Biogen Drug Gives New Momentum to Decades-Old Protein HypothesisJason Gale, Makiko Kitamura and Cynthia Koons
The results of Biogen Idec Inc.’s experimental drug for Alzheimer’s disease provide the best evidence so far that the memory-robbing condition is caused by an errant protein in the brain that, if stopped, could lead to an effective treatment.
German psychiatrist Alois Alzheimer was the first to connect dementia to abnormal protein deposits in brain tissue back in 1906, but it took another 80 years for scientists to understand where the protein, known as beta amyloid, was made and to see it as a potential target in treating Alzheimer’s disease.
No clinical trial had previously reduced beta amyloid in subjects’ brains while also slowing the deterioration in their cognition. Now, the findings on BIIB037, Biogen’s medication, show that it’s possible.
In an early-stage trial of 166 patients, BIIB037 reduced beta amyloid in the brain and also reduced cognitive decline, with higher doses and longer treatment resulting in more improvements, the company said Friday. Based on what’s called the Clinical Dementia Rating, the drug showed a 71 percent reduction in cognitive decline among patients who took the highest dose, compared with those on placebo, exceeding analyst expectations.
“It’s a major advance in confirming amyloid beta is the right target,” said Colin Masters, a laureate professor at the University of Melbourne and senior deputy director of the Florey Institute of Neuroscience and Mental Health. He began purifying amyloid from human brains in collaboration with a German group in the 1980s. The group was the first to sequence the molecule’s amino acids, helping identify the gene responsible for its production in the brain.
There are 47.5 million people living with Alzheimer’s disease and other forms of dementia —- more than the population living with HIV/AIDS. The number is set to almost double by 2030 and more than triple by 2050. The cost of dementia care, estimated at about $600 billion in 2010, is projected to reach $1 trillion by 2030.
Biogen’s drug was originally developed by the Swiss biotech Neurimmune Holding AG, which creates human-derived monoclonal antibodies with characteristics closely resembling those occurring in healthy elderly people. BIIB037’s antibodies were derived from those taken from hundreds of healthy Swiss donors over the age of 65, said Jan Grimm, chief scientific officer at Neurimmune, who helped discover the drug. Neurimmune cloned the genetic information underlying the antibodies to then engineer therapeutic antibodies, he said. Biogen licensed the drug from Neurimmune in 2007.
“There’s a chance that this could be the first registered disease-modifying drug for Alzheimer’s disease,” said Ashley Bush, a neuroscientist at the Florey Institute of Neuroscience and Mental Health in Melbourne, who ranks among the top 1 percent of most-cited researchers in neuroscience and behavior. He wasn’t involved in Biogen’s trial.
As Biogen prepares for late-stage trials of the drug later this year, the company is pushing rapidly ahead into an area where other drugmakers have tried and fell short in final-stage trials. The medications solanezumab, from Eli Lilly & Co., and bapineuzumab, developed by Pfizer Inc., Johnson & Johnson and Elan Corp., both failed to show a significant effect on the disease in trials.
Lilly is currently retesting solanezumab in earlier-stage patients, while bapineuzumab has been scrapped. Roche Holding AG is continuing to sponsor a trial of its amyloid-targeting drug in Alzheimer’s patients with mild dementia, though in December it abandoned a study of people with early stages of the disease because of poor results.
Even if the beta amyloid hypothesis is found to be correct, it may have problems. Biogen’s drug had side effects, particularly the brain swelling known as amyloid-related imaging abnormalities, or ARIA. Among patients carrying the ApoE4 gene, which is strongly linked with Alzheimer’s, 55 percent of patients on the highest dose reported ARIA. That resulted in 35 percent of the ApoE4 carriers on the highest dose discontinuing treatment. And 22 percent of those who took the drug had headaches, versus 5 percent on a placebo.
“The field is still learning about ARIA, but it appears to occur more frequently with these anti-amyloid therapeutics,” said James Hendrix, director of global science initiatives at the Alzheimer’s Association, a Chicago-based nonprofit advocacy group. “This is an important adverse event that has to be monitored as they move into Phase 3.”
Even with the promising results from Biogen’s study, Alzheimer’s should be tackled from multiple angles, he said. Drugmakers including Biogen are also exploring medications that target tau protein in the brain as well as immunological approaches.
“It’s not an either/or,” Hendrix said. “There needs to be as many of those as possible so we can have a fuller understanding of Alzheimer’s.”