A 2014 report provided a stark frame of reference for the challenge of fighting Alzheimer’s disease, showing that 99.6 percent of all drugs in the field had failed in one way or another.
Led by Jeffrey Cummings, director of the Cleveland Clinic’s Lou Ruvo Center for Brain Health, the same authors recently published a new report on the Alzheimer’s drug pipeline.
The failure rate has only gotten worse since 2014; there have been other significant developments, as well, not least of which is a recent Centers for Disease Control and Prevention report showing that the death rate from Alzheimer’s has increased signficantly since 1999.
Perhaps the biggest biopharmaceutical news came last year: another failure of Eli Lilly’s (NYSE: LLY) solanezumab, this time with Lilly betting unsuccessfully that the amyloid-clearing drug would have a notable effect on people who weren’t as deep into the disease when they began treatment.
It was another blow to the so-called amyloid hypothesis, which holds that Alzheimer’s is the result of clumps of amyloid protein, called plaques, and that preventing their formation or clearing them from the brain might slow or even halt the decline. Many drugs have now failed to show that clearing amyloid is helpful.
Many drug makers are pressing on with anti-amyloid drugs. One of the highest profile is Biogen (NASDAQ: BIIB), which jumped its drug aducanumab from Phase 1 into a massive Phase 3 trial last year. Former CEO George Scangos said more than once that Biogen would end up spending $2.5 billion on aducanumab development. Data are due in 2019.
But the anti-amyoid wave might have crested, according to the new analysis. Of the 105 drugs the authors found in clinical studies as of this January, 41 are designed to attack amyloid in one form or another. More than half of the drugs in Phase 3 are anti-amyloid. But the percentages in Phase 2 are much lower—14 of 52 drugs—suggesting that for next-generation programs, companies are thinking twice about committing big bucks in Phase 2, where costs generally start to mount. “Biopharma and academics are definitely diversifying the targets of interest,” says Cummings.
Anti-amyloid drugs are considered “disease-modifying”—that is, they aim to fundamentally change the course of Alzheimer’s disease. Less ambitious are drugs that aim to blunt the symptoms, including confusion and memory loss. The only two Alzheimer’s drugs ever approved in the U.S. are symptomatic treatments that temporarily slow patients’ cognitive decline. If RVT-101, a drug currently in Phase 3 that also aims to slow cognitive decline, produces positive data this year, it could shift the calculus of investors and drug developers, says George Vradenburg, chairman and founder of advocacy group USAgainstAlzheimer’s. Getting to market with a drug that treats symptoms could be “cheaper and faster” for several reasons and also could be more attractive to insurers, Vradenburg says. (His organization has its own pipeline analysis of Alzheimer’s drugs; he says it and the Cummings-led survey are “directionally similar.”)
Cummings and his coauthors admit some programs could be missing from their new analysis, which used the ClinicalTrials.gov database. Despite mandates to publish information, drug companies and academic researchers can be slow to share their studies on ClinicalTrials.gov, which is overseen by the U.S. Department of Health and Human Services.
But even with caveats, the authors deem ClinicalTrials.gov “the most complete of any existing database—and a sound basis for drawing conclusions about AD drug development.”
One bottleneck that worries the authors is trial recruitment. They have compiled the number of participants that will be necessary for current studies, many of which have shifted focus to people who don’t yet have full-blown symptoms. For example, studies of people with little to no symptoms (known as “prodromal” Alzheimer’s) will require 22,000 participants. Studies of preclinical Alzheimer’s will require more than 8,000. That’s on top of the more than 22,000 needed for mild-to-moderate Alzheimer’s studies.
These numbers are “daunting,” the authors write: “Trial recruitment is among the slowest and most expensive of all aspects of clinical trial conduct. The recruitment of such large numbers of participants will represent a substantial challenge to the system, and reforms are necessary to accelerate clinical trials and enhance recruitment.”
Asked to elaborate, Cummings says recruitment is the “largest single roadblock to conducting trials efficiently.” Biomarkers—that is, genetic peculiarities and other biological signs that a person might be more likely, say, to develop symptoms earlier or to respond well to a certain type of drug—will be of limited use in finding people for studies, Cummings says.
Vradenburg points out that if a shift toward drugs that treat symptoms in fact occurs, recruitment could become less onerous. “You’d be dealing with diagnosed individuals” already experiencing cognitive losses, he says, instead of people who seem fine but whose biology is waving red flags. “When families really start to recognize [a relative’s] problems every day, they go to the doctor” and ask for help.