To say that Biogen’s Alzheimer’s drug aduhelm is controversial wouldn’t do its rocky road to approval justice. To say it’s complicated is even less satisfying, given that the studies leading to its approval were started, stopped and started again. Add to that reports of questionable meetings between the drug company’s scientists from Biogen and Food and Drug Administration (FDA) officials that led to an ongoing FDA investigation of the drug’s approval, and it’s understandable that the drug that was supposed to change the way Alzheimer’s is treated hasn’t exactly taken the patient and doctor community by storm.
And at least one death has been associated with aduhelm, according to the FDA, related to the medication’s known side effect of brain swelling and bleeding.
The drug’s June approval was immediately questioned by many in the medical community, partly due to the questionable relationship between Biogen and FDA officials but also because many doctors who treat Alzheimer’s patients feel that the complicated data do not provide convincing evidence that the medication can actually improve patients’ declining mental functions. It is clear that aduhlem has the ability to reduce amyloid plaque. This sticky protein, which builds up in patients’ brains, can cause damage to brain neurons, and may be linked with cognitive impairments such as reasoning and memory. What’s less clear is whether that reduction translates into clinical benefits, in the form of patients’ scores on mental skills tests. FDA has approved the drug for treatment of the primary cause of the disease.
The new Biogen data
At the 2021 Clinical Treatment for Alzheimer’s Disease conference in Boston, Biogen hoped to clear the air. The company presented its final report on the pivotal studies examining aduhelm’s effectiveness—the ones behind the drug’s approval—in people with mild cognitive impairment or mild Alzheimer’s dementia. The main difference from earlier reports was the new finding that aduhelm also lowers levels of another protein, tau, that tends to accumulate and compromise nerve function later in Alzheimer’s disease. The levels of this protein dropped 13-16% in the participants who took aduhelm, whereas the placebo group saw an 8-9% increase. The tau findings, the company says, are further proof that the drug can help slow down Alzheimer’s progression.
This data was compiled from over 1,800 individuals who were participating in aduhelm trials. These trials were stopped briefly in 2019 and they resumed approximately a year and a quarter later. Due to the fact that patients were not enrolled in a placebo-controlled trial, it is possible that this population was biased and motivated to keep taking the drug. Data show that patients who did better in cognitive tests tend to stay on the drug. The researchers still hoped the patients could help them see the potential impact that stopping and starting the drug again might have on the progression of amyloid and the risk to their health.
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Overall, the data suggested that the gap of not taking the drug didn’t seem to adversely affect the patients; any decline in amyloid levels, as measured by brain imaging for amyloid, that was achieved during the original study was maintained by the beginning of the restarted study. That’s encouraging, and the ongoing study, which will follow the participants for two years, will continue to evaluate whether those levels of amyloid continue to decline—and more importantly, if that has any effect on improving brain function.
The new results will resolve the aduhelm issue.
Biogen officials hope that, taken together, the tau findings and the evidence that a gap in medication doesn’t cause harm, will make more doctors and patients comfortable with trying the drug, which hasn’t been prescribed as quickly as they expected. Doctors have largely been hesitant because they aren’t confident yet that reducing amyloid in the brain will translate into improvement in scores on cognitive tests. Aduhelm is a side effect of brain disease that brain specialists worry about. It’s an inflammation in the brain which can be detected early with regular scans. If left untreated, it can cause brain bleeding and death.
It doesn’t help that after Biogen scientists realized there was some potential benefit from their drug, they met with FDA officials at a conference to discuss next steps, which some critics see as inappropriate. Biogen says that it will stand behind its drug approval process and the integrity of all subsequent steps. Janet Woodcock, acting FDA director, launched an internal investigation into the controversy to make sure that there were no violations of regulatory protocols.
STAT reports that only 100 people are using the drug at present. STAT reports that doctors at Mount Sinai and Cleveland Clinic have already decided to not give the drug to patients. Patients who want to receive aduhelm must go to another place for infusions. The Alzheimer’s Association, which supports the FDA approval of the drug as an important option for patients, still questions the price of the medication, which runs $56,000 a year. “We completely disagree with Biogen’s pricing decision, and we’ve made that very clear,” says Harry Johns, president and CEO of the Alzheimer’s Association. Centers for Medicare, Medicaid Services currently examines whether to cover Aduhelm. Its decision sets often the standard for other insurers. If CMS decides not to cover the medication, that could discourage other drug makers from pursuing anti-amyloid treatments for Alzheimer’s.
Johns says that this would represent a loss for patients. “For us this has always been about opening the door to treatments. As the first treatment approved to treat Alzheimer’s, [aduhelm]While it’s far from being a cure all, it does provide some scientific support. And we believe it does.”
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The Mayo Clinic has not yet treated any patients with aduhelm, but a committee consisting of neurologists and radiologists was established to review each case. This is to make sure that there are no serious side effects. Dr. Ron Petersen, director of the Alzheimer’s Disease Research Center at Mayo, says that the new data on tau likely won’t change people’s perceptions of the drug—what is needed, he notes, is for more people to be treated so that scientists can get a better picture of its actual impact on people. “The drug does what it’s supposed to do biologically,” he says. “But does it have a huge clinical effect? I do think there is a clinical effect, but I don’t think it’s very large.”
Petersen also points out that Biogen’s studies followed patients for only several years, while the process of accumulating amyloid likely takes years, if not decades. And that for many patients, it’s not realistic to expect any change of their condition over such a short period of time. “The fact is that amyloid is mis-processed and deposited in the brain over years, and maybe decades, so the thought of removing it in 12 to 18 months and expecting clinical impact is probably pretty ambitious,” he says. “We are not looking for clinical improvement here. We are just asking for stabilization of their condition.”
Aduhelm’s approval opened the door for other companies, including Eli Lilly and Roche, to revisit their similarly working drugs that chew up amyloid. It’s likely that the class of anti-amyloid drugs, following aduhelm’s lead, will become a new option for Alzheimer’s patients—at least after the growing pains of the first one are resolved. And while the FDA is investigating the conditions surrounding the drug’s approval, the final report is not expected until 2023, and for patients eager to try the drug in hopes of stalling their disease, that’s too long to wait.