SAN DIEGO — Fresh data didn't do much to clear up questions around the most closely watched drug in all of biotech, an experimental treatment for what many consider the underlying cause of Alzheimer's disease.
Well before Thursday's presentation, there was skepticism. Two late-stage studies meant to show aducanumab can slow cognitive decline were halted prematurely because an interim peek at the data found chances for success slim.
The drug appeared to have joined the long list of failed Alzheimer's medicines — that is, until October, when developer Biogen said analyses from a larger dataset found one trial actually succeeded. The other still failed, but the biotech claimed there were some findings supporting efficacy.
Biogen intends to seek approval for aducanumab based on the successful study, titled EMERGE, which showed patients on the drug's highest dose had significantly less cognitive decline than those on placebo, as measured by a rating scale for dementia. At the first full day of the 12th annual Clinical Trials on Alzheimer's Disease conference, the company offered data confirming suspicions the higher dose resulted in a 0.4-point lower decline than placebo in that trial.
Patients in both EMERGE and its twin, titled ENGAGE, entered the study with an average baseline score of about 2.5. As is expected with a degenerative disease, scores in both groups increased over the course of the 78-week study, with what Biogen claims to be aducanumab's benefit showing up most clearly after week 50.
Researchers and analysts have sought better context from Biogen about what effect this reduction has on the trajectory of a disease that unfolds over years, if not decades. Panelists, including study investigators who worked on the trial and received grant or consulting fees from Biogen, said they believe the results are meaningful. But others want more complete data.
"What people want to be able to see, consistently, is: I'm able to remember conversations better, I don't forget to take my medication anymore, I'm not relying on 20 Post-its today to keep track of what I'm supposed to do," said Jeffrey Kaye, director of the Layton Aging and Alzheimer's Disease Center at the Oregon Health & Science University.
"Those are the meaningful outcomes that we need," Kaye said. "A couple points better or worse on a cognitive scale is not actually easily translatable, certainly in the span of a year or two."
Biogen did present data showing patients on the higher dose in EMERGE were better able to perform day-to-day activities like eating, grooming or managing finances. Most of the company's presentation, however, was spent trying to unpack why the EMERGE study had such different results than ENGAGE.
The studies each enrolled around 1,650 patients and were amended multiple times, which itself poses questions about the data's reliability. The last amendment was enacted in March 2017 to allow patients with a certain genetic profile the ability to receive the highest aducanumab dose. Prior research had raised concerns about the safety of giving those patients such a dose.
By March 2017, ENGAGE had enrolled about 200 more patients than EMERGE. Therefore, Biogen's theory is that ENGAGE failed because fewer of its patients received the most effective dose. In fact, 22% of the ENGAGE patients got the maximum number of high-dose treatments, versus 29% of the EMERGE patients.
Biogen's challenge will be convincing the Food and Drug Administration this theory holds water, and that the complicated protocol design hindered ENGAGE rather than lifted up EMERGE.
The agency will have this explanation to chew on as it weighs whether aducanumab's potential benefits are worth its risks.
In both ENGAGE and EMERGE, around 35% of patients on high-dose aducanumab experienced a side effect known as ARIA-E, a type of brain swelling that can cause headache and nausea. Usually these symptoms are mild and the swelling goes down on its own.
Even so, brain swelling is a side effect likely to unnerve FDA officials, particularly for a drug that could be prescribed to millions of U.S. patients. Another type of ARIA was fairly common and consistent across the trials, with around 18% of high-dose patients experiencing a micro-hemmorhage because of it.
Constantine Lyketsos, a professor of psychiatry and behavioral sciences at Johns Hopkins Medicine, said the side effects stand out, and would make him nervous to administer aducanumab for more than a year or two for fear of having a serious ARIA event.
While Biogen offered up new safety and efficacy data points, one thing left out was an explanation of how genetics could have affected the results. Two-thirds of patients enrolled in both trials tested positive for APOE-4, a gene that was also important in the evaluation of another Biogen Alzheimer's drug named BAN2401.
Research suggests Alzheimer's gets worse quicker in patients with the APOE-4 gene. The thinking, then, is that these patients would experience bigger effects from Alzheimer's drugs. If more patients who received the maximum number of high-dose treatments were positive for this gene, it could exaggerate the benefit for a broader Alzheimer's population.
"This particular analysis is what also turned the BAN2401 data from good to bad," wrote Salim Syed, an analyst at Mizuho Securities USA, in a note to investors. "And today, BIIB deliberately chose not to present it. One has to be skeptical of this as the company is putting forth its best argument."
Investors, though, appear to have some renewed confidence in Biogen's argument. Shares of the Massachusetts biotech rose 5% directly after its presentation and ended the day up 3%.
The hundreds of doctors and scientists in the audience also seemed energized by Biogen's presentation and the panel's affirmations, offering up a fair amount of applause at the end of the session.
"It is a big deal," said Sharon Cohen, a panelist who serves as medical director for the Toronto Memory Program, referring to the reduction in decline seen with high-dose aducanumab. "Those of us who know this disease, know what it means to lose yourself slice by slice, and anything you can hang on to and do well is a triumph."
However, this is just the beginning of the analysis — and scrutiny — Biogen's data are likely to receive.
"People like me, and lots of others who sat in there, really want to do a deep dive. We don't want descriptive statistics; we want spaghetti plots," John Harrison, associate professor in the Alzheimer Center at Amsterdman's AU Medical Center, told BioPharma Dive. "I think we're all looking for access to a much finer level of detail."
Correction: A previous version of this article compared data points on two different rating scales.