Following the news that Eli Lilly published full results from its TRAILBLAZER-ALZ 2 (NCT04437511) study of anti-amyloid-beta (Aβ) monoclonal antibody (mAb), donanemab, in Alzheimer’s disease (AD);

Rose Joachim, Director of Neurology at GlobalData, a leading data and analytics company, offers her view:

“On the heels of the US FDA’s approval of Eisai and Biogen’s Leqembi (lecanemab) earlier in the month, these data from Lilly help to further validate the importance of the amyloid hypothesis in AD. Top-line data from TRAILBLAZER-ALZ 2 were shared by the company in May, but the full results from the study, published in JAMA on July 17, further solidify donanemab as a fierce future source of competition for Leqembi, if approved by regulatory agencies.

“Due to its first-to-market advantage, GlobalData expects Leqembi to dominate sales in the anti-Aβ drug class throughout the 8MM* in 2030 ($3.5 billion), with donanemab following close behind ($2.0B). Although these two anti-Aβ mAbs appear similar at first glance, there are several differences between the products.

“Firstly, they target different forms of Aβ: Leqembi binds to soluble Aβ protofibrils while donanemab binds to an insoluble form of Aβ present only in brain amyloid plaques. Time-course data from TRAILBLAZER-ALZ 2 demonstrate a rapid drop in amyloid burden (by PET** scan) among donanemab-treated patients***—about -60 centiloids after 6 months (-88.0 centiloids after 18 months). Patients receiving Leqembi in Clarity AD (NCT03887455) also saw a strong drop in amyloid burden, about -35 centiloids after 6 months (-55.5 centiloids after 18 months). Whether these drugs differ in their abilities to clear Aβ remains a question for a future head-to-head study. Considering both products reduced mental decline similarly over the course of their 18-month studies, it is unclear whether differences in the Aβ form targeted impacts the clinical profile.

“Another key differentiator is the frequency of administration. Both products are administered intravenously, but Leqembi is dosed once every two weeks, while donanemab is dosed once every four weeks. Halving the number of trips to a hospital or infusion center with donanemab could be a gamechanger for many patients.

“Another win for Lilly’s product is the potential to stop taking it once amyloid burden improves. In TRAILBLAZER-ALZ 2, donanemab-treated patients who had achieved ‘study completion criteria,’ according to their level of amyloid burden, were switched to placebo. Nearly half of donanemab-treated patients met the treatment completion criteria after a year and switching to placebo did not impact clinical improvements made. How long until patients would need to be re-treated (if ever) will need to be captured in future studies. Although creating treatment cut-off points could limit sales for Lilly, the promise of a non-indefinite treatment period could make it a preferred product among payers, giving it a significant advantage over Leqembi.

“Although donanemab has many positive differentiators, Leqembi may still have the drug beaten in regards to certain measures of safety, particularly the occurrence of ARIA****. For example, the rate of ARIA-Edema among patients receiving Leqembi in Clarity AD was 12.6% (1.7% among placebo) while the rate was 24.0% in those receiving donanemab*** in TRAILBLAZER-ALZ 2 (1.9% among placebo). In line with this heightened risk for ARIA, three of the 16 deaths in TRAILBLAZER-ALZ 2 were considered due to study drug and subsequent to ARIA, while zero met this criteria in Clarity AD. Although head-to-head studies are needed to confirm, the frequency of ARIA may be another key factor in differentiating these two products.”

*8MM: eight major markets (The US, France, Germany, Italy, Spain, the UK, Japan, China)

**positron emission tomography

***Data from TRAILBLAZER-ALZ 2 study were presented separately for patients with intermediate levels of tau at baseline (low/medium tau) and high levels of tau at baseline. Any data points included here are from combined analyses of patients with intermediate and high levels of tau.  

****ARIA: amyloid-related imaging abnormalities