Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive and behavioral impairment that significantly interferes with social and occupational functioning.
Alzheimer's is a devastating disease affecting an estimated 50 million people worldwide. It is estimated that the number will reach 152 million in 2050.
The pathogenesis of AD has not yet been fully elucidated, and there are various descriptive hypotheses, including the amyloid/Aβ hypothesis (amyloid‐β is overproduced and aggregates to form amyloid plaques), Tau propagation hypothesis (Tau proteins are over-phosphorylated and then misfold to form neurofibrillary tangles), cholinergic hypothesis, calcium homeostasis hypothesis, neurovascular hypothesis, and inflammatory hypothesis, etc. Currently, most academics believe that Aβ plays a pivotal role in the pathogenesis of AD, and the main research works focused on decreasing Aβ as a key player in AD development and progression.
▲Figure 1. The amyloid hypothesis of Alzheimer's disease. Source: reference 
Currently, the drugs approved for marketing for AD can only moderately relieve patients' symptoms and have some adverse effects. Therefore, the development of a drug that is safe and can target the underlying causes of AD pathology to achieve a cure for AD is an ongoing quest for researchers.
AD Drug Development: Aducanumab, Lecanemab & Donanemab
It has been more than 30 years since the Aβ hypothesis was proposed, but AD drug development is still difficult. According to statistics, the failure rate of AD drug development is as high as 99.6%. At present, the cumulative global R&D investment in Alzheimer's disease has exceeded 600 billion dollars, but from 2003 to the present, only two AD drugs have been approved worldwide.
In 2021, the FDA granted accelerated approval for aducanumab (Aduhelm). In January 2023, lecanemab (Leqembi), developed by Eisai and Biogen, received accelerated approval from the FDA, and in July 2023, it received full FDA approval. Eli Lilly and Co. is seeking FDA approval for donanemab.
Aduhelm (aducanumab) is the first new FDA-approved therapy for the treatment of AD in nearly 20 years. Aducanumab is a high-affinity, fully human IgG1 monoclonal antibody against a conformational epitope found on Aβ. It selectively binds to amyloid deposits in the brains of AD patients and then removes the deposited protein from the brain by activating the immune system.
However, Biogen withdrew its application for marketing authorization of aducanumab in Europe in 2022. In fact, there is some controversy surrounding aducanumab since its approval.
Controversy 1: Conflicting results from two phase 3 trials
In March 2019, Biogen announced the discontinuation of the two global Phase 3 trials, ENGAGE and EMERGE, after an interim analysis found aducanumab failed to beat placebo and was deemed unable to improve cognitive function in AD patients. after an interim analysis found aducanumab failed to beat the placebo and was deemed unable to improve cognitive function in AD patients.
However, after analyzing a larger dataset, Biogen found that high-dose participants in EMERGE experienced a 23% reduction in decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at week 78 compared with placebo, reaching the primary endpoint. Additionally, on several other secondary endpoints, the high-dose aducanumab-treated group also showed a sustained reduction effect compared to placebo. Imaging data also showed significant reductions in amyloid plaque burden levels in the aducanumab-treated group at weeks 26 and 78 compared to the placebo group. In addition, the high-dose aducanumab treatment group also demonstrated a sustained reduction in several other secondary endpoints compared to placebo. Imaging data also showed significant reductions in amyloid plaques in the aducanumab-treated group at weeks 26 and 78 compared to the placebo group.
However, one of the major controversies surrounding the approval of aducanumab is precisely that the results of the two Phase 3 trials have been questioned as conflicting. While CDR-SB improved in the high-dose aducanumab patient group in the EMERGE study, no statistical difference was shown in the ENGAGE study, and the data showed that CDR-SB scores were worse in patients treated with high-dose Aducanumab.
The results of other scores assessing cognitive ability (MMSE, ADAS-Cog13, ADCS-ADL-MCI) showed similar contradictory results, with statistical differences in one group and not in the other, and even different trends of change in the two groups.
▲ Figure 2. EMERGE and ENGAGE Topline Results, source: reference 
Controversy 2: Unclear clinical benefits
Due to the discrepancy between the CDR-SB results of the two trials, the FDA approved aducanumab under the Accelerated Approval pathway based on the surrogate endpoint of reduction of amyloid beta plaque. After the surrogate endpoints were determined, the FDA conducted a number of data analyses based on trials of Aducanumab to assess efficacy, including a double-blind, randomized, placebo-controlled dose-ranging in patients with Alzheimer's disease. The results of the study showed a significant reduction in β-amyloid plaques in patients receiving the treatment, while amyloid plaques were not reduced in patients in the control group.
However, the controversy regarding aducanumab is not so much the correlation between the drug and β-amyloid plaques, but rather whether the choice of this surrogate endpoint is justified. Members of the Peripheral and Central Nervous System Drugs Advisory Committee, writing in the NEJM, have shown that, a number of clinical trials of the drug, which was developed on the basis of the Aβ hypothesis, have not provided substantial evidence that reduced β-amyloid predicts clinical benefit.
The data failed to convincingly demonstrate that the drug slowed the decline in patients' cognitive function, with no clear clinical benefit compared to the risk of drug-induced adverse events such as brain swelling or bleeding. According to data disclosed by Biogen, the incidence of serious adverse events in patients in the high-dose group was approximately 12%.
▲Figure 3. Safety summary of aducanumab, source: reference 
Lecanemab (Leqembi) is the first amyloid beta-directed antibody to be converted from an accelerated approval to a traditional approval for the treatment of Alzheimer's disease.
In January 2023, the FDA granted accelerated approval to lecanemab for the treatment of Alzheimer's disease based on reduction in amyloid beta plaques observed in patients. In July 2023, experts on an FDA advisory committee voted 6 to 0 in favor of fully approving lecanemab based on critical findings from Clarity AD (Study 301), a Phase 3 randomized, controlled clinical trial.
In the Clarity AD trial, lecanemab demonstrated a statistically significant and clinically meaningful reduction of decline from baseline to 18 months on the primary endpoint, the CDR-SB, compared to placebo. The change in mean CDR-SB scores was 27% lower at Week 79 compared to the placebo group.
▲Figure 4. Longitudinal Change From Baseline for CDR-SB, FAS+ Population, Study 301, source: FDA official website
In addition, the change in the primary endpoint, the CDR-SB score, was supported by consistent improvements in several secondary endpoints, including the ADAS-Cog 14 score, which independently assesses cognitive ability, and the ADCS-ADL-MCI score, which assesses activities of daily living. The FDA noted that these two clinical endpoints had been used as co-primary endpoints in other studies. The significant differences in these clinical endpoints further support the clinical relevance of improved CDR-SB scores.
▲Figure 5. Secondary Clinical Endpoint Analysis, source: FDA official website
In addition, in this study, biomarker studies showed a significant reduction in amyloid deposition in patient brains over time, reflecting the fact that lecanemab interacts with the target and affects downstream tau protein pathology and neurodegenerative lesions. This evidence also supports the clinical benefit of lecanemab.
▲Figure 6. Change From Baseline in Brain Amyloid (Centiloid), Study 301, source: FDA official website
In terms of safety, the main adverse event of concern was amyloid-related imaging abnormalities (ARIA). During the randomized, double-blind phase of this study, the percentage of patients who developed ARIA within 30 days of receiving treatment was 21% in the lecanemab group and 9% in the placebo group.
▲Figure 7. Most Common Treatment-Emergent SAEs, source: FDA official website
Donanemab is an investigational antibody that targets a modified form of beta-amyloid plaque called N3pG. By targeting N3pG beta amyloid, donanemab treatment has been shown to rapidly result in high levels of amyloid plaque clearance, as measured by amyloid imaging.
On July 17, 2023, Lilly announced complete results from the Phase 3 clinical study of TRAILBLAZER-ALZ 2, which showed that donanemab significantly slowed cognitive and functional decline in patients with early symptomatic Alzheimer's disease.
In this multicenter, randomized, double-blind, placebo-controlled, 18-month phase 3 trial, researchers analyzed 1,736 participants with early symptomatic Alzheimer's disease with amyloid and low/medium or high tau pathology. Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks.
The primary outcome was change in the iADRS score from baseline to 76 weeks in either the low/medium tau population or combined (low/medium and high tau) population. Prespecified secondary outcomes included changes from baseline to 76 weeks by sum of boxes of the Clinical Dementia Rating Scale (CDR-SB), the ADAS-Cog13, the ADCS-iADL, and MMSE in the low/medium tau or combined population.
The study showed that Donanemab met its primary and secondary endpoints in the Phase 3 study, with a significantly slowed decline by 35% on iADRS and 36% on CDR-SB in the low/medium tau population and 22% on iADRS and 29% on CDR-SB in combined populations,
▲Figure 8. iADRS and CDR-SB in low/medium tau population & combined population, source: reference 
Those participants treated with donanemab also had a 39% lower risk of progressing to the next clinical stage of disease over the 18-month trial.
In terms of safety, the study found that amyloid-related imaging abnormalities (ARIA) occurred in 36.8% of the Donanemab treatment group and resulted in ARIA-related deaths in three patients.
Lilly will continue to study donanemab in a number of clinical trials, including TRAILBLAZER-ALZ 3 - a trial focused on preventing the progression of symptomatic Alzheimer's disease in subjects with preclinical Alzheimer's disease, TRAILBLAZER-ALZ 5 --a registration study currently underway in China for early symptomatic Alzheimer's disease, and TRAILBLAZER-ALZ 6 - a trial to increase awareness of ARIA through new MRI sequences, blood biomarkers, and different dosing regimens of donanemab.
Despite the research advances made by antibody drugs in the treatment of Alzheimer's disease, there are still challenges. For example, one of the key issues in the treatment of Alzheimer's disease with antibodies is determining whether the antibody can cross the blood-brain barrier (BBB). The blood-brain barrier is a protective barrier that restricts the entry of most drugs and substances into the central nervous system. Therefore, future efforts are still needed to improve the design and optimization of antibody drugs to increase penetration, stability, and therapeutic efficacy.
Recently, lipid nanoparticles as drug delivery systems have gotten great attention. Biopharma PEG provides large-scale GMP manufacture of high-purity PEG derivatives and other lipids components, such as DSPE & Cholesterol, for LNPs for commercial applications and clinical trials.
 Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022;21(4):306-318. doi:10.1038/s41573-022-00391-w
 EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease https://investors.biogen.com/static-files/8e58afa4-ba37-4250-9a78-2ecfb63b1dcb
 FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval, Retrieved July 6, 2023, from https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
 Results from Lilly's Landmark Phase 3 Trial of Donanemab Presented at Alzheimer's Association Conference and Published in JAMA. Retrieved July 17, 2023 from https://investor.lilly.com/news-releases/news-release-details/results-lillys-landmark-phase-3-trial-donanemab-presented
 Donanemab in Early Symptomatic Alzheimer, DiseaseThe TRAILBLAZER-ALZ 2 Randomized Clinical Trial, https://jamanetwork.com/journals/jama/fullarticle/2807533