Data on Biogen’s Alzheimer’s drug raise more questions than answers
SAN DIEGO — Biogen (BIIB) on Thursday presented detailed data making a case for its resurrected Alzheimer’s drug, arguing that its mixed study results can be explained away by differences in whether patients got the highest dose of the medicine.
But the new data deepen sharp questions about the prospects of the drug and are unlikely to convince skeptics who doubt whether the Food and Drug Administration will be willing to approve it. Biogen’s stock was up 1.75% midday on Thursday after its presentation here at the Alzheimer’s research conference known as CTAD.
The drug, known as aducanumab, was tested in two identically designed late-stage studies. Biogen had halted both of those trials in March because the drug appeared to have failed. But in October, the company announced that a new analysis reflecting previously unavailable data showed that the drug actually reduced decline in patients with early-stage Alzheimer’s in one of the studies, called Emerge. The other study, called Engage, failed.
What was different between the two studies? On Thursday, Biogen presented numbers to try to show that the differing results were driven by the downstream effects of a late-stage change Biogen made to its studies: allowing patients to receive higher doses of the medicine.
In the main analysis of Emerge, patients on aducanumab saw their rate of decline on a questionnaire called the CDR-Sum of Boxes slow by 14% if they were on a low dose, and 23% if they were on a high dose. Only the high dose result was statistically significant. In Engage, on the same scale, patients saw their decline decrease 12% on the low dose and accelerate 2% on the high dose.
But Biogen argues that this difference can be explained by the change midway through the study that resulted in more patients receiving high-dose aducanumab.
Crucially, Engage had enrolled 200 more patients than Emerge at that time of the protocol amendment, affecting how many patients in each trial ultimately got the higher dose. Before this protocol amendment was made, only 29% of the patients in Emerge and 22% of those in Engage received the full 14 doses of the highest 10-milligram-per-kilogram dose. After the amendment, 51% of the patients in Emerge and 47% of those in Engage received this full dose.
Once more patients were given the higher dose, in Emerge there a 24% reduction in the rate of decline of the patients on the low dose, and 30% in the high dose. In Engage, these figures were 20% and 27%. Still, the benefit was only statistically significant for the high-dose group.
Researchers and investors will both want to know why researchers saw increased potency extend to the low-dose groups and not just the high-dose ones. On Thursday, shares of Biogen were up nearly 4% in early afternoon trading.
For the regulators at the FDA who will decide whether to approve the drug, the standard will be whether there is one positive study and supporting data. The Emerge study could count as the positive study. The question is whether they find this after-the-fact analysis credible.
Experts on stage at the CTAD meeting said that the halting of the study created many problems when it comes to interpreting the data, but that they believe aducanumab is effective.
Paul Aisen, an Alzheimer’s researcher at the University of Southern California, called the result “a hugely important result and it represents a major advance for the field.” Steve Salloway, a neurologist at Brown University, added: “After full review, this could represent the first treatment that targets a core pathology and open a new era.”
But the CTAD panel of experts did not include likely critics who doubt the hypothesis that a drug that targets amyloid in the brain, as aducanumab does, will be effective, or statisticians to comment on the highly unusual practice of presenting a positive study after it was halted. During her presentation, Samantha Bud Haberlin, Biogen’s vice president for clinical development, said that Biogen collected only 55% of the data it would have had if the study had been completed. (The company said in October it would begin re-dosing patients.)
Even in Biogen’s most optimistic take on the results — looking only at patients who got the highest dose for the longest period of time — aducanumab outperformed placebo by just 0.5 points on a three-point scale of dementia. To skeptics, that’s a minuscule effect unlikely to provide meaningful benefits to patients with Alzheimer’s. The doctors on stage agreed that it was substantial and meaningful.
The new details Biogen released about the safety profile of the drug may also sharpen questions about its prospects. In the Emerge study, about 35% of patients who got the high dose experienced form of brain swelling known as amyloid-related imaging abnormalities, or ARIA, compared to 25% who got the low dose group. Those who experienced symptoms had issues that were “generally mild,” including headache, dizziness, visual disturbances, nausea, and vomiting, Bud Haberlin said. While there were 16 deaths across the two studies, none of the deaths was related to ARIA.
At the STAT Summit last month, Al Sandrock, Biogen’s chief medical officer, highlighted the stakes for the FDA. “Here’s the decision that FDA is going to have to make,” Sandrock said. “Do we believe there is enough evidence to approve it now? Or do we ask the company to do another trial, wait five years and how many people have to get demented in that time period?”
That question remains unanswered.
Damian Garde contributed reporting.