On 17 July, Eli Lilly published full results from its TRAILBLAZER-ALZ 2 (NCT04437511) study of its anti-amyloid-beta (Aβ) monoclonal antibody (mAb), donanemab, in Alzheimer’s disease (AD) in Journal of the American Medical Association. Following the FDA’s approval of Eisai and Biogen’s Leqembi (lecanemab) earlier in the month, this data from Eli Lilly helps to further validate the importance of the amyloid hypothesis in AD. Top-line data from TRAILBLAZER-ALZ 2 was shared by the company in May, but the full results from the study 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 eight major markets (US, France, Germany, Italy, Spain, UK, Japan, and China) in 2030 ($3.5bn), with donanemab following close behind ($2bn). Although these two anti-Aβ mAbs appear similar at first glance, there are several key differences that will likely set them apart.
They target different forms of Aβ, as 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 demonstrates a rapid drop in amyloid burden (by positron emission tomography scan) among donanemab-treated patients—specifically, about -60 centiloids after six months and -88.0 centiloids after 18 months. Data from the TRAILBLAZER-ALZ 2 study was presented separately for patients with intermediate levels of tau at baseline (low/medium tau) and high levels of tau at baseline. The data points included here are from combined analyses of patients with intermediate and high levels of tau. Patients receiving Leqembi in Clarity AD (NCT03887455) also saw a strong drop in amyloid burden, about -35 centiloids after six months and -55.5 centiloids after 18 months. Whether these drugs differ in their ability to clear Aβ remains a question for a future head-to-head study. Since both products reduced mental decline similarly over the course of their 18-month studies, it is unclear whether differences in the targeted Aβ form actually impact the clinical profile.
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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 game-changer for many patients. Another win for Eli Lilly’s product is the potential to actually 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 a placebo. Nearly half of donanemab-treated patients met the treatment completion criteria after one year, and switching to placebo did not impact the clinical improvements that had been made. The amount of time until patients would need to be retreated, if ever, will need to be captured in future studies. Although creating treatment cut-off points could limit sales for Eli 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 advantage regarding certain measures of safety, particularly the occurrence of amyloid-related imaging abnormalities (ARIA). For example, the rate of ARIA-edema among patients receiving Leqembi in Clarity AD was 12.6% (1.7% among those receiving placebo) while the rate was 24.0% in those receiving donanemab in TRAILBLAZER-ALZ 2 (1.9% among those receiving placebo). In line with this heightened risk for ARIA, three of the 16 deaths in TRAILBLAZER-ALZ 2 were considered to be due to the study drug and subsequent to ARIA, while zero met the criteria in Clarity AD. Although head-to-head studies are needed to confirm this, the frequency of ARIA may be another key factor in differentiating these two products.
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