On June 10, 2024, an 11-member panel of independent scientific and clinical advisors, convened by the Food and Drug Administration (FDA), voted unanimously to recommend Eli Lilly’s drug donanemab for approval in the treatment of Alzheimer’s disease, citing that the potential benefits outweigh the risks. The FDA will consider the panel’s recommendation before making a final determination to approve or reject the drug. If approved, donanemab would become the second drug currently available on the market to treat Alzheimer’s disease. Leqembi, a drug in the same class, was approved in 2023.

”We are excited to see a second drug reach this milestone in the FDA regular approval process. We thank the FDA and the members of the Advisory Committee for their thoughtful, patient-centric discussion of donanemab and its risk/reward profile for individuals in the earliest stages of clinical Alzheimer’s disease, and look forward to the FDA’s final decision later this year.” 

Background

Donanemab is a monoclonal antibody that targets a form of amyloid beta that builds up in the bundles of plaque that accumulate in the brain. Anti-amyloid monoclonal antibody drugs, including donanemab, are immunotherapies designed to increase the normal clearance of this pathology by the brain’s innate immune cells.

At the end of the 18-month trial, the treatment group had declined 29% less on an assessment of cognitive function than the untreated participants, even though many in the treatment group were able to stop treatment in a year or less due to reduction of beta-amyloid. This result is similar to that seen in the phase 3 trial that led to FDA approval for another anti-amyloid monoclonal antibody, Leqembi.

AdComm Background and Results

The AdComm voted unanimously that donanemab should be approved and that its clinical benefits outweigh the risks of brain swelling and hemorrhage associated with this class of drugs.

In news coverage from STAT, one member of the AdComm, Stanford neurologist Kathleen Poston, summarized the group’s thinking: “The benefits outweigh the risks, as long as the risks are being monitored.”

• The FDA convenes panels of outside experts, often clinicians, to provide input to its drug approval decision-making. These experts review extensive data and analysis prepared by the drug sponsor and FDA staff. The FDA does not have to convene these meetings to approve a drug and does not have to follow their recommendations, but it often does ask AdComms to vote on specific questions about a drug and whether it should be approved.
• Members of the public are also offered an opportunity to provide input and the AdComm discussion touched on how differently individual patients may judge the risks and rewards of treatment for Alzheimer’s.
• The donanemab AdComm was closely watched for two reasons. First, the FDA disregarded negative guidance from an AdComm and moved forward to approve aducanumab (marketed as Aduhelm), the first anti-amyloid immunotherapy alleged to show cognitive benefit to a treatment subgroup in a phase 3 clinical trial. Many AdComm members resigned and Aduhelm was eventually removed from the market after poor sales and severe restrictions on coverage from the Centers for Medicare and Medicaid. Second, Leqembi is another drug in this class with similar efficacy and safety data, so the FDA’s decision to call an AdComm on donanemab late in the approval process was a surprise.
• In discussions, the AdComm and FDA also indicated that the drug’s label, which indicates the guidelines for prescriptions, should not require confirmation that patients have tau pathology. Tau imaging is not widely available clinically, and requiring it would significantly reduce access to donanemab.
• AdComm members also highlighted that the donanemab trial, similar to the Leqembi and Aduhelm trials, had insufficient numbers of Black and Hispanic participants to provide adequate safety and efficacy data for these populations.

On July 2, the FDA approved donanemab for the treatment of early symptomatic Alzheimer’s disease. Donanemab will be sold under the brand name Kisunla™ and will be delivered via once-monthly IV infusion.  The annual drug cost of Kisunla alone – not including provider or administration costs – is set at $32,000, but physicians can consider whether to halt treatment once an amyloid PET scan indicates the patient’s brain amyloid level is sufficiently cleared; in the clinical trial, 69% of patients were able to end treatment by 18 months.

The field expected that donanemab would be approved but some anticipated that the label, which guides physician prescription decision making, would narrowly define eligibility based on pathology and/or the absence of risk factors that increase potential side effects. However, the FDA label does not identify any comorbidities that should preclude treatment with Kisunla, but does indicate physicians should be cautious if a patient has risk factors for intracerebral hemorrhage such as pretreatment microhemorrhages or extensive white matter hyperintensities, use of anticoagulant (blood thinning) therapies, or MRI findings suggestive of cerebral amyloid angiopathy.

The FDA label for Kisunla recommends genetic testing to determine APOE4 status due to the higher risk of serious side effects observed in people who carry two copies of APOE4. The label directs physicians to confirm the presence of amyloid pathology prior to prescribing Kisunla but does not recommend or require that the presence of tau pathology be established.  Four MRIs spaced out over the course of the earliest treatment months are indicated to assess the patient for the brain swelling, lesions, and bleeding side effects that are for most people asymptomatic but that can be in rare cases catastrophic. All of this testing will incur costs in addition to those of the drug and its administration.  For most eligible people, Medicare will cover some but not all of these costs.