EXPERT REACTION: Drug reported to slow Alzheimer's progression by 35%

After Lecanemab was shown as a promising disease-modifying treatment for Alzheimer’s disease (AD) in January, the Donanemab antibody from Eli Lilly, has also shown similar results in phase III clinical trials. Both antibodies help clear away amyloid plaques in the brain, a buildup of sticky protein widely known to drive the symptoms of AD. Donanemab even produced amyloid plaque clearance as early as 6 months after the start of the treatment (34%) and 12 months (71%). Based on the long-held theory that amyloid reduction may lead to reduced cognitive decline, the most exciting outcome of the trial is slowing cognitive and functional decline in patients with early stage of AD.

Donanemab employed a different trial design than Lecanemab. Both phase III trials recruited around 1700 participants, however, Donanemab enrolled some people with high levels of tau at baseline, who are predicted to progress to AD more quickly and less responsive to therapy. The donanemab trial also has a different primary endpoint than the Lecanemab trial.

Similar, potentially serious, side effects to those observed with Lecanemab, including brain swelling and bleeding were seen in a small subset of participants. We should closely monitor this, in particular with people who carry the gene mutation APOE4 (which is linked to an increased risk of AD).

This is an exciting report, and emphasises the value of early diagnosis of Alzheimer’s Disease to support access to these treatments aiming to clear amyloid plaques. Delaying cognitive and functional decline helps people living with early stage dementia to continue engaging in other support programmes and activities designed to maximise their wellbeing and maintain their independence. This also includes engagement with allied health services providing vision and hearing care, which are increasingly important forms of post-diagnosis support, as highlighted in the 2022 World Alzheimer’s Report. It will be interesting to see progress with other trials of this drug in mentioned areas such as pre-clinical Alzheimer’s Disease. Delaying progression to subsequent stages may extend the window of opportunity to address other modifiable risk factors for cognitive decline, such as sensory impairment, through interventions such as prompt cataract surgery, hearing screening, and ensuring glasses are up to date.

A second drug is now proven to slow decline in persons with mild Alzheimer’s disease, the cause of most cases of dementia in Australia. A monthly injection of Donanemab cleared the brain of amyloid plaques that drive the development of Alzheimer’s disease. It did this in 12-18 months in most participants and slowed the rate of decline in brain function by 35%. Compared to the trial of the previously approved drug Lecanemab, this drug requires less frequent dosing and removes amyloid faster so that treatment can be stopped after 12 months in many patients. The benefits and risks of serious side-effects appear similar to Lecanemab with serious side-effects seen in 1.6% of participants receiving Donanemab. Importantly, the Donanemab trial showed greater benefit in those with lower brain tau levels. Tau build up follows amyloid build up in Alzheimer’s disease so this is important evidence that the earlier treatment is given, the greater the benefit. With new blood tests for Alzheimer’s disease emerging there is a real possibility that very early detection and treatment will reduce the prevalence of severe dementia and turn the tide on this devastating illness.

Very exciting news. Looks marginally better than the Eisai competitor. We are looking forward to regulatory approval in Australia; even better performing biologics in this class are in development.

This is exciting news. This is the third monoclonal antibody in a row to show positive results and the second to show clinical benefits. The future for the treatment of Alzheimer's disease is looking increasingly promising. Of course, we need the full data to evaluate it, and the rate of adverse effects is a concern, but I am heartened by the news.

The donanemab Phase 3 study results are potentially promising, as they indicate not only plaque clearance, but also demonstrable slowing of cognitive/functional decline in early symptomatic Alzheimer’s disease across both the primary and multiple secondary endpoints. Encouragingly, 47% of participants showed no progression of disease severity over a 1-year period (compared to 29% on placebo). This is a marked improvement over previous trials of other amyloid-targeting antibodies, which have largely failed to sufficiently demonstrate cognitive benefit. In fact, the clinical approval of such compounds has been met with controversy.  

Despite early promise, however, full evaluation will not be possible until a comprehensive profile of results, particularly safety data, is released for peer review. Concerningly, preliminary results indicate amyloid-related imaging abnormalities (ARIA) in multiple participants (24% ARIA-E and >30% ARIA-H). While most of these were mild-moderate and resolved/stabilised, 1.6% experienced serious ARIA, with 3 deaths (2 attributed to ARIA and one following an incident of serious ARIA). Thus, donanemab is not without potentially significant risk. As treatment was completed once plaque clearance was achieved, questions also remain about long-term benefits, given that cognitive/functional decline is not dependent on plaque pathology alone. While I am cautiously optimistic, key questions remain.

Alzheimer’s disease is a debilitating condition and little progress has been made in developing treatments over multiple decades. As such the press release from the drug company Eli Lilly is exciting and shows some promising results indicating that their compound (donanemab) slows the progression of Alzheimer’s disease symptoms and ability to perform day-to-day activities, giving people with Alzheimer’s more time.

This is particularly the case for people earlier in their Alzheimer’s disease journey (32-43% slowing of decline) but positive effects were also seen in intermediate/later stages (19-29%). Some side effects have been found and these have to be appropriately managed moving forward.

Nevertheless, this is exciting news for people living with Alzheimer’s disease and their families. The Alzheimer’s research community looks forward to seeing the full report.

The results of this study are very encouraging for patients with Alzheimer’s disease. While the full results are yet to be published, the data that have been released show it significantly slows progression of Alzheimer’s. Most impressive was that the drug met all primary and secondary endpoints meaning that it is likely that patients and carers will notice the effect. However, it is definitely not a cure for Alzheimer’s.

Nonetheless, it slows the inevitable worsening of the disease allowing patients more quality time with loved ones. The drug acts in a similar way to other amyloid monocloncal antibodies and is associated with a similar small risk of cerebral microhaemorrhages and oedema. It is hoped that the drug will be available in the not too distant future.

Alzheimer’s disease is a progressive neurodegenerative disease that affects memory and is now the leading cause of disability and the second most common cause of death in Australia. After decades of research, we have a handful of drugs that can only treat the symptoms of the disease, and a long list of failed drug candidates. One of the hallmarks of Alzheimer’s disease is the accumulation of a protein called beta-amyloid.

Originally thought to play a critical part in the death of brain cells, nearly a decade of failures with drugs aimed at beta-amyloid have undermined this idea. Most recently, antibodies to beta-amyloid have been trialled to remove the protein. Again, most of these have been abject failures, or produced marginal results at best.

In contrast, Donanemab is an amyloid plaque–specific antibody, and the recently published clinical trial in participants with early symptomatic Alzheimer’s disease showed clinically significant reductions in disease progression. However, despite near total removal of amyloid plaque, the disease still did progress, although at a much slower rate than without treatment. The patients were also highly selected, and this success may not be as effective in the more general population, and the cost of therapy may be prohibitive. While this result is greatly encouraging, it is clear we still have a lot more work to do to successfully treat Alzheimer’s disease.