On June 24, the FDA granted breakthrough therapy designation (BTD) to two pipeline drugs: Eisai and Biogen’s lecanemab (BAN2401) and Eli Lilly’s donanemab for the treatment of Alzheimer’s disease (AD). Currently, the AD market is dominated by symptom-based therapies with modest efficacy. Earlier this month, Biogen’s Aduhelm (aducanumab) received FDA approval, and thus it is the first and only approved AD disease-modifying treatment (DMT). GlobalData forecasts that Aduhelm will generate $5.5B globally by 2027. Lecanemab and donanemab could be the next monoclonal antibodies (mAbs) against amyloid to receive FDA approval.

The BTD for lecanemab was supported by data from a placebo-controlled, double-blind, parallel-group, Bayesian adaptive randomization design, Phase II clinical trial in patients with mild cognitive impairment (MCI) due to AD and mild AD with confirmed presence of amyloid pathology (Study 201, NCT01767311). Following a pre-specified analysis, investigators reported that lecanemab showed a dose-dependent reduction in amyloid-beta (Aβ) and a reduction of clinical decline as measured using the Alzheimer Disease Composite Score (ADCOMS) after an 18-month treatment period. The BTD for donanemab was based on a randomized, placebo-controlled, double-blind, Phase II clinical trial in patients with early, symptomatic AD (RAILBLAZER-ALZ, NCT03367403). When compared with placebo, investigators found a reduction in cognitive and functional decline as assessed by the change from baseline in the Integrated Alzheimer’s Disease Rating Scale (iADRS) following 76 weeks of treatment with donanemab. A significant difference in amyloid plaque levels between placebo and donanemab treatment was not found.

However, both pipeline candidates will need to demonstrate long-term safety, tolerability, and efficacy profiles in Phase III clinical trials. The Phase III study for lecanemab in patients with early AD (Clarity AD, NCT03887455) has a primary completion date in June 2022, while the Phase III study for donanemab in patients with early symptomatic AD (TRAILBLAZER-ALZ 2, NCT04437511) has an estimated primary completion date in February 2023. GlobalData forecasts that lecanemab and donanemab will be launched in 2023 and 2024 in the US, respectively.

Both drug candidates are intravenously administered mAbs that aim to reduce the formation of amyloid plaques in the brain of AD patients. Lecanemab targets soluble Aβ monomers while donanemab binds to a modified form of Aβ, N3pG, that is localized in amyloid plaques. Reduction of these toxic proteins is hypothesized to be of significant clinical value in AD and treating the disease in the early stages, and consequently slowing clinical decline.

For efficacious amyloid-based therapies, early diagnosis is important. Despite the increase in the level of research on AD biomarkers in the past few years, a reliable and accessible biomarker remains an important unmet need. The availability of improved biomarkers will assist with efficient diagnosis of AD during the early and prodromal stages. Furthermore, it will be necessary for monitoring amyloid pathology to assess treatment response.

In addition, concerns regarding the development of amyloid-related imaging abnormalities (ARIAs) from amyloid-based therapies could represent a barrier for the uptake of mAbs against Aβ. Physicians will be required to conduct regular

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magnetic resonance imaging tests (MRIs) to determine if patients have ARIA reactions. With consideration of the high costs of biologics, regular MRI or positron emission tomography (PET) scans, and the need to monitor adverse events, the uptake of anti-amyloid DMT could be limited. GlobalData forecasts that lecanemab and donanemab will generate global sales of $684M and $858M, respectively, by 2026.