Alzheimer’s disease is upending the rules of drug discovery, with a handful of companies abandoning caution to keep pursuing an elusive hypothesis because the potential payoff is so great.
Even the merely forgetful, whose lives have yet to be derailed by the disease, have become candidates for clinical tests.
Scanning the brain for telltale signs of Alzheimer’s earlier — and ratcheting up drug dosage — might help turn failures into breakthroughs, AC Immune SA chief executive officer Andrea Pfeifer said.
The Swiss company’s partner on its experimental drug, pharmaceutical giant Roche Holding AG, last week said it would embark on a second advanced test, undeterred by a failed intermediate trial.
Pfeifer’s optimism is a case study of the industry’s unusually high risk tolerance on Alzheimer’s, where more than 100 experimental drugs have already failed — with two recent setbacks from Merck & Co and Eli Lilly & Co. Like Roche and its partner, Biogen Inc is chipping away at the same target that has eluded rivals. Merck and Lilly have opted to keep testing their medicines in patients showing only hints of the degenerative disease.
Each advanced trial can cost hundreds of millions of US dollars, according to Lilly.
“It’s always a question — are you throwing good money after bad?” Zurich-based Rahn & Bodmer Co fund manager Birgit Kulhoff said. “If you were to be successful, it would be an extremely big market.”
Drugs that halt the progress of Alzheimer’s disease could be a market worth as much as US$30 billion in the US alone, Sanford C Bernstein & Co analysts estimate.
Cancer is the only other disease for which companies are this willing to look deep into a failed study for a positive trend to chase, Kulhoff said, adding that Alzheimer’s tests are probably more expensive because researchers follow patients for longer and monitor them closely.
The drugmakers would not disclose how much they have spent on clinical tests.
A final-stage trial in Alzheimer’s disease can cost more than US$200 million, Cowen & Co analyst Eric Schmidt said.
Such a study in a cancer like melanoma would tend to be much smaller and could cost about US$50 million to US$100 million, he said.
Just arranging and administering the brain scans needed to make sure people have signs of the disease cost about US$15,000 to US$20,000 per person in a small test, AC Immune said.
Roche made its cost-benefit calculation two-and-a-half years ago. Crenezumab, the medicine it is working on with AC Immune, had failed to help patients think more clearly or retrieve memories in a mid-stage trial, a hurdle potential drugs usually must clear before they go into the last, largest and most expensive stage of clinical studies.
Instead of abandoning the compound, Roche looked at a trend toward benefit in the least sick patients and spent the next two years figuring out how high it could safely ratchet up the dose. Then last year, it started another 750-patient study, with results expected in 2021.
Now it is embarking on a separate trial, also with 750 patients with a very mild form of the disease. It is unclear how that test is to differ from the first one. It is also trying a higher dose for another Alzheimer’s compound, gantenerumab, after a late-stage trial failure.
Both Roche drugs are aimed at protein pieces called beta amyloid that clump together in the brain and are thought to play a role in triggering the disease. Trouble is, so did the Lilly medicine that failed a test in patients last year. Last month’s unsuccessful trial from Merck also centered on beta amyloid as a target, although the type of medicine was thought to prevent the substance from forming. Those failures have cast doubt on the whole approach.
“Clearly those are two strikes against that theory,” said Brent Saunders, chief executive officer of US specialty-drug maker Allergan PLC. “My hope is that we’ll keep going, but we’ll see.”
Allergan is thinking hard before starting patient trials on an experimental drug that belongs to the same family of drugs as Merck’s after seeing the two recent failures, Saunders said.
The company also sells medicines that temporarily ease symptoms of the disease — the sole form of treatment currently available.
Alzheimer’s disease is on the rise across wealthy countries as their populations age. Globally, dementia unseated AIDS as one of the top 10 killers in the WHO’s latest rankings.
“We’re not going to have a reversible cure any time in the near future,” said Phyllis Ferrell, who leads Lilly’s Alzheimer’s program.
However, “I think in our lifetime we will have something that slows this disease,” she said.
Darryle Schoepp, the head of neuroscience research at Merck, acknowledges that the industry might have been “a little too optimistic” about Alzheimer’s trials, but said that all the years of painful outcomes have taught companies how best to test their theories.
While Merck is also looking at what’s next beyond beta amyloid, Schoepp said the big unanswered question is whether stopping the buildup before dementia begins can make a dent in the disease — something it is testing in another big final-stage trial.
Similarly, for Pfeifer, all the failures are signposts on the path toward eventual success, as scientists get better at peering into the brain, identifying Alzheimer’s potential before patients become very sick and figuring out which antibodies attack amyloid beta at its most toxic stages.
She compared the Alzheimer’s field to where the study of cancer stood when she was a young oncology researcher at the US National Institutes of Health about 30 years ago.
“We are now finally getting to the molecular level where I think the science in Alzheimer’s has to go,” Pfeifer said. “We were just not scientifically exact enough. That’s where I have big hopes.”
Another drugmaker that has faced questions — despite largely positive results — is still gung-ho about the beta amyloid route.
Biogen clinical development executive Gilmore O’Neil said many industry studies so far have looked at patients who were already so sick that they would probably be beyond saving even if the hypothesis were true — or patients that might not have had Alzheimer’s disease at all.
After promising initial findings, Biogen pushed its top compound, aducanumab, into final-stage studies immediately without running an intermediate study to confirm the early findings. Subsequent analysis was not all positive: Lower doses did not show a cognitive benefit and the drug was linked to a swelling of the brain.
Lilly also has not abandoned the quest. It has 10 projects being tested in humans, including a molecule, partnered with AstraZeneca PLC, in the same family as the Merck compound that failed most recently. Like other drugmakers, it is seeking earlier patients — including in some cases people who merely have brain scans showing amyloid and are not showing signs of forgetfulness at all.
“It’s like cancer,” Ferrell said. “You want to catch it at stage 1, not at stage 4.”
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