Quest to cure Alzheimer’s disease shows symptoms of failure
Failed drug trials have led some scientists and Big Pharma executives to doubt the central theory behind its cause
The suspense inside the offices of Eli Lilly this autumn was all but unbearable. After working on a drug to fight Alzheimer’s disease for 15 years, employees of the Midwestern drugmaker were about to find out if the medicine — known as Solanezumab, or Sola — actually worked. Some staff compared the experience to being pregnant.
In an interview in October, just weeks before the trial concluded, Hong Liu-Seifert, a statistician at Lilly, described the atmosphere as one of “excitement, anticipation and anxiety”. She and her fellow workers were experiencing sleepless nights, she said.
When Ms Liu-Seifert and colleagues sat down last week to sift through data from the trial of 2,100 patients with mild Alzheimer’s, they concluded the drug had flunked the study.
Although those on the drug performed slightly better than patients taking a placebo, the benefit on cognition was so small it could not be deemed statistically significant. The news wiped $10bn off Lilly’s market capitalisation in a single day, and knocked around 5 per cent off Biogen, a biotech company developing a rival medicine.
Analysts had predicted that Sola could transform the group’s fortunes, generating up to $3bn in peak annual sales and making it the company’s best-selling medicine by some distance.
But the failure of the study has ramifications well beyond Lilly’s sprawling corporate campus in downtown Indianapolis. The trial was one of the biggest tests of the amyloid hypothesis, which holds that Alzheimer’s is caused by the build-up in the brain of a sticky plaque called beta amyloid.
For the past 25 years, neurologists have coalesced around this theory, believing it offered the best chance of finding a treatment for the nearly 44m people who suffer from Alzheimer’s worldwide. In the absence of a medical breakthrough, the number of people aged over 65 with Alzheimer’s is forecast to nearly triple to 13.8m by 2050 in the US alone, according to the Alzheimer’s Association. Drugmakers followed suit, spending billions of dollars researching drugs designed to clear beta amyloid.
Now some scientists and pharmaceutical executives are asking if it is time to accept that the hypothesis is flawed.
“The problem with Alzheimer’s is we still don’t really know or understand how the disease happens,” says Dr Amit Roy, a founding partner at Foveal Research. “We do see changes in the brain like plaques, but it could be an association not a cause.”
The focus on medicines that target beta amyloid is akin to developing a “drug for lung cancer that targets yellow fingernails”, Dr Roy argues. “The amyloid hypothesis has been around for a long time and it always fails,” he adds. “It looks nice but it’s unproven, and it falls over again and again.”
‘Throwing spaghetti at the wall’
It is almost a decade since the first drug designed to rid the brain of beta amyloid, Tramiprosate, made by the now-defunct Neurochem, failed in the final “phase III” stage of testing — and there has been a near-constant string of high-profile failures ever since. The most notable was Bapineuzumab, developed by a consortium of Pfizer, Johnson & Johnson and Elan, which crashed out of trials in 2009. Not only was it ineffective, it also caused dangerous brain swelling in some patients.
Sola also failed in two Phase III trials in 2012, although Lilly believed it could succeed by retesting the drug, this time limiting the study to patients with mild disease. The company blamed the original failed trials on the fact that many Alzheimer’s sufferers are actually misdiagnosed, and are in fact suffering from other forms of dementia.
Lilly believed — wrongly, it now turns out — that it could generate a positive result by excluding these miscategorised patients through the use of a new type of brain scan that can detect plaques.
Despite the disappointments, drugmakers have persevered, attracted by the economics of an ageing population and the rich financial rewards if they succeed. Of the 10 new drugs for Alzheimer’s currently being tested in late-stage trials, six target beta amyloid, including medicines from Biogen, Roche, Johnson & Johnson, Lilly, AstraZeneca and Merck and Co in the US.
Less charitable observers argue the potential profits on offer are so large — some estimate as much as $13bn a year for a single drug — that Big Pharma is happy to back trials that are founded on shaky science. “They’re just throwing spaghetti at the wall in the hope that something will stick eventually,” says one executive at a drugmaker not involved in Alzheimer’s research. Lilly has spent $3bn on its Alzheimer’s programme in the past three decades.
That said, drugmakers are often accused of being too timid, of focusing their research budgets on medicines that offer incremental benefits in areas where there are already several treatments on offer. “I don’t fault them,” says one investor in Lilly. “You’ve got to take the risk sometimes, and I thought it was a reasonable bet.”
Few doubt that beta amyloid and Alzheimer’s are linked; upon autopsy, many patients are found to have brains that are riddled with the plaques. Genetically modified mice inserted with diseased human genes also develop the sticky deposits and have tended to respond well to amyloid-clearing drugs.
But there is less proof that the build-up of beta amyloid is the primary culprit, or that it is more important than other factors, such as twisted protein tangles in the brain, known as tau.
“How many times do you need to disprove the same hypothesis before you reject it?” asks Vivek Ramaswamy, chief executive of Axovant, which is developing a drug for Alzheimer’s that does not target amyloid. “I believe it’s time for the field to take a step back and evaluate new approaches. This may be a wake-up call.”