At the AD/PD 2023 International Conference on Alzheimer’s disease (AD) and Parkinson’s disease (PD), Lilly presented new data from its donanemab clinical programme over several sessions taking place on 30 March about amyloid beta (Aβ) targeting therapies in AD, and Aβ and tau targeting therapies in AD. With the FDA approval of Biogen’s Aduhelm (aducanumab) in 2021 and Eisai and Biogen’s Leqembi (lecanemab) in January 2023, competition between the anti-Aβ monoclonal antibodies (mAbs) is set to increase, with Lilly’s donanemab expected to be the third anti-Aβ mAb to enter the market. As such, the developers are all looking at how to best position their product on the market and what differentiates their respective therapies from their competitors.
The new data presented by Lilly highlights the potential durability of treatment with donanemab from the Phase II TRAILBLAZER-EXT study (NCT04640077). This is a follow-on study of the original Phase II TRAILBLAZER-ALZ trial (NCT03367403), in which patients in the donanemab treatment arm experienced a significant 76% reduction in amyloid positron emission tomography (PET) from baseline. In TRAILBLAZER-EXT, these patients, who had not received donanemab treatment for over a year since the end of the original trial, demonstrated minimal amyloid reaccumulation, with a 72% reduction in amyloid PET from baseline to the end of the extension study. This demonstrated the potential durability of treatment with donanemab as cessation of treatment did not result in rapid reaccumulation of Aβ. Furthermore, in TRAILBLAZER-EXT, patients who had received donanemab in TRAILBLAZER-ALZ showed a slower rate of clinical worsening, measured by clinical dementia rating scale sum of boxes (CDR-SB), compared with patients who had received placebo, indicating the potential for beneficial effects of donanemab to continue beyond the end of treatment. Lilly is the first company to investigate the effect of halting treatment with an anti-Aβ mAb, which could help to give donanemab a competitive advantage when it reaches the market.
While these results are important for donanemab’s prospects, it should be noted that there are several limitations to this data. Firstly, the sample size for this new data is very small (n=17 for patients randomized to donanemab in TRAILBLAZER-ALZ who entered the TRAILBLAZER-EXT study), and secondly, because there was over a year between the end of TRAILBLAZER-ALZ and TRAILBLAZER-EXT, there is a returner bias in the patients who are analysed in TRAILBLAZER-EXT. Therefore, it will be important to see the results from the Phase III TRAILBLAZER-ALZ 2 (NCT04437511) long-term extension study, which is expected to provide more robust insights into the durability of treatment with donanemab, and its long-term effects on clinical outcomes. Topline data from TRAILBLAZER-ALZ 2 is expected in Q2 2023, with the long-term extension study data likely not available until 2024 at the earliest.
In a later session, Lilly presented further results from the Phase II TRAILBLAZER-ALZ study (NCT03367403). Firstly, infusion-related reactions (IRRs) were characterized. Although IRRs were only seen in the donanemab treatment arm (7.6%), the results highlighted that most IRRs were mild or moderate in severity and resolved within one day. Currently, IRR is a poorly defined term that can range from mild discomfort to life-threatening anaphylaxis. Lilly is looking to characterize IRR by building upon the presented data with further data from TRAILBLAZER-ALZ2 in order to allow patients and physicians to make better-informed decisions on the potential risks/benefits of donanemab as a treatment. Secondly, immunogenicity results from TRAILBLAZER-ALZ were presented, showing that 92.2% of evaluable donanemab-treated patients were anti-drug antibody (ADA) positive, the majority of which were treatment-emergent ADAs. However, the study was able to demonstrate that while patients in the high ADA titer group showed a modest attenuation of Aβ plaque clearance compared with the low ADA titer group, the effect was not significant at week 76 and both groups demonstrated significant Aβ plaque clearance compared with placebo, which is expected to translate to clinical effect.
While these results are important for Lilly, building up a promising picture of the treatment effects and safety profile of donanemab as the company looks to position the drug to compete with the other anti-Aβ mAbs, it will be important for these results to be replicated and evaluated in further detail in the larger ongoing Phase III clinical trials of donanemab.