By Sarah Toy
After Biogen Inc. /zigman2/quotes/201531540/composite BIIB +1.00% announced last week it was discontinuing Phase 3 trials of a potential blockbuster Alzheimer’s drug, Mizuho analyst Salim Syed declared, “Aducanumab is dead, and we’d argue so is the beta-amyloid hypothesis.”
Other analysts agreed. Biogen’s news, along with Roche’s discontinuation of two amyloid-based trials in January, “nearly close the door on the amyloid hypothesis,” SVB Leerink’s Marc Goodman wrote in a note on Thursday. Baird analyst Brian Skorney said in another note that the failure of aducanumab “should be the final nail in the coffin.”
Alzheimer’s researchers disagree.
The so-called amyloid hypothesis holds that the buildup of sticky protein fragments called beta amyloid plays a primary role in the progression of Alzheimer’s disease. And while none of the drugs targeting amyloid in Alzheimer’s patients has worked, that doesn’t mean that the hypothesis isn’t true.
The problem is when researchers are targeting beta amyloid, researchers say. By the time someone shows symptoms of Alzheimer’s — even very mild symptoms — it’s too late. Biogen's aducanumab, a monoclonal antibody, targeted beta amyloid in patients with very early signs of Alzheimer's disease.
“We know amyloid occurs at least a decade before symptoms appear,” said Rudy Tanzi, an Alzheimer’s researcher and vice chair of the neurology department at Massachusetts General Hospital in Boston. The build-up of amyloid leads to the formation of tau-containing neurofibrillary tangles, which kill a small number of brain cells. But the big problem is those tangles trigger neuroinflammation, killing neurons on a much larger scale.
Dr. Tanzi likens amyloid to a match that starts little brush fires of neurofibrillary tangles. Those brush fires spread and cause neuroinflammation, a forest fire that eventually destroys the brain.
“You don’t try to blow out the match after the fire is already blazing,” he said.
Biogen is still forging ahead on the amyloid hypothesis. On Friday, one day after the aducanumab announcement sent shares plummeting 29%, the company’s drug development partner Eisai Co., Ltd. /zigman2/quotes/202565502/delayed ESALY -1.30% announced it was starting a Phase 3 trial of BAN2401, another drug that targets and promotes the clearance of beta amyloid in early-stage Alzheimer’s disease.
Dr. Tanzi was skeptical of the new trial, saying, “That’s too late, even for patients with mild symptoms. If you want to target amyloid, you have to do it in people who are still well.”
Roche Holding AG /zigman2/quotes/208994986/delayed RHHBY +0.61% is doing just that with one of its trials of crenezumab, another monoclonal antibody designed to bind to and remove beta amyloid. The company pulled the plug earlier this year on two Phase 3 trials evaluating crenezumab’s effects on early Alzheimer’s symptoms, but the company is still evaluating the drug in a group of subjects in Colombia. These people, all healthy when enrolled, have a genetic mutation that leads to an early-onset form of Alzheimer’s disease. The idea here is that researchers are attacking amyloid earlier, before symptoms emerge and significant brain damage occurs.
Dennis Selkoe, an Alzheimer’s researcher and neurologist at the Brigham and Women’s Hospital in Boston, thinks drugmakers should focus more on such prevention-type trials. He likened the approach to the use of statins in the prevention of cardiovascular disease. Patients who have certain cardiovascular risk factors take statins to lower their risk of a heart attack or stroke. Dr. Selkoe envisions something similar for Alzheimer’s: A drug that people who have a genetic predisposition or elevated levels of beta amyloid can take long before they begin to experience memory loss.
“The main reason targeting amyloid has failed isn’t because it’s biologically implausible, but because trials are targeting it too late in the disease,” Dr. Selkoe said. “The most advanced shots on goal are still amyloid approaches, whether investors like it or not.”
Some companies have ditched amyloid-based efforts, while others have left the Alzheimer’s space altogether. In June, AstraZeneca Plc /zigman2/quotes/200304487/composite AZN +7.52% and Eli Lilly & Co. /zigman2/quotes/200106384/composite LLY +0.53% announced they were scrapping late-stage trials of lanabecestat, a beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor designed to prevent the production of beta amyloid. Pfizer Inc. /zigman2/quotes/202877789/composite PFE +1.05% said in January 2018 that it was abandoning the development of Alzheimer’s and Parkinson’s drugs.
Several companies are branching out and moving beyond amyloid. Neurotrope Inc. /zigman2/quotes/202408812/composite NTRP -0.87% is studying a drug called Brystatin, which targets both amyloid and tau protein. What makes it different from other amyloid-busting drugs is that it also aims to restore the lost connections between brain cells, called synapses.
Alector Inc. /zigman2/quotes/209168087/composite ALEC +1.73% is looking at ways to possibly restore the brain’s immune system. The biotech is studying ways to target mutated genes that have been linked to neurodegeneration, with the goal of slowing or reversing the deterioration of the brain’s immune cells.
Denali Therapeutics Inc. /zigman2/quotes/200043077/composite DNLI +5.04% is zeroing in on ways to target brain inflammation, one of which is a drug that targets receptor-interacting protein kinase 1 (RIPK1), an enzyme that plays an important role in inflammation and cell death.
“We should be looking at other approaches,” said Brigham and Women’s Dr. Sekoe. “But the amyloid hypothesis is not dead.”