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 $10 billion 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 44 million 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 13.8 million 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.”
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."
Sceptics argue that there is an inability in the field of Alzheimer’s research to accept failures for what they really are. Most recently, TauRx, a Singapore-based drugmaker, hailed the failure of its drug LMTX in phase III trials as “hugely encouraging” by pointing to results from a tiny subset of patients. Some news organisations reported the data under misleading headlines, including one that read: “Scientists create the first drug to halt Alzheimer’s.”
“It’s preposterous just how dishonest some companies are,” says one industry veteran. “You would never get away with this if you were developing drugs for oncology or infectious diseases.”
Others argue it is still too early to give up on the hypothesis, including Lilly, which has a further six Alzheimer’s medicines in its pipeline, most of which target amyloid.
"It's not game over for the amyloid hypothesis, but in terms of general perception, it's certainly a strike against confidence in the approach," says Dr Martin Farlow, a neurologist who ran Sola trials in Indiana. He predicts the bad news will hurt investment in biotech start-ups from venture capitalists.
Dr Farlow and other supporters of the amyloid hypothesis cite several reasons for their enduring faith despite the failure of Lilly’s drug. First, Sola does not cross the blood/brain barrier and enter the central nervous system to attack the plaques themselves. It is instead designed to trap soluble forms of amyloid in the blood to stop the material building up in the first place.
Others believe that mild Alzheimer’s is a misnomer: by the time a patient has developed symptoms or plaques, then it could be too late to have much of an effect. Lilly is continuing to test Sola in patients who have yet to show outward signs of the disease.
Nor is the drug as potent as some of the rival medicines still being developed. Some investors now say they are disappointed that Lilly did not experiment with higher doses of Sola in smaller groups of patients before spending hundreds of millions of dollars on another 18-month clinical trial.
Dr Eric Siemers, a Lilly scientist who worked on Sola, is not so sure. "Even in hindsight if we'd increased the dose and spent two or three years generating safety data, I think we could be having much the same conversation as today."
Whether the amyloid hypothesis remains the main explanation of what causes the illness hinges in part on data that are due to be published at the annual meeting of the Clinical Trials on Alzheimer’s Disease in San Diego, which begins on December 8.
Now that Lilly’s Sola has failed, investor attention has turned to Biogen, which is planning to use the conference to update investors on its amyloid-clearing medicine, Aducanumab. The drug has shown some promise in small, preliminary trials, although the dosages at which it was most effective led to dangerous swelling on the brain.
Biogen has since been experimenting with different dosages, but it may be difficult to find a perfect balance: drugs that are powerful enough to clear the brain of plaque might inherently cause intolerable side effects.
"I've been sceptical of the amyloid hypothesis for a long time, and in particular of approaches that use the immune system to deal with amyloid," says Dr Lawrence Friedhoff, the scientist behind Aricept, one of the only Alzheimer's treatments, which is readily available as a generic drug. "It is predictable that they will cause toxicity," adds Dr Friedhoff, who is now an executive at Axovant.
Lilly will also use the San Diego forum to unveil more detailed results from its failed studies of Sola, which could provide some clues as to the strength of the amyloid hypothesis.
The doomsday scenario is that the drug did manage to clear the plaques from patients’ brains, but barely improved their cognition. Such an outcome would suggest the link between beta amyloid formation and memory loss is not so pronounced after all.
"If the data show that Sola removed a substantial amount of plaque, that would not bode well for Biogen's Aducanumab, which is designed to specifically remove plaques," says John Scotti, an analyst at Evercore ISI. "Moreover, it also would cast a shadow on the amyloid hypothesis more generally."
If the amyloid hypothesis were to be cast asunder, questions arise over what could replace it as a central theory of the cause of Alzheimer’s. Some scientists believe tau tangles are to blame, while others point to signs of inflammation and the brain’s fading ability to metabolise energy as people get older. But none of these theories has been tested in a large clinical study.
“I used to be an optimist, but I got that beaten out of me years ago,” says Dr Farlow, who has spent a quarter of a decade trialling Alzheimer’s drugs. “But I’m not a pessimist either. If you keep asking questions, then sooner or later you’re going to get a definitive answer.”
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- Copyright The Financial Times Limited 2016
