Donanemab, marketed as Kisunla, received TGA approval for the treatment of early Alzheimer’s disease this week, making it the first drug registered in Australia that has been proven to significantly slow progression of AD.

Clinical trial data showed that the amyloid-targeting therapy slowed cognitive and functional decline by up to 35% compared to placebo at 18 months. Response was greatest in those treated at the earliest stages, highlighting the need for earlier diagnosis.

But while donanemab is being hailed as a breakthrough, experts are also emphasising its limitations.

“It needs to be given at the first signs of the disease and closely monitored to avoid serious side effects,” the Australian Dementia Network said in a statement this week.

“Currently there is an average three-year delay between first signs and getting a diagnosis of AD and waiting times to see dementia specialists in many areas are over a year. Monthly infusions and frequent brain imaging is required when on treatment. To meet the expected demand for this treatment the health system will need to rapidly change.”

Slows decline, but not curative

Associate Professor Steve Macfarlane, head of clinical services at Dementia Support Australia says that for the “small but important” subgroup of eligible patients who are diagnosed in the very early stages and can afford access, the impact on slowing progression can be significant – but it’s also important to temper expectations.

“This is not a cure. It’ll buy you significant amounts of time, but it’s not going to make your symptoms better or your memory improve,” he explains. “What it does is it slows down the progression of the disease by significant amounts over an 18-month period.”

Associate Professor Michael Woodward, geriatrician and head of Aged Care Research and the Memory Clinic at Austin Health in Melbourne concurs, saying that while the drug is not curative, the slow in decline is clinically significant.

“If it’s used early enough, in the very early stages of mild cognitive impairment, with Alzheimer’s proven, and with amyloid proven, then you might be able to buy three or four years,” Associate Professor Woodward says.

In other words, it can take three to four years longer to reach the degree of deterioration they would have had without the drug.

Will that be enough to justify hefty costs?

Associate Professor Woodward says the anticipated cost of donanemab is about $47,000 per year, with up to 18 months of treatment.

Donanemab is not PBS-listed, though the PBAC will review an application by the drug’s manufacturer, Eli Lilly, in July.

Associate Professor Macfarlane points out that there are also other associated costs, including monitoring with MRIs to check for brain swelling throughout the treatment period.

Before treatment can commence, patients also need genetic testing to make sure they don’t have two copies of the Apolipoprotein E ε4 (ApoE ε4) gene, as well as an amyloid PET scan to demonstrate they have the pathology the drug is targeting.

“Not only are there costs associated with all of those, but there’s also significant periods of waiting time,” he adds.

Who is eligible?

Associate Professor Woodward says the drug is suitable for people with mild Alzheimer’s disease, including those with mild cognitive impairment or mild dementia, “but it has to be due to Alzheimer’s disease.”

Patients must be ApoE ε4 heterozygotes or non-carriers. (This is because homozygous ApoE ε4 gene carriers have increased risk of Amyloid-Related Imaging Abnormalities or ARIA.)

“You also have to demonstrate that the patient has amyloid, which means in most cases going to a specialist and having an amyloid PET scan, or a spinal fluid study (CSF) in some cases where PET scans are less available,” Associate Professor Woodward says.

Anticoagulants also increase the risk of side effects, and the product information for the drug advises caution in “patients with factors that indicate an increased risk for intracerebral haemorrhage and in particular for patients who need to be on anticoagulant therapy or patients with findings on MRI that are suggestive of cerebral amyloid angiopathy.”

Associate Professor Woodward says appropriate-use guidelines are being developed, and a final decision on anticoagulants has not yet been made.

Health system limitations

Access will likely be limited by other factors too. Infusions are required every four weeks.

“Currently, probably the main barrier apart from cost is the health infrastructure isn’t really set up to run infusions on the scale that are likely to be required,” Associate Professor Macfarlane says.

“If we treated everybody with early Alzheimer’s who was eligible, there’s probably tens of thousands of people in Australia who would be suitable for the drug.”

Only a small number of private centres are set up to do these infusions, and public hospitals are unlikely to because the cost is too high, he says.

“There’s going to be a lag time before that infrastructure can be made available to scale up the ability to run these infusions.”

Pressure to identify and diagnose earlier

Experts say reducing the delay between the first signs of memory loss and diagnosis will be paramount.

“That three years is really time that’s wasted for people who would be most suitable to get this drug,” Associate Professor Macfarlane says, adding that early referral will be crucial.

“GPs are going to be really central to sending people on for specialist evaluation early, because now we can do something.” – Associate Professor Steve Macfarlane

Associate Professor Woodward agrees, noting that it will be particularly important to take memory complaints seriously.

“I’m not saying screen everybody after a certain age, but if a person comes in or their wife rings up and says, he’s losing it, take that seriously. Particularly now that with an accurate diagnosis, we potentially have an amyloid-targeting therapy.”

What does the future hold?

Change is on the horizon with blood biomarker tests to diagnose Alzheimer’s likely commercially available in the next year and a half.

“So there’ll be a whole lot more people with positive blood tests who haven’t had an amyloid scan,” Associate Professor Macfarlane notes.

“So the floodgates run the risk of being well and truly open once that screening test is available, without patients necessarily having been confirmed that they are suitable for the treatment.”

Associate Professor Woodward is optimistic that even more effective therapies with fewer side effects will be coming. “Some of those are being tested at our site now, and they look very promising. But for the moment, this is a major breakthrough,” he says.

“This is a good day at work because we finally have a drug that targets the underlying disease process, the accumulation of amyloid, which itself sets off other processes such as accumulation of tau, and some would argue that tau is driving most of the symptoms.”