A Food and Drug Administration expert panel of advisors voted 11-0 yesterday to recommend that the agency approve the Alzheimer’s disease drug donanemab. The panel concluded that the therapeutic is effective in treating the memory-robbing condition in patients with mild cognitive impairment and early-stage dementia and that the drug’s benefits outweigh the risks.
The panel did, however, raise concerns about certain safety risks and insufficient representation of Hispanic and Black patients in the Phase 3 trial.
The FDA will soon decide on donanemab’s marketing authorization. Though the agency isn’t required to follow the recommendations of its advisory committees, it usually does, in which case donanemab would become the third beta amyloid-directed monoclonal antibody approved in the U.S.
Nearly seven million Americans are living with Alzheimer’s, approximately two million of whom are in the early stages of the disease. Disease-altering treatments have only recently become available. All three approved monoclonal antibodies—clones of human antibodies—are the first disease-modifying therapies for AD that slow clinical decline by reducing beta amyloid plaque in the brain. Amyloid plaques are accumulations of beta amyloid proteins that clump together between the neurons in the brains of AD patients. Physicians confirm the existence of beta amyloid plaque in patients by performing brain scans.
The first beta amyloid-directed biologic, Aduhelm (aducanumab), underwent an extraordinarily controversial approval process in 2020 and 2021 in which the FDA ignored advice given by an independent advisory committee to not approve the therapeutic. The FDA never gave a compelling justification for its decision.
After this controversy, the Centers for Medicare and Medicaid Services issued a national coverage determination in April 2022 that severely restricted coverage of all beta amyloid-directed monoclonal antibodies unless they had regular, as opposed to accelerated, approval by the FDA and were deemed to offer at least some clinically meaningful benefit.
Once the FDA granted regular approval of the second biologic, Leqembi (lecanemab), in July 2023, CMS lifted most restrictions, paving the way for reimbursement so long as Medicare beneficiaries who take Leqembi enroll in a patient registry to collect more data on the drug. Medicare is the predominant payer for AD diagnostics and prescription drugs.
Leqembi and donanemab aren’t cures. They are modestly effective in lessening cognitive decline.
The Phase 3 clinical trial for donanemab measured cognitive impairment in people with accumulated beta amyloid plaque and different levels of the tau biomarker. After 76 weeks of treatment, researchers found that donanemab had significantly slowed cognitive and functional decline. Specifically, the study trial showed that donanemab slowed progressive impairment by 35% for those with low and medium levels of tau and 22% for the entire population, when compared to those on placebo. Moreover, participants taking donanemab experienced a 39% lower risk of progressing to the next stage of disease compared to placebo.
Panelists considering the evidence suggested that there was sufficient slowing of cognitive decline to be “meaningful” to patients, according to NPR.
There are lingering questions regarding precisely what the label will look like once the FDA makes its expected approval decision.
For example, the FDA will still need to weigh whether donanemab should be limited to people who have deposits of tau in their brains. If so, a PET scan would be necessary to detect tau, as Neurology Live reported. Advisors cautioned on Monday that such a requirement could present a hurdle to patient access to treatment, as such scans are costly and time consuming.
And so, Biopharma Dive reported, that the advisors want “more clarity about the role the tau biomarker would play in clinical decision-making if the drug gets approved.”
Also, the FDA had asked the panel to provide guidance on whether and when it’s safe for people to stop taking donanemab based on reductions in beta amyloid plaque. The drug’s developer and manufacturer, Eli Lilly, notes that its proposed dosing regimen—700 mg intravenous infusion every four weeks, followed by 1,400 mg every four weeks—may be stopped once the plaque is cleared.
While in principle some panelists favored the idea of stopping treatment, they also asked whether discontinuation would necessarily be prudent. What would happen, one panelist asked, if amyloid began accumulating again in patients’ brains?
On the drug’s safety, the advisors expressed concerns about the risks of mild brain swelling that may result from donanemab and other beta amyloid-directed monoclonal antibodies.
The panel raised specific questions about the drug’s possible causal role in amyloid-related imaging abnormalities, which were found in nearly 25% of patients in the Phase 3 study.
Prior to the advisory committee meeting, the FDA posted a briefing document that pointed to an “imbalance in deaths” in patients treated with donanemab. However, “there was no unusual grouping of deaths that would suggest a causal relationship.”
For people at high risk of ARIA, such as those with a genetic marker named APOE4, Eli Lilly recommends closer monitoring.
The already approved AD drug Leqembi has a black box warning. It would seem likely that donanemab will also be tagged with such a warning on the label.
Finally, FDA advisors stated that more data is needed to explore how well the drug performs in underrepresented groups in the clinical trials, including Black and Hispanic patients. Of the 1,736 people enrolled in the Phase 3 trial, only 35 were Black and 59 Hispanic participants, representing just 5% of the total.
The FDA advisory committee’s unanimous decision that donanemab’s overall risk-benefit profile is favorable bodes well for its ultimate approval. In turn, this would provide AD patients and their caregivers another treatment option in a therapeutic area with a considerable amount of unmet need.
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