Just a month after it gave the new Alzheimer’s drug aducanumab (Aduhelm) the green light, the FDA decided to change the label.

The agency approved an updated label narrowing who should receive the drug, stating that aducanumab should be initiated in Alzheimer’s patients with “mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials,” drug maker Biogen announced Thursday.

“There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied,” the new prescribing information states.

The revision comes after criticism from experts in the field — including those who supported the drug’s approval and those who didn’t — who said the original FDA-approved label, which stated that aducanumab was “indicated for the treatment of Alzheimer’s disease,” was too broad.

“We recommend that the patients treated with aducanumab have features similar to those included in the EMERGE/ENGAGE trials: early symptomatic Alzheimer’s disease with evidence of brain amyloid,” wrote Stephen Salloway, MD, MS, of Brown University in Providence, Rhode Island, and Jeffrey Cummings, MD, ScD, of University of Nevada Las Vegas, in a viewpoint essay published in Neurology on Wednesday, the day before the new label was announced.

The FDA’s decision to approve aducanumab in June was based on two identically designed phase III trials, EMERGE and ENGAGE, of people with early Alzheimer’s disease who were amyloid positive. The drug was approved under the accelerated approval pathway based on a surrogate endpoint of reduced amyloid-beta plaque.

“At trial initiation, participants were randomized to high dose, low dose, or placebo. A dose increase from 6 mg/kg to 10 mg/kg was made for APOE4 gene carriers midway through the trial; EMERGE participants had higher doses for longer periods since the EMERGE trial began later than the ENGAGE trial and patients had more time on the 10 mg/kg dose,” Salloway and Cummings wrote.

“An interim efficacy analysis showed no foreseeable drug-placebo difference, and both trials were stopped,” they continued. “Blinded data continued to accrue and the final data set at week 78 demonstrated that EMERGE met its primary outcome with a 22% drug-placebo difference in slowing on the Clinical Dementia Rating (CDR-SB) in the high dose group (P=0.01).” Secondary outcomes also favored aducanumab.

However, “the ENGAGE trial showed no drug-placebo difference for the primary and secondary clinical outcomes in the final data set,” Salloway and Cummings noted.

‘We as Neurologists Need a Strategy”

“We as neurologists need a strategy to advise our patients in this unusual situation where the drug was approved without evidence of consistent clinical benefits,” observed David Knopman, MD, of the Mayo Clinic in Rochester, Minnesota, and Joel Perlmutter, MD, of Washington University School of Medicine in St. Louis, in another viewpoint essay published in Neurology on Wednesday.

“Based on the prescribing information, the sponsor shows data from only the positive trial and fails to provide the negative trial’s cognitive and functional outcomes. Neurologists should have access to all of the relevant data in these clinical trials; however, they will have to go elsewhere to find it,” they pointed out.

The clinical benefit of aducanumab “amounted to about 3 months’ worth of delay in decline over a year (annualized Clinical Dementia Rating Scale ‘sum of boxes’ 0.26 rating points reduction in decline with the high-dose aducanumab in the setting of 1.17 points annualized decline in the placebo group),” Knopman and Perlmutter continued.

“Because our field has not established what constitutes clinical meaningfulness, this benefit could be perceived as having value by some patients and their families. However, this range of delay and progression is well within the untreated variability of groups of patients with mild cognitive impairment or dementia due to Alzheimer’s disease,” they wrote.

Neurologists also must consider aducanumab’s risks since “the recommended monthly doses of aducanumab comes with safety concerns, especially in the form of amyloid related imaging abnormalities (ARIA) – edema or hemorrhage,” Knopman and Perlmutter noted.

“Neurologists will have to manage therapeutic perceptions by presenting their patients and families with unbiased information about the benefits and risks,” they concluded. “This is even more challenging as no peer reviewed publication has yet appeared.”

Before the FDA approved aducanumab in June, its advisory committee voted overwhelmingly against the trial data presented about the drug. Since the drug’s approval, some groups, including the Alzheimer’s Association, have expressed support. Others have voiced doubts about the drug’s effectiveness and the process leading up to its approval.

Last month, the House Committee on Oversight and Reform announced an investigation into aducanumab’s approval and pricing. And in a letter to the Senate Finance Committee, Senators Elizabeth Warren (D-Mass.) and Bill Cassidy, MD, (R-La.) called for a hearing to examine the “vexing new questions and challenges” that aducanumab’s $56,000 annual price tag poses for Medicare and other health programs.

On Friday, Acting FDA Commissioner Janet Woodcock, MD, called for the HHS Office of Inspector General to investigate how agency staff interacted with Biogen before aducanumab was approved. “We believe an independent assessment is the best manner in which to determine whether any interactions that occurred between the manufacturer and the agency’s review staff were inconsistent with FDA’s policies and procedures,” Woodcock tweeted.