endeavor. We were anxious to move ahead—I certainly was—and got imperfect drugs and poor trial design.”
Biogen appears to have taken the lessons to heart, starting with the design of the drug itself. Aducanumab stems from a pact formed in 2007 between Biogen and the Swiss biotech firm Neurimmune to develop antibodies against aggregated amyloid-β.
Neurimmune is founded on technology developed by University of Zurich neuroscientist Roger Nitsch and takes what he calls a “reverse translational medicine approach.” Because aggregated proteins implicated in diseases such as Alzheimer’s have a different structure or conformation than normal proteins, he reasoned, the immune systems of healthy people must develop antibodies against them.
Furthermore, a memory of antibodies against aggregated amyloid-β should live on in the B cells in the bone marrow of healthy aging people. Neurimmune screened millions of B cells, a kind of white blood cell, to decipher the genetic information encoding antibodies with the right qualities, including the ability to pass through the blood-brain barrier but not interact with other tissues in and outside of the brain, Nitsch explained at the Boston neuroscience event.
“In a sense, the human body did much of the work engineering this antibody,” says Jeff Sevigny, Biogen’s senior director of neurodegenerative disorders. The companies then altered part of the antibody to improve its performance.
The partners derived multiple antibodies from Nitsch’s technology and eventually settled on aducanumab, which targets the aggregated form of amyloid-β and did well at clearing the protein in animal studies.
When Biogen designed the much-lauded study of aducanumab, “our main task was to ensure that 100% of the subjects enrolled had the disease,” Sevigny says. The firm says its study is the first to require amyloid plaque buildup to be confirmed by PET imaging. And the company only included people who were in early enough stages of the disease that lowering amyloid could make a difference.
The strategy worked. Last December, Biogen announced that preliminary results of its Phase Ib trial of aducanumab were good enough that the drug candidate would bypass Phase II studies and graduate to Phase III, the last step before seeking regulatory approval.
At a neuroscience conference in March, the company provided more details: The Phase Ib study of 166 people included about 30 people each at four dosage strengths and 40 who were given a placebo. PET scans showed that the higher the dose, the more plaque that was removed from the brains; even better, the higher the dose, the better that people performed on cognitive tests.
For scientists who have been plugging away at the amyloid hypothesis for decades, the results were gratifying. “No doubt there’s a little over-the-top enthusiasm,” Harvard’s Selkoe says. “You have to be measured, but I think these results are hard to explain away, scientifically, and that’s all that matters to me.”
Still, much work lies ahead, Selkoe cautions. For starters, Biogen will need to repeat the results in far more patients. One big question for aducanumab is whether brain swelling, a side effect observed in all amyloid-clearing antibodies, will keep patients from being given the highest, most effective dose.
Although aducanumab has been getting the headlines, the first drug to actually make it to market could be Lilly’s solanezumab. Whereas aducanumab targets aggregated amyloid-β, solanezumab binds to soluble, monomeric forms of the protein. The antibody failed in two large Phase III studies, but a subset of patients who were in the early throes of the disease appeared to benefit from it. Lilly is well along in a Phase III trial to test the drug in that narrower group and expects to have results by October 2016. If they are favorable, the first disease-modifying drug for Alzheimer’s could reach patients in 2017.
The other advanced drug is a Merck & Co. small molecule that blocks BACE, an enzyme that helps trim a larger protein down into amyloid-β. Unlike earlier BACE inhibitors—including an antibody from Genentech and small molecules from Lilly and Bristol-Myers Squibb—that were pulled for reasons of efficacy and toxicity, MK-8931 has made it to Phase III. Merck is expected to unveil results late next year or in early 2017.
Meanwhile, Genentech is further behind with its antibody crenezumab, which binds to both monomeric and aggregated forms of amyloid-β. The drug failed to improve cognition in a Phase II study, but as Lilly found with solanezumab, people with a mild form of the disease seemed to benefit. Genentech recently launched a smaller Phase I safety study of higher doses of the treatment in people with mild to moderate Alzheimer’s. Like Biogen’s aducanumab trial, this one requires the disease to be confirmed by PET scan.
At the same time, Genentech is deep into a long-term study of crenezumab that could support targeting amyloid. The five-year Alzheimer’s Prevention Initiative (API), a partnership between Genentech, the National Institutes of Health, and Banner Alzheimer’s Institute, seeks to determine whether the antibody can stave off Alzheimer’s in an extended Colombian family afflicted with a rare genetic mutation that causes an early-onset form of the disease.
Carole Ho, who leads nononcology early clinical development at Genentech and plays a key role in the API study, says the trial could have implications for the broader Alzheimer’s population. In addition to testing the amyloid hypothesis, the study is collecting vast amount of imaging and biomarker data that the team hopes will correlate with cognitive benefits.
That data could, in turn, be used as clinical measurements, or end points, for future Alzheimer’s studies. “While we have end points that have been used across multiple trials in the past, we don’t really have good end points for the early stages of the disease,” Ho says.
Even as researchers await clinical evidence confirming—or refuting—the amyloid hypothesis, they also acknowledge that clearing amyloid is unlikely to be a cure.
The “unifying theme” of the data from studies of solanezumab, crenezumab, and aducanumab is that “we may be able to have an effect on the disease with antiamyloid therapies, but the magnitude of the effect may not be transformative,” Genentech’s Ho says. “It may be a start, but what I see in the future is we’re going to be looking toward combination therapy.”
The most obvious candidate to combine with an amyloid-β-targeted agent is a drug that takes aim at the other problematic protein in Alzheimer’s patients: tau. Whereas amyloid-β forms sticky plaques that coat their brains, tau causes “tangles”—snarls of aggregated filaments found inside neurons. And the two are connected: Amyloid-β kicks off tau’s tangle formation by a yet-to-be-determined mechanism.
Just five years ago, tau was considered a daunting drug discovery target. The protein plays a critical biological role in stabilizing microtubules, a structural and transportation component in neurons. At the same time, it’s hard to access because, unlike amyloid-β and its aggregates, tau resides inside cells.
A cluster of recent discoveries is helping drug developers understand tau and its role in cognitive decline. “You can have plenty of amyloid on the brain but barely altered cognitive function,” says Morgan Sheng, Genentech’s vice president of neuroscience and molecular biology. “But after roughly 10 to 15 years of amyloid accumulation, tau starts to misfold and aggregate. Then you start to see signs of dementia.”
Researchers have learned that tau “is not just the secondary pathology that it’s been relegated to, but perhaps it is as important if not more important than amyloid,” says Karen Duff, an Alzheimer’s researcher at Columbia University.
Duff is one of several researchers who showed in recent years that dysfunctional tau is self-propagating. Whereas amyloid-β plaques build up slowly and steadily over many years, tau can spread in a prionlike fashion, moving from a sick neuron to a neighboring healthy neuron, thereby spreading the pathology throughout the brain.
Buildup of amyloid-β triggers the initial accumulation of tau, but as Duff explains, at some point the relationship decouples and tau becomes a runaway train. That means that even if a drug effectively clears amyloid from the brain, if the disease has progressed too far, tau tangles can still spread and cause damage.
Duff’s work helps fill in the picture about how Alzheimer’s unfolds and also opens the door to developing drugs that block tau. Targeting tau inside cells is tough, but a dysfunctional version of the protein that propagates outside cells would be more easily accessed by a drug.
“Over the past five years, it is becoming more and more accepted, if not proven, that tau pathology might spread at least in part between cells,” Genentech’s Sheng says. “That extracellular transmission gives an opportunity for an antibody to come and block the spread.”
Another spur to the development of anti-tau therapeutics is the advent of tau radiotracers. Just as amyloid imaging transformed clinical trials for drugs such as aducanumab, an effective tau tracer will allow researchers to pick the right patients for trials and track drug efficacy.
“We’re seeing a really significant evolution with the advent of the tau tracer,” says Lilly’s Hutton, who prior to joining the pharmaceutical industry spent a decade studying tau pathology at the Mayo Clinic in Jacksonville, Fla. Tau tracers have already confirmed the observation from brain autopsies that, starting around age 60, everyone develops tau tangles. They are benign unless amyloid plaques are also present.
Lilly is one of several companies working on tau tracers, which Columbia’s Duff calls “the best thing that’s happened in the last year.” Lilly already markets Amyvid, an 18F-based tracer that detects amyloid plaques in patients with cognitive impairment.
Although the science around tau is still evolving, companies are forging ahead with drug development, and industry watchers expect a flood of new candidates.
In January, J&J partnered with AC Immune to develop anti-tau vaccines in a deal that includes ACI-35, which is in a Phase Ib study. AC Immune’s vaccines are built to stimulate B cells to wage an antibody response against phosphorylated tau, the misfolded form of the protein that causes tangles.
Genentech has been working with AC Immune to find antibodies against tau since 2012. Biogen and Neurimmune hope to replicate their amyloid success with antibodies against tau.
Even though tau drugs trail antiamyloid therapies by a decade, researchers are excited by the possibility that they could treat people with more advanced disease. “For amyloid treatment, you have to go very early, almost preventative,” Genentech’s Sheng says. “But tau maybe has a little bit longer window of opportunity such that patients who have already started to show symptoms can be treated.”
Even as companies make progress against amyloid and tau, a major gap exists in understanding how the two proteins are connected. If researchers could unravel the mechanism by which amyloid triggers tau proliferation and figure out how tau injures neurons, promising drug targets might follow.
“If there’s an area I’d really like to see progress from in the next five years, it would be that really fundamental level of how amyloid and tau toxicity works,” Lilly’s Hutton says. “No doubt there will be additional drug targets to come out of that work.”
And despite significant progress against Alzheimer’s since the trial failures of 2012, researchers are quick to acknowledge that the challenges go beyond simply finding a treatment. Drugs, whether taken for life or for a short stint, are going to be expensive. Companies would not be placing such risky bets if they didn’t expect financial rewards.
Moreover, a stigma around dementia lingers. As Hutton points out, people are scared of Alzheimer’s, so they often don’t see their doctor about symptoms until they’re past the point where the antiamyloid therapies now in the clinic could help.
“I’m optimistic therapies will come,” Hutton says. “What I’m less sure about is how they’ll get applied in the real world.”
Two Start-ups Push Beyond Traditional Alzheimer’s Drug Development
Ever since leaving his academic neurology post two decades ago, venture capitalist Doug Cole had been on the lookout for a worthwhile investment in neurodegenerative disease. But for more than a decade, he couldn’t muster enough confidence in the field to back a biotech firm working on tough diseases like Alzheimer’s or Parkinson’s. The fundamental biology of those diseases was too unclear, and running a clinical trial was fraught with challenges.
Cole’s mind has clearly changed. Last month, Flagship Ventures, where he is a managing partner, joined several other firms to put $217 million into newly launched Denali Therapeutics, a South San Francisco-based biotech founded by three former Genentech executives, including onetime research chief Marc Tessier-Lavigne, to tackle neurodegenerative diseases. The hefty cash influx is believed to be the largest first round of financing in the biotech industry’s history.
Denali is one of two neuroscience-focused biotechs launched this year by high-profile founders. Cambridge, Mass.-based Yumanity Therapeutics, unveiled in January to much fanfare, has at its helm biotech veteran Tony Coles, who led Onyx Pharmaceuticals before it was acquired by Amgen.
Their creation signals growing interest in a field that not so long ago was seen as a minefield for drug developers. Company founders say the right tools, including better brain imaging and a growing body of genetic data, are coinciding with improved understanding of how to test Alzheimer’s drugs. “We’re at a very special time right now,” says MIT molecular biologist Susan Lindquist, who is the other big-name founder of Yumanity.
Denali is providing few details about the targets or technology it will use. Chief Executive Officer Ryan Watts will say that the company is founded on the belief that genetics will soon enable broadly defined neurodegenerative diseases to be broken into subpopulations, much like what has already occurred in cancer. In the process, new drug targets will open up.
In its pursuit of Alzheimer’s treatments, Denali will work on inflammation, an area of research that drug developers have yet to broach—at least publicly. Although amyloid plaques and tau tangles are widely accepted as telltale signs of the disease, in recent years, inflammation is increasingly understood to speed up its progress.
Some scientists say not enough is known about whether inflammation is a cause or consequence of the disease, making drug discovery tricky. Watts isn’t deterred. “If you look at the human genetics of Alzheimer’s, 60 to 70% of the genes implicated are enriched in the microglia,” cells that act as the brain’s personal immune system.
That has made inflammation “a really hot space,” Watts says. Even if amyloid and tau trigger the disease, inflammation likely plays a role in accelerating it.
Another area of interest for Denali is how neurons die, a subject near and dear to Watts, who studied it as a graduate student at Stanford University. One way to study neuronal death in Alzheimer’s is with assays that can parse whether neurons are dying of natural causes or because of damage by disease. After identifying the players responsible for the cell death, scientists can tease apart which pathways are involved and eventually turn up drug targets.
With such big scientific questions to tackle, Denali will be “built to last,” says Chief Operating Officer Alexander Schuth. The firm is assembling a team of scientists with a translational medicine group at its core.
If Denali has at its foundation the belief that genetics will expand the array of targets for Alzheimer’s drugs, Yumanity is driven by the use of model organisms to point researchers to the best targets.
Yumanity’s search for Alzheimer’s drug candidates hinges on phenotypic screening—the testing of compounds in whole cells or organisms rather than against an isolated drug target. Phenotypic screens have so far not been used for Alzheimer’s drug discovery for two main reasons: Figuring out the target of a “hit” from a phenotypic screen can be tough, and the screens themselves are a challenge to set up.
“Right now, it is so difficult to grow neurons and have them operating in normal biology in the tiny format you need for drug screening,” MIT’s Lindquist explains.
Lindquist’s lab has overcome those hurdles. By engineering yeast cells to express proteins like amyloid-β, compounds can be cheaply and quickly screened. Although yeast do not perfectly replicate human disease, “you can capture a lot of the biology,” she says.
The hits from the yeast screens are put into neurons derived from induced pluripotent stem cells, which themselves were derived from the skin cells of patients. Researchers can then test whether compounds that worked in yeast will actually rescue the neurons of a patient who has the disease, Lindquist explains. The last step is to return a promising compound to the yeast and use genetics to find its target.
Although Yumanity is further along in its work with Parkinson’s disease, the company has “already been able to use our yeast cells to connect the pathology of amyloid with several genes,” Lindquist says. “I think the ability to use the cell to tell you what’s going to make it better, and then figure out how it’s working, will really be illuminating.”