FDA Filing of Alzheimer’s Therapy Aducanumab Delayed to Late 2020, Biogen Says

Biogen is pushing back the submission of aducanumab, its investigational treatment for Alzheimer’s disease, to the U.S. Food and Drug Administration (FDA) to the third quarter of this year due to the COVID-19 pandemic, the company announced.

“The COVID-19 pandemic has created a challenging situation for people and companies throughout the world, and Biogen personally felt the painful impact of this global crisis,” Michel Vounatsos, Biogen’s CEO, said in a company report. “Outside the U.S., we have had initial aducanumab discussions with regulators in Europe and Japan, although these interactions are still in the early stages.”

Although the company had originally anticipated filing the biologics license application with the FDA by early this year and has already started to submit parts of the application, Biogen now says it will complete the submission only after a meeting with the FDA, scheduled for the summer.

“It’s been difficult to predict the timing partly because [the BLA filing] has been an unusual process right from the beginning,” Al Sandrock, Biogen’s head of research and development, said in a business update from Biogen. “Nothing has come up with the data that has changed our interpretation.”

Meanwhile, the first patient has been dosed in the Phase 3 EMBARK clinical trial (NCT04241068), which is investigating re-dosing aducanumab in patients who participated in previous trials.

Aducanumab, in development by Biogen and Eisai, is an investigational human monoclonal antibody that works by targeting the toxic clumps of amyloid beta, thought to be the underlying cause of Alzheimer’s.

Aducanumab was investigated in ENGAGE (NCT02477800) and EMERGE (NCT02484547), two Phase 3 trials that evaluated two doses of aducanumab in people with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia.

The studies were designed to test whether monthly aducanumab infusions for 18 months could slow the progression of cognitive and functional impairment compared with a placebo. But in March 2019, after 1,748 patients in both trials completed the 18 months of treatment, a monitoring committee said aducanumab was not likely to produce meaningful benefits for patients.

While this led to the halt of both trials and two other trials testing aducanumab in Alzheimer’s, a later analysis — including a larger population of 3,285 patients, 2,066 of whom completed the full 18 months of treatment — ultimately showed that EMERGE met its primary goal.

In that analysis, high-dose aducanumab significantly slowed the progression of cognitive and functional impairment, assessed by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB score), compared with a placebo. Secondary measures of cognitive functioning were also significantly better for patients receiving aducanumab over the 18 months.

In EMERGE, clinical decline was not reduced in the overall population, but an analysis of patients who had sufficient exposure to high-dose aducanumab did show significant benefits over a placebo, supporting the findings from EMERGE.

In both studies, the safety profile of aducanumab was consistent with prior studies. The most commonly reported adverse events were headaches and amyloid-related imaging abnormalities-edema, the latter usually resolving within one to four months without causing symptoms.

These findings led Biogen to announce it would seek approval of aducanumab for Alzheimer’s disease. If approved, this would be the first Alzheimer’s therapy that treats the disease directly rather than alleviating symptoms, and would be the first new Alzheimer’s treatment for nearly two decades.

To continue studying the long-term safety and tolerability of aducanumab, Biogen launched the open-label Phase 3 EMBARK trial to start re-dosing Alzheimer’s patients who participated in the four studies halted in 2019.

The EMBARK trial is enrolling patients who were previously in ENGAGE, EMERGE, the EVOLVE safety trial (NCT03639987), or the long-term extension of the Phase 1b PRIME trial (NCT01677572).

The trial dosed its first participant in March. Regardless of having received prior aducanumab or placebo, all patients in EMBARK will receive a high dose (10 mg/kg) of aducanumab, given via intravenous (into-the-vein) infusions, every four weeks for 100 weeks.

In March, Biogen also acquired a new small molecule inhibitor, BIIB118, from Pfizer. The therapy, which inhibits the protein casein kinase 1 and has the ability to enter the central nervous system, is intended to treat a phenomenon called sundowning — a state of confusion and restlessness occurring in the late afternoon — in people with Alzheimer’s as well as for Parkinson’s disease patients with sleep problems.