Topline data about the controversial Alzheimer's drug candidate, aducanumab, generated wide-ranging reactions from enthusiasm to skepticism on Thursday.
Biogen at a late-breaking session of the Clinical Trials on Alzheimer's Disease () conference in San Diego in an attempt to show why two phase III trials of the anti-amyloid agent had mixed results -- and why the drug still has potential for approval.
The parallel trials, and , were terminated in March of this year for futility. Both had a primary endpoint of change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) at week 78 in patients with early Alzheimer's disease. The futility analysis determined aducanumab was unlikely to outperform placebo at completion.
In October, Biogen reversed its position, saying a review of previously unavailable data showed the drug actually reduced cognitive decline in EMERGE -- but not in ENGAGE -- and announced plans to seek regulatory approval.
On Thursday, Biogen vice president Samantha Budd Haeberlein, PhD, tried to strengthen the company's case for the drug's efficacy, pointing to a subgroup of patients who received 14 treatments of the highest dose (10 mg/kg) of aducanumab who reaped the most benefit.
Different enrollment periods and a midstream protocol amendment accounted for differences in the EMERGE and ENGAGE data, she argued.
Before the protocol was changed in March 2017, APOE4 carriers -- who made up two-thirds of the study -- were not eligible for the highest dose of the drug. At that point, ENGAGE had 200 more patients than EMERGE. In the end, only 29% of EMERGE and 22% of ENGAGE participants had 14 of the 10 mg/kg doses, Budd Haeberlein pointed out.
At week 78, a subset of EMERGE patients who received the highest dose after the protocol change showed a difference of -0.53 (95% CI -1.05 to -0.02) points on the CDR-SB compared with placebo, representing a 30% improvement. In a similar ENGAGE subset, the difference of -0.48 (95% CI -1.02 to 0.06) points, a 27% improvement over placebo, was not significant.
Budd Haeberlein also outlined safety issues, including a roughly 40% incidence of ARIA-E (brain edema) or ARIA-H (cerebral microhemorrhage, macrohemorrhage, or superficial siderosis) in the high-dose groups. ARIA-E episodes generally resolved in 4 to 16 weeks and most patients with ARIA continued in the trial, she said.
"The data is complex," noted Paul Aisen, MD, of the University of Southern California, a panelist at the CTAD presentation. But after differences in dosing are considered, "we are left with an overall positive interpretation of the data from the aducanumab studies that represent a truly major advance for the field," he said.
Two CTAD panelists who were site principal investigators, Sharon Cohen, MD, of the Toronto Memory Program, and Steve Salloway, MD, of Brown University, echoed this view, saying the results were "clinically meaningful." Cohen added that measurements of activities of daily living, which improved in high-dose EMERGE participants, might matter more to patients than CDR-SB scores.
Other experts were hesitant to draw conclusions, however, especially from subsets of data. "The clinical outcomes, in my view, were not that different from before, and continued to give me pause, because there really was no substantial divergence of the three study groups -- placebo, low-dose, and high-dose -- at the final visit," observed Howard Fillit, MD, founding executive director of the Alzheimer's Drug Discovery Foundation in New York City, who wasn't involved with the research.
"There are biomarker signals and clinical signals that show promise," Fillit told ľֱ. "But to get this drug over the regulatory hurdle of an FDA approval, or just to convince the scientific community that it really works, we need to see another phase III trial."
"While not definitive, findings from the discontinued aducanumab trial are encouraging," said Eric Reiman, MD, executive director of the Banner Alzheimer's Institute in Phoenix.
"They support the potential roles of anti-amyloid drugs in the treatment and prevention of Alzheimer's disease," Reiman told ľֱ. "If confirmed, however, they could benefit our affected patients, reinvigorate the interest of our industry colleagues in the fight against Alzheimer's, and give us a fighting chance to find effective prevention therapies before 2025."
Fillit also noted that, in the current healthcare environment, the drug's clinical performance isn't the only issue at stake. "This drug may potentially have a huge impact, in terms of societal cost and in terms of patients' ability to pay co-pays over a long period of time," he said.
"We're talking potentially millions of people on a relatively expensive drug on a monthly basis," he added. "It's going to be a very big payer decision."