Doubts persist for claimed Alzheimer’s drug

 

 

Last week, with trading in the company’s stock halted for the widely anticipated event, Biogen gave its first scientific presentation in defense of its startling claim to have developed the first drug that can change the devastating course of Alzheimer’s disease. But some scientists and analysts had hoped for more detail, and the community remains divided over whether the drug is a turning point in the quest for an Alzheimer’s treatment—or a false hope.

At the Clinical Trials on Alzheimer’s Disease congress in San Diego, California, Samantha Budd Haeberlein, Biogen’s head of clinical development, tried to clarify what had emboldened the Cambridge, Massachusetts–based biotech to say in October it would soon ask the U.S. Food and Drug Administration (FDA) to approve its drug, aducanumab. That announcement was a striking turnaround for a drug the company had publicly abandoned in March after a discouraging preliminary analysis. But after examining more patient data, she explained, investigators found in one trial that the higher of two tested doses led to 22% less cognitive decline than a placebo after 78 weeks. However, the small margins separating the treated and placebo groups and the failure of a second trial leaves some researchers with a grim outlook.

“I surely don’t think that it should be given market approval on the basis of these data,” says Robert Howard, a psychiatrist at University College London who has run clinical trials of potential Alzheimer’s treatments. By touting positive results from a subset of patients who weren’t preselected at the trial’s launch and remaining mum about other details of the data, he says, “[Biogen has] broken all the rules, really, about how you analyze data and report it.”

Yet some welcome the glimmers of clinical benefits Biogen reported. In a panel discussion at the meeting, Sharon Cohen, a behavioral neurologist at the Toronto Memory Program in Canada and a principal investigator in the Biogen-funded trial, pointed to ratings on a scale of daily activities that suggest aducanumab helped trial participants retain some independence. “Those of us who know this disease well know what it means to lose yourself, slice by slice, and anything you can hang on to and do well is a triumph.”

Aducanumab is among the last potential drugs standing that targets beta amyloid, the protein fragment that forms sticky plaques around neurons in the brains of people with Alzheimer’s. The failure of several antiamyloid drugs in large clinical trials have suggested that plaque buildup, though a hallmark of Alzheimer’s, might be the wrong target for stopping disease progression once people show symptoms.

 

 

 

Still Biogen and its partner, Tokyo-based Eisai, had high hopes for aducanumab, a monoclonal antibody that binds to and eliminates forms of brain amyloid that are thought to be particularly noxious. In 2015, the companies launched two parallel clinical trials, known as ENGAGE and EMERGE, each testing two different doses of aducanumab against a placebo in more than 1600 people with early-stage Alzheimer’s and confirmed amyloid buildup in the brain.

In March, Biogen and Eisai halted the trials after a planned “futility analysis” in a subset of participants suggested the drug wasn’t helping. Then came the October surprise: the announcement that there were signs of benefit after all. In both trials, aducanumab had reduced amyloid buildup, Biogen reported, and in the EMERGE study, the high-dose group showed less cognitive decline than the placebo group, based on a standard dementia rating scale. But in ENGAGE, the high-dose group declined slightly more than the placebo group.

Budd Haeberlein tried last week to explain the conflicting results. A major factor, she said, was how the trials treated participants who had a genetic variant called APOE4. Those participants had an increased risk of brain swelling—a side effect of antiamyloid antibodies that occurred in about one-third of people getting the high dose and can cause symptoms such as headache, dizziness, and nausea. Patients in both arms with APOE4 received a reduced amount of the antibody at first, as a precaution, but in 2017, the researchers decided they could safely ramp up.

ENGAGE started about 1 month before EMERGE and had more participants already enrolled at the time of the change. As a result, a smaller proportion of its participants got a full, uninterrupted course of the maximum dose—15% versus 21% in EMERGE, which might account for the lack of overall benefit. When Biogen analyzed the subsets of EMERGE and ENGAGE participants who consented to the change in protocol early enough to get a full maximum-dose course, they saw about a 30% reduction in cognitive decline compared with placebo in both trials.

The need for high, sustained dose of the antibody is “a reasonable explanation,” for the results, says Zaven Khachaturian, editor-in-chief of Alzheimer’s & Dementia. But, “The final answer will come [when] studies with higher doses for longer periods replicate these findings.”

Whether Biogen should be allowed to market aducanumab in the meantime, perhaps through a conditional approval that requires a follow-up trial, is hotly debated. Biogen’s Chief Medical Officer Al Sandrock drew criticism last month for suggesting that if FDA requires another trial before any approval, it would consign many people to dementia. Agency officials can start that knotty calculus for themselves when Biogen’s data hit their desks early next year.

 

 

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