The new Alzheimer’s drug: Why Donanemab, yet to be approved, has generated excitement

What are the findings?

Over an 18-month period, the trial met the primary endpoint of slowing cognitive decline in those with early Alzheimer’s. Along with a 35% slower cognitive decline in those who received the drug, it noted a 40% less decline in people’s ability to do day-to-day tasks.

This result was based on data from 1,182 patients with intermediate levels of tau protein, which is associated with the severity of Alzheimer’s. Interestingly, the drug slowed meaningful cognitive decline even when the data of 552 patients with high levels of tau – representing those in the later stage of the disease – was added to the results. When results from both the populations were combined, cognitive decline slowed down by 22% in 18 months.

More importantly, the study found that there was no cognitive decline in 47% of the people who received the drug as compared with 29% of those who received a placebo.

To be sure, these are the findings that have been announced by the company in a statement, and a detailed study is yet to be published. More data could also become available when the company applies for regulatory approvals.

“Based on these results, Lilly will proceed with global regulatory submissions as quickly as possible and anticipates making a submission to the US Food and Drug Administration (FDA) yet this quarter. Lilly will work with the FDA and other global regulators to achieve the fastest path to traditional approvals,” Eli Lilly said in its statement.

How does the drug work?

Donanemab is a monoclonal antibody that targets the abnormal plaques of amyloid beta protein characteristically seen in brain images of those with Alzheimer’s. Its mechanism of action is similar to Lecanemab, the drug developed by Japanese and American companies Eisai and Biogen that received a fast-track approval from the FDA earlier this year.

Another drug by Eisai and Biogen called Aducanumab, which was the first Alzheimer’s drug to receive approval in 2021 after decades, also has a similar mechanism of action.

All three of them are linked to similar side effects – temporary swelling and tiny bleeds in the brain, called amyloid-related imaging abnormalities (ARIA). Researchers believe this class of monoclonal antibodies weaken blood vessels as they attack the amyloid plaques, resulting in the side-effects.

“The side-effects were more with Aducanumab and there weren’t any functional benefits. Lecanemab has fewer side-effects and has shown functional improvement to offset the risks. The results announced for the new drug show it has a similar safety profile,” said Dr MV Padma Srivastava, head of the neurosciences centre at the All India Institute of Medical Sciences (AIIMS).

Eli Lilly reported temporary swelling in the brain in 24% patients with visible symptoms in 6.1%. It also reported micro-haemorrhages in 31.4% participants as compared with 13.6% in the placebo group.

How do the two drugs compare with each other?

Although there is no head-to-head trial to compare the results of Donanemab with its predecessor Lecanemab, both have used similar scales to measure the impact of the medicines.

The 35% slower cognitive decline is measured using a scale called integrated Alzheimer’s Disease Rating Scale (iADRS). This equates to 37% on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the scale used by Lecanemab. In the case of Lecanemab, a phase III trial on 1,795 participants had found cognitive decline slowed by 27%.

The scales assess performances of the patient in six areas — memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.

Another difference in the two drugs is the dosage. Lecanemab is given once every two weeks intravenously. Donanemab, on the other hand, is administered once a month and is stopped once patients reach a certain threshold for amyloid levels.

Why are the findings significant?

While the cases of Alzheimer’s are on the rise – an estimate suggests that India’s burden of dementia, of which Alzheimer’s is a part, will increase to 14 million by 2050 – scientists are yet to agree upon what causes the disease.

Now, the consecutive success of three therapies in two years in slowing cognitive decline in patients with early Alzheimer’s establishes more firmly the theory that one of the main causes of the disease are the abnormal clumps of amyloid beta protein around brain cells.

However, others believe that Alzheimer’s could be an autoimmune disorder where the body’s immune system cannot distinguish between brain cells and the fats that make up the envelope of bacteria.

Still others believe that Alzheimer’s is caused by excessive deposition of iron in the brain and depletion of an antioxidant called glutathione, which keeps the iron levels in check.

Dr Padma said, “A lot of research has happened and is ongoing. So far, most have been off bull’s eye. That is one of the reasons for excitement over these medicines.”

She however, remained cautious, saying that the medicines have followed the patients only for a small duration of 18 months. “We are yet to see how the disease progresses over longer periods.”

She said that with the high cost of therapies being a major road-block to access, India should still focus on preventing Alzheimer’s as much as possible.

How can Alzheimer’s be prevented?

Lifestyle modifications that are known to reduce risks of other non-communicable diseases, like diabetes and hypertension, are also associated with a lower risk of Alzheimer’s. Doctors prescribe a healthy diet, exercising regularly, sleeping well, and reducing the risk of diabetes and heart disease. They also suggest stopping smoking and reducing drinking.

Other than that, doctors suggest that people, especially the elderly and those with family history, should keep their brains active and engaged. Solving puzzles, learning new languages or new skills, and going out and making friends can all help.