Donanemab | A muted cheer

The drug, according to clinical trials, was far from promising a cure but slowed cognitive decline of those in the earliest stages of Alzheimer’s

July 23, 2023 01:56 am | Updated 01:56 am IST

A new drug prescribed for Alzheimer’s patients, donanemab, has generated considerable interest on whether a ‘breakthrough’ in treating the disease, the most common form of dementia, is in sight. Unfortunately, there is only very little to cheer.

On the July 17, donanemab’s American manufacturer Eli Lilly published results of a trial on 1,736 persons in the Journal of the American Medical Association (JAMA). The drug was far from promising a cure but among those in the earliest stages of the disease, it significantly slowed cognitive decline in 47% of those who took the drug, as opposed to 29% of those who were administered a placebo. Some 860 people received the drug, every four weeks for 72 weeks and 876 did not.

Damage to brain cells

Donanemab is a monoclonal antibody, meaning they are lab-synthesised to mimic antibodies, which our immune systems produce to fight antigens, or harmful, invasive agents. The philosophy underlying the use of donanemab is that it can be used to neutralise the build-up of amyloid protein, believed to be most significantly associated with the disease. Elevated levels of amyloid trigger another protein called tau that damages brain cells, and causes the cognitive decline typified by the disease.

Two other drugs, aducanumab and lecanemab — also monoclonal antibodies and premised on the amyloid-tau hypothesis — were in recent weeks also reported to have reduced amyloid concentrations. However, an analysis of trial results showed that its effects at reducing cognitive decline were vague. Two aducanumab trials showed minimal benefit and a follow-up after six months revealed a 22% slower cognitive decline in those on the drug compared to placebo. A lecanemab trial in 1,800 patients with early onset Alzheimer’s over 18 months reported similar results — a 26% slower cognitive decline. In effect, this means a “six-month benefit”, according to researchers Yen Ying Lim and Emily Rosenich, of the Monash University, Australia, in an article for The Conversation.

In the case of donanemab, those with low or moderate levels of tau declined 35% slower over 76 weeks than those on a placebo. However those with high tau levels declined at a similar rate regardless of donanemab or placebo. “The drug also cleared around 90% of the total amount of amyloid from the brain. Once people had minimal amyloid levels, the investigators switched them to a placebo. In the year after the switch, those who had taken donanemab continued to decline at a slower rate than those who had initially received a placebo,” says a report on the outcomes of the trial in the science journal Nature.

Cognitive decline

The degree of cognitive decline was assessed in patients by evaluating their ability to drive, pay bills and attend to affairs outside of their homes at various intervals ranging up to 18 months. Ultimately, both groups — treatment and the placebo — declined overall. The drug failed to benefit those with any more than mild systems and similar to aducanumab and lecanemab, the patients managed to stave off cognitive decline for 5-6 months.

There were a further set of complications associated with donanemab in the trial. Donanemab, like lecanemab and the related drug aducanumab, could case amyloid-related imaging abnormalities (ARIA), a class of conditions that could lead to potentially fatal brain bleeding and seizures. Nearly a fourth of the participants in Eli Lilly’s phase III trial developed ARIA, and three died of the condition. ARIA was most common among study participants who carry the APOE4 genetic variation, which raises the risk of developing Alzheimer’s, according to the report in Nature.

While donanemab has already been approved by the U.S. Food and Drug Administration, it is expected to be fairly expensive at an estimated $26,500 — putting out of reach of a large fraction of those afflicted unless there are significant government subsidies in place. While it may be early to be hopeful about reigning in Alzheimer’s disease, donanemab and other drugs of its class only underline what has been known about the disease over a quarter century — early diagnosis offers the best chance yet to manage the disease.

India is expected to have about 7.6 million afflicted by 2030, as per the Dementia in India Report, 2020, majority of whom are likely to be diagnosed with Alzheimer’s.

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