Alzheimer’s drug Donanemab receives support from FDA expert panel

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An expert panel of advisers to the Food and Drug Administration voted 11-0 yesterday to recommend that the agency approve the Alzheimer’s disease drug donanemab. The panel concluded that the drug is effective in treating memory loss in patients with mild cognitive impairment and early-stage dementia, and that the drug’s benefits outweigh its risks.

However, the panel did raise concerns about certain safety risks and inadequate representation of Hispanic and Black patients in the phase 3 trial.

The FDA will soon decide on donanemab’s marketing authorization. Although the agency is not required to follow the recommendations of its advisory committees, it usually does so, in which case donanemab would become the third beta-amyloid-targeted monoclonal antibody approved in the US.

Nearly seven million Americans live with Alzheimer’s disease, about two million of whom are in the early stages of the disease. Disease-modifying 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 collections of beta-amyloid proteins that clump between neurons in the brains of AD patients. Doctors confirm the existence of beta-amyloid plaque in patients by performing brain scans.

The first beta-amyloid-targeted biologic, Aduhelm (aducanumab), underwent an extremely controversial approval process in 2020 and 2021, with the FDA ignoring the advice of an independent advisory committee not to approve the therapeutic. The FDA never cared a convincing justification for his decision.

Following this controversy, the Centers for Medicare and Medicaid Services issued a national coverage determination in April 2022 that severely limited coverage of all beta-amyloid-targeted monoclonal antibodies unless they had received regular, rather than accelerated, approval from the FDA and were deemed were expected to provide at least some clinically meaningful benefit.

After the FDA granted regulatory approval of the second biologic, Leqembi (lecanemab), in July 2023, CMS lifted most restrictions, clearing the way for reimbursement as long as Medicare beneficiaries taking Leqembi enroll in a patient registry to collect more data about the drug. . Medicare is the primary payer of AD diagnostics and prescription drugs.

Leqembi and donanemab are not medicines. They are modestly effective in reducing cognitive decline.

The Phase 3 clinical trial for donanemab measured cognitive impairment in people with accumulated beta-amyloid plaque and varying levels of the tau biomarker. After 76 weeks of treatment, researchers found that donanemab had significantly slowed cognitive and functional decline. Specifically, the study found that donanemab slowed progressive disorders by 35% in people with low and moderate levels of tau and by 22% in the entire population, compared to those who received a placebo. In addition, participants taking donanemab had a 39% lower risk of progressing to the next stage of the disease compared to placebo.

Panelists who reviewed the evidence suggested that this was the case sufficient delay of cognitive decline to be “meaningful” to patients, according to NPR.

Questions remain about what exactly the label will look like once the FDA makes its expected approval decision.

For example, the FDA will still have to consider whether donanemab should be limited for people who have tau deposits in their brain. If so, a PET scan would be needed to detect tau, such as Neurology Live reported. Advisors warned on Monday that such a requirement could pose a barrier to patients’ access to treatment as such scans are costly and time-consuming.

And thus, Biopharma dive reported, that the advisors want “more clarity on the role the tau biomarker would play in clinical decision-making if the drug is approved.”

The FDA had also asked the panel to provide guidance on whether and when it is safe for people to stop taking donanemab based on the reduction in beta-amyloid plaque. The drug’s developer and manufacturer, Eli Lilly, notes that the suggested dosing schedule – 700 mg intravenous infusion every four weeks, followed by 1,400 mg every four weeks – can be stopped once the plaque is gone.

While some panelists supported discontinuing treatment in principle, they also questioned whether discontinuation would necessarily be wise. What would happen, one panelist asked, if amyloid started to build up again in patients’ brains?

Regarding the safety of the drug, the consultants raised concerns about the risks of mild brain swelling that could result from donanemab and other beta-amyloid-targeting monoclonal antibodies.

The panel asked specific questions about the drug’s potential causal role in amyloid-related imaging abnormalities, which were found in nearly 25% of patients in the phase 3 study.

Before the advisory committee meeting, the FDA posted a briefing document orphan to an ‘imbalance in deaths’ in patients treated with donanemab. “However, there was no unusual group of deaths that could indicate a causal relationship.”

For people at high risk for ARIA, such as those with a genetic marker called APOE4, Eli Lilly recommends closer monitoring.

The already approved AD drug Leqembi has a black box warning. It seems likely that donanemab will also carry such a warning on the label.

Finally, FDA advisors stated that more data is needed to examine 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 study, there were only 35 black and 59 Hispanic participants, which represented just 5% of the total.

The FDA Advisory Committee’s unanimous decision that the overall risk-benefit profile of donanemab is favorable bodes well for its eventual approval. This, in turn, would provide AD patients and their caregivers with another treatment option in a therapeutic area with a significant amount of unmet need.

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