The idiom ‘third time’s a charm’ may have some significance in this instance. The panel that advises the FDA just voted unanimously in favor of Eli Lilly’s experimental drug, donanemab. There is no mandate that the FDA must follow the panel’s advice, but it usually does. The panel decided that the benefits of Donanemab outweigh the risk. Donanemab would be the third Alzheimer’s therapy cleared for the market in the U.S.  The medicines break up the sticky, toxic amyloid beta that is believed to cause Alzheimer’s.

The first two approved drugs were:

• Eisai and Biogen’s Aduhelm was first approved but then withdrawn from the market under heavy controversy
• A second product called Leqembi is doing moderately well but launching the product has been extremely challenging

About the Clinical Trial

Lilly’s application for approval was based on a trial with almost 1,700 individuals in the first stages of Alzheimer’s. Trial results showed that people given donanemab had a 22% slower decline in symptoms than people in the control group. The ratings were determined by a combination of two prominent scoring systems that evaluate Alzheimer’s systems.

One of the questions voiced by the panel pertained to the majority of the Alzheimer’s general population, noting that all study participants were in the early stages of the disease. The researchers found that the study included unique elements. The enrollees had to show that they tested positive not only for amyloid but also for one other protein that is tied to Alzheimer’s development. When that protein was introduced into the evaluation, evidence was found that the disease increased at an even slower pace for the donanemab-treated patients who harbored low levels of the “tau” protein.

The panel of experts agreed that they will need additional data on the tau population, but they agreed that it should not be a requirement due to cost and difficulty in patient access to the testing locations.
Although the FDA’s director of neuroscience told members that the tau burden would not affect the agency’s approval, she did note that it may be a consideration involving labeling instructions. A threshold was established setting a precedent that if amyloid levels fell below a specific threshold, donanemab should be discontinued. This opened another window to determine how the decision relates to the real world. In other words, what would happen if amyloid began to accumulate again? Colette Johnson, who is the patient representative to the panel, said that it would be a problem if they are not getting follow-up information once the dosing was discontinued.

Even more concern was directed at bleeding and brain swelling collectively called ARIA. This occurred to several people who received donanemab or similar drugs. ARIA has been known to be asymptomatic and therefore it is only identified by magnetic resonance images. However, two patients and possibly a third patient treated with donanemab died due to an ARIA episode. This brought about questions whether to approve the drug for general use.

Lilly countered by saying that further into the trial they will be able to more easily identify asymptomatic patients by having them undergo frequent MRIs. As a precaution, the company held off on additional infusions of the drug until swelling in the brain subsided. Other than people who are asymptomatic, some ARIA patients are rated “high risk.” This group carries a genetic marker called APOE4. In these cases, the Lilly executives agreed to more frequent monitoring.

About the Hearing

The hearing consisted of patients, physicians, and caregivers with almost all asking the committee to recommend their approval. One of the people who testified at the hearing was a patient aged 75 who had an emergency infusion-related side effect. Rather than request that the panel vote against approving the drug, he decided that donanemab’s benefits deserved further consideration and he decided to stay in the study. Everyone involved in the study is aware that donanemab will delay, but not cure the disease. However, it is vital to those who are living with early Alzheimer’s to maintain their personality, cognition and independence for as long as possible.