An FDA advisory committee on Monday
unanimously supported the investigational drug donanemab for treating
early Alzheimer’s disease.
In an 11-0 vote, the Peripheral and Central Nervous System Drugs
Advisory Committee said the benefits of donanemab outweighed its risks
for the population of Alzheimer’s disease patients with mild cognitive
impairment and mild dementia enrolled in the donanemab clinical trials.
The committee also voted 11-0 that available data showed that
donanemab was effective in treating Alzheimer’s disease in that
population. Though FDA staffers raised concerns last weekopens in a new tab or window
that Alzheimer’s patients with no or very low tau were excluded from
the pivotal donanemab trial, the committee agreed overall that the drug
should not be restricted to Alzheimer’s patients with a specific tau
burden.
“The
evidence over the population studies in the trial is very strong and
consistent across subgroups,” said committee member and NIH
biostatistician Dean Follmann, PhD.
“The biomarker data also were convincing of the effect,” added
committee member Kathleen Poston, MD, MS, of Stanford University in
California. “The benefits outweigh the risks, as long as the risks are
being monitored.”
But, throughout the meeting, Poston and others voiced concerns about
the lack of data on donanemab and other anti-amyloid drugs in
African-American and Hispanic populations. “That will be important in
the future to obtain to make sure that these encouraging findings can be
extrapolated to everyone with Alzheimer’s disease,” she said.
While the risks, especially for amyloid-related imaging abnormalities
(ARIA), were clear in the trial data, many of them could be mitigated,
FDA advisors suggested. Safeguards to manage ARIA could be put in place
and risks could be “safely clarified with a proposed MRI program and
training,” noted committee member Cynthia Carlsson, MD, MS, of the
University of Wisconsin School of Medicine and Public Health in Madison.
Neurologist
Marwan Sabbagh, MD, of the Barrow Neurological Institute in Phoenix,
who wasn’t involved with the donanemab trials, summed up the views of
most Alzheimer’s patients who spoke at the public hearing discussion
during the meeting. Patients with Alzheimer’s “have a 100% chance of
getting worse and losing autonomy — juxtaposed against a 6% chance of
symptomatic ARIA,” Sabbagh said.
Donanemab was tested in the phase III TRAILBLAZER-ALZ 2opens in a new tab or window
trial of 1,736 early Alzheimer’s patients. The drug met the trial’s
primary endpoint of change from baseline in the Integrated Alzheimer’s
Disease Rating Scale (iADRS), slowing decline relative to placebo (P<0.001).
The drug also met a key secondary endpoint, showing less decline on the
Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 76 weeks (P<0.001).
Like other anti-amyloid drugs, donanemab’s safety issues centered
around ARIA with edema or effusion (ARIA-E) and ARIA with
microhemorrhages and hemosiderin deposits (ARIA-H). ARIA occurs more
frequently in APOE4 homozygotes than in heterozygotes or noncarriers.
In
TRAILBLAZER-ALZ 2, 24% of donanemab-treated participants had ARIA-E and
31.4% had ARIA-H. Two ARIA-related deaths were attributed to donanemab.
If approved, donanemab will be the third amyloid-targeted drug to
come to market: the first being the controversial aducanumab (Aduhelm),
which received accelerated approval but was subsequently abandoned,opens in a new tab or window and the second being lecanemab (Leqembi), which received full FDA approvalopens in a new tab or window last year.
The FDA has not named a date for its final decision about donanemab.
While the agency isn’t required to follow its advisory committees’
recommendations, it typically does.
