Accelerated approval and use of surrogate markers are among the friction points. But some see the OK as spawning a new generation of drug development for treating Alzheimer’s disease.
It seems almost every year the drug pipeline is marked by a landmark approval — a drug that upends the prior way of managing a disease and sets treatment strategies off in a new direction. The 2021 version almost certainly seems to be the FDA’s accelerated approval of Aduhelm (aducanumab).
The approval on June 7 was the first in nearly two decades for a drug for Alzheimer’s disease. It also was the first for a medication with a “disease-modifying” mechanism of action that many believe addresses the underlying pathology of this disease, which affects approximately
6 million Americans.
Aduhelm engendered controversy before it received approval. In 2019, Biogen shelved the development of the treatment after a futility analysis from an independent committee said the treatment would be unlikely to benefit patients. Months later, the company announced that it was reviving the development of Aduhelm after its analysis showed the treatment reduced cognitive decline in patients who took high doses. But in November 2020, an independent advisory panel of experts recommended the FDA not approve the drug.
When Biogen announced the FDA’s accelerated approval of Aduhelm in June, concerns about the drug’s effectiveness in slowing disease progression remained and new concerns emerged as the company announced that the annual price tag would be $56,000. (That is the wholesale acquisition cost price. After debates and discounts, it will be lower for many payers.)
Following the approval, three members of the advisory panel resigned. One of them, Aaron Kesselheim, M.D., J.D., M.P.H., called it “the worst drug approval in U.S. history,” noting side effects such as brain swelling and bleeding, falls, confusion and disorientation associated with taking the drug.
Why the controversy?
One source of controversy about Aduhelm is a schism within the agency itself. Agency documents have shown that FDA statisticians said the data from the two clinical trials used to support the approval did not meet statistical standards but that agency leaders overruled them. Another friction point is that Aduhelm received accelerated approval, a separate approval track designed to get medications on the market faster.
The FDA has tended to grant accelerated approvals based on evidence from smaller early-stage trials. But Aduhelm was tested in two fairly large phase 3 trials, so the issue with Aduhelm is not the size of the trials but whether the evidence from them merited an FDA OK. As is often true with accelerated approvals, Aduhelm’s approval was based on a surrogate marker, the effect the drug has on beta-amyloid plaques in the brain. Approvals based on such surrogate markers are controversial because of the uncertainty about whether the marker translates into improved symptoms and outcomes.
As part of Aduhelm’s approval, Biogen must complete a large trial that confirms that clearing the beta-amyloid plaques does, in fact, have cognitive benefits for patients. Theoretically, if the results do not confirm this, the FDA could revoke the approval. One argument for the Aduhelm approval is that it will stimulate new drug development for Alzheimer’s disease in the same way the accelerated approval of many cancer drugs has led to new approved cancer agents. However, critics of the FDA accelerated approvals say too many have been granted, resulting in a large number of drugs, some of them expensive and many for cancer, getting on the market with limited evidence.
Another subplot in the tortuous Aduhelm saga are questions about role that beta- amyloid plays in the disease. After several other drugs attacking beta-amyloid failed, many Alzheimer’s disease researchers argued that it was time to move on and figure out another target. The Aduhelm approval threw a life preserver to the beta-amyloid hypothesis. Dennis Selkoe, M.D., an Alzheimer’s researcher at Brigham and Women’s Hospital in Boston, has been among the most prominent proponents of the beta-amyloid hypothesis.
In an interview with Managed Healthcare Executive®, Selkoe compared Aduhelm’s approval to the 1987 approval of lovastatin, the first statin to decrease low-density lipoprotein (LDL) cholesterol. Although it now is accepted that LDL cholesterol is a main driver of coronary artery disease, there was a lack of consensus on the causal relationship at the time of lovastatin’s approval. The FDA approved lovastatin knowing it lowered cholesterol levels but without having concrete evidence that the treatment could decrease the risk of heart attack and strokes. That evidence, Selkoe says, didn’t come until years later, when studies assessed whether patients on the treatment had better cardiovascular outcome. But he predicts that it may be months rather than years for data to emerge that the treatments targeting beta-amyloid reduce cognitive decline as other treatments targeting beta-amyloid enter the market.
Competition on the horizon?
The precedent set by the FDA’s approval of Aduhelm based on beta-amyloid reduction has already started to influence the Alzheimer’s disease drug pipeline. Once thinking it would need to wait for more comprehensive data from a phase 3 trial, Eli Lilly announced in late June that it plans to file for accelerated approval of its Alzheimer’s drug, donanemab, later this year based on phase 2 data.
What’s notable about the available data on donanemab is not just that the treatment cleared the plaque in the brains of two-thirds of patients but that it also slowed cognitive decline — albeit just by a bit. The 131 patients receiving the treatment had a 32% slowed progression in cognitive decline after 76 weeks compared with the 126 patients receiving a placebo. The treatment was so effective at targeting the plaque in some patients that their beta-amyloid levels dropped to those of healthy people.
Roche also has a drug targeting beta-amyloid in its pipeline. Although a report in June stated that the Swiss pharma giant would be filing for early approval of gantenerumab, the company issued a statement that it would not “comment on speculations” and is continuing with its phase 3 trial. Data from the trial are expected later this year.
Gantenerumab, like Aduhelm, was once shelved based on setbacks in clinical trials before Roche reversed course and resumed development of the treatment with hopes that a higher dose would be more effective. Gantenerumab is delivered subcutaneously for five minutes, which could be an advantage over Aduhelm, which is administered intravenously for longer periods of time.
The price tag Biogen put on Aduhelm added fuel to the controversies engulfing the drug. A report from the Institute for Clinical and Economic Review said the $56,000 yearly cost is not in “reasonable alignment with its clinical benefits” and that it would need to be priced between $3,000 and $8,500 a year to fit under commonly used thresholds of cost effectiveness. Medicare is likely to be the payer most affected by Aduhelm’s approval and price because Alzheimer’s disease is a condition that affects older people almost exclusively. CMS is weighing coverage options that will go a long way toward determining the sales of Aduhelm and any competitors that come to market. Meanwhile, members of Congress have announced investigations of Aduhelm’s approval and price.
In addition to the cost of the drug, treatment with Aduhelm may require expensive brain imaging studies to determine if the plaques of beta-amyloid are present. But Selkoe says most patients can be tested via a spinal tap, which would be less costly than brain scans.
Jaime Rosenberg is a freelance medical writer based in Jersey City, New Jersey.