Biogen surprised the Alzheimer's disease community this morning when it announced plans to pursue regulatory approval for aducanumab, its investigational monoclonal antibody targeting beta-amyloid protein in early Alzheimer's disease.
Earlier this year, Biogen and partner Eisai terminated their phase III trials of aducanumab after interim analyses indicated the drug was ineffective.
But today, Biogen said a "new analysis of a larger dataset showed that aducanumab reduced clinical decline in patients with early Alzheimer's disease as measured by the pre-specified primary and secondary endpoints," and based on discussions with the FDA, the company plans to submit its application to the FDA in early 2020.
The EMERGE and ENGAGE trials of aducanumab were stopped in March based on a pre-specified futility analysis that relied on early data of 1,748 patients who completed the 18-month study period, the company explained. Since then, a larger dataset of 3,285 patients became available; of these, 2,066 patients completed the full 18 months of treatment.
A new analysis of this larger dataset showed a different outcome from what the futility analysis predicted. The EMERGE trial showed statistically significant results on the pre-specified primary endpoint of clinical decline from baseline in Clinical Dementia Rating-Sum of Boxes scores at 78 weeks of 23% versus placebo (P=0.01).
The ENGAGE trial did not meet its primary endpoint. Biogen said, however, that it "believes that data from a subset of ENGAGE support the findings from EMERGE," and the problem with ENGAGE was that fewer patients received a high dose of aducanumab because the study started earlier.
What this new data means is a question of controversy: while investors were positive this morning, skeptics voiced concerns over inconsistencies in the new data, both within the ENGAGE study and comparisons between the two trials.
The ENGAGE trial, for example, showed worse symptoms and faster decline in patients who received the high dose of the drug versus placebo. The low-dose group performed better than the high-dose group in some measures. And neither trial reported data in absolute terms that would shed light on the findings' clinical significance.
Biogen was also cagey about safety, saying only that the drug's adverse-event profile in the two trials was "consistent with previous studies of aducanumab," but provided no details for the newly enlarged high-dose groups.
"The bottom line is they ran two parallel trials, and one was positive and one was negative," said Ron Petersen, MD, PhD, of the Mayo Clinic, who has consulted for Biogen but was not a trial investigator. "The million dollar question is why."
Changing the ENGAGE study protocol allowed more patients who were APOE4 carriers to be allocated to the high-dose group, Petersen told MedPage Today. "When they analyzed the subgroup of patients in the failed study who had had adequate exposure to the high dose of the drug for an adequate period of time, those data looked like the data from the positive study," he said. "That's what they're hanging their hat on."
"Finally, we see something that's working for Alzheimer's," noted Zaven Khachaturian, PhD, editor-in-chief of Alzheimer's & Dementia.
The data so far "looks pretty impressive," but Biogen only released the "show-and-tell for investors" and not details, Khachaturian told MedPage Today. "If the findings hold, that would be great," he said. "Even if it works on a small subset of patients, it is good news. Given the heterogeneity of the disease, it would be unreasonable to expect that it would work on every Alzheimer's case."
But whether the FDA will require another study is unknown: "Typically, FDA requires two pivotal studies," Khachaturian said. "Given the fact that Alzheimer's is such a national problem, they might overlook that and go along with just the data from these trials."
Like other clinicians and researchers on Tuesday, Eric Reiman, MD, of Banner Health in Phoenix, expressed cautious optimism. "We need to see the data presented to better understand the full implications," Reiman told MedPage Today. "But this news provides a shot in arm at the right time for amyloid-focused research, giving hope to those currently impacted by this terrible disease as we actively explore implications for future prevention trials."
Biogen plans to present data from the trials at the Clinical Trials on Alzheimer's Disease meeting in December 2019.
If approved, aducanumab would become the first drug to reduce the clinical decline of Alzheimer's disease and the first to show that removing beta-amyloid burden led to better clinical outcomes.