What’s the new Alzheimer’s drug, Donanemab, all about? Can it be a turning point?

What are the challenges that the new drug faces?

Experts have pointed out several challenges that come with administering the therapy in the real world. These involve getting the Alzheimer’s diagnosis early on, selecting carefully the Alzheimer’s patients who can receive the therapy, screening eligible patients and following them up with expensive tests and keeping an eye out for severe adverse events that may lead to death.

With the most significant impact of Donanemab seen in patients with early stages of Alzheimer’s disease, the editorial mentioned above argues that there is a need for validated tools and expertise so that the disease might be suspected by primary care physicians and diagnosed through biomarkers in speciality dementia clinics.

New drug on Alzheimer’s (Designed by Abhishek Mitra)

Another editorial said that a special and expensive PET scan would be needed to stage the protein abnormality levels in the brain before and during the treatment. The availability of these machines are limited in clinical settings, it said. Those being screened for the therapy also need to get tested for the APOE4 gene, which has been associated with a higher risk of adverse events. “The costs will be substantial, not just for the medication itself, but also for the biomarker and imaging workup,” the editorial said.

In short, most Alzheimer’s patients will not benefit from the therapy with the strict selection criteria for the therapy. The likely high cost of the therapy will also be a deterrent.

So, is the therapy worth it? What of adverse effects?

The phase III study shows that Donanemab slows down cognitive decline in early Alzheimer’s patients by 35.1 per cent in 76 weeks. The result was based on a study with 1,736 patients, of whom 860 received the infusion every four weeks till the amyloid beta plaque clears.

“This 35 per cent less decline is measured through various tests that look at the memory and motor skills. This translates into small daily activities like talking to another person. The therapy slows down the progression of the disease, it does not ultimately treat the disease,” said Dr Pravat Mandal, senior researcher from the National Brain Research Centre, who is working on an alternative hypothesis on the underlying cause of Alzheimer’s disease.

While the results cannot be compared head to head with the 27 per cent slower cognitive decline with Lecanemab — both use different scales for measuring cognitive decline — the recently published study does show that Donanemab may have slightly higher adverse events.

Other than infusion-related reactions, the main adverse effect with drugs that clear out amyloid beta proteins is Amyloid-related imaging abnormalities (ARIA) such as swelling or bleeding in the brain, most of which is asymptomatic. The study showed that 24 per cent participants given Donanemab had ARIA involving brain swelling and 19.7 per cent had ARIA involving brain bleeds. There were also three treatment-related deaths reported in the study.

Many experts still preferred Donanemab as the infusion needs to be given every four weeks instead of every two weeks with Lecanemab. The patients switched over to placebo after there was a certain level of protein clearance in the Donanemab study. “This is a welcome difference for patients and payers, limiting infusion-related burdens as well as longer-term costs,” the editorial said.

What do physicians say?

Dr Mandal feels that given the huge costs, “it is inadvisable to administer the therapy for limited benefits; unless someone has the money and really wants to go for it. As I said earlier, the therapy also does not cure, meaning the benefits will be for a limited time.”

Dr PK Sethi, neurologist at Sir Ganga Ram Hospital, says he will adopt a wait and watch approach. “It is a very new drug; we still do not know all the adverse effects that it might cause. We have to wait and see what happens when the drug is administered in larger populations. This is besides the high cost of the therapy. We have to do a cost-benefit analysis,” he said.

Why is there a need to focus on other modalities?

While there has been excitement in the scientific community that an Alzheimer’s drug was able to demonstrate efficacy and receive approval, there is a continuous quest to find something better. “Alzheimer’s disease has multiple modalities and we would need various therapies to address them. While the amyloid beta protein therapy has been at the forefront, there is a need to investigate other targets as well,” said Dr Mandal. His team is investigating the impact of iron build-up and oxidative stress in the brain as a result of declining levels of an anti-oxidant called glutathione.

Dr MV Padma Shrivastav from the All India Institute of Medical Sciences had previously told the Indian Express: “A lot of research has happened and is ongoing keeping in mind different mechanisms for Alzheimer’s and so far most have been off bull’s eye. That is one of the reasons for excitement for these medicines. But, there are more drugs in the pipeline with several different targets.”

One of the editorial quoted above said: “Ultimately it seems likely that a combination of drugs targeting additional molecular pathways involved in Alzheimer’s Disease pathophysiology will be needed to more profoundly affect the trajectory of disease.”