When neurosurgeon Matthew S. Schrag learned that the Food and Drug Administration had approved a controversial Alzheimer’s drug, he was taken aback. In his opinion, there was little evidence that the treatment worked.
Even more concerning, according to Schrag, is the FDA’s apparent acceptance of a long-debated theory about Alzheimer’s disease, which affects more than 6 million Americans. The amyloid hypothesis, which has dominated the field for decades, holds that toxic clumps in the brain known as amyloid beta are the primary cause of the disease and that removing them will slow cognitive decline. However, years of testing drugs that target amyloid had resulted in a string of failures, and Schrag and others had been pushing the field to focus on other possible factors, such as brain inflammation or damage to tiny blood vessels. They claimed that anti-amyloid efforts had squeezed out other approaches that could be more promising.
The role of sticky clumps of protein in the brain has long divided researchers, and it is once again at the forefront following the FDA’s recent approval of the first drug to treat the disease in nearly two decades. It is one of several controversies that have erupted since the FDA approved Aduhelm on June 7.
Members of Congress have promised to hold hearings on the FDA’s relationship with the drug’s manufacturer, Massachusetts-based Biogen. Analysts are concerned that the drug’s list price — $56,000 per patient per year — will devastate Medicare’s finances. Doctors are arguing that the FDA-approved label, which includes all Alzheimer’s patients, is far too broad.
However, within the scientific community, the debate over the amyloid hypothesis has caused some of the most uproar and could have a far-reaching impact on the future of Alzheimer’s treatment. There is widespread agreement that amyloid beta buildup is a hallmark of Alzheimer’s disease, which robs people of their memory and ability to perform daily tasks. To some, however, logic and science dictate that removing the amyloid clumps is critical. Others see that as a costly diversion.
One thing is certain: Decades after the amyloid hypothesis was proposed, the relationship between the substance and dementia is “more complicated than originally thought,” according to Peter Stein, director of the FDA’s Office of New Drugs, in a decision memo on Aduhelm. Much of the outrage has centered on the FDA’s use of “accelerated approval” to clear the drug after determining that there was insufficient evidence of clinical efficacy for full approval. Biogen discovered a modest slowing of cognitive decline in the high-dose group of one study and no clinical benefit in the other in two large clinical trials for early-stage patients.
However, Aduhelm, also known as aducanumab, was clearly effective at removing plaque, and the FDA concluded that the amyloid reduction would slow the disease. Based on that “surrogate marker,” the FDA approved the drug and directed Biogen to conduct another trial to confirm the clinical benefit.
Accelerated approvals were implemented decades ago to expedite access to AIDS medications. They are frequently used in cancer therapies today, with tumor shrinkage, for example, serving as a surrogate marker. Aduhelm was the first Alzheimer’s drug to receive accelerated approval.
Since 1906, when Alois Alzheimer, a German psychiatrist, described the mysterious case of a patient named Auguste Deter, who exhibited bizarre behavior and cognitive impairment before her death, questions about Alzheimer’s disease have swirled. Her autopsied brain revealed extensive plaques and tangles, which became known as disease characteristics.
Only a half-dozen drugs are currently approved to treat Alzheimer’s disease. Five of them aim to treat symptoms and have only minor effects. Aduhelm, a monthly infusion, is the first drug designed to alter the disease’s underlying course. The treatment is a monoclonal antibody, which is a protein created in the lab that can bind to substances in the body and was originally derived from the cells of elderly people who did not show signs of cognitive problems.