Author (Year) Purpose and Intervention Results and Findings Conclusions
Alexander et al.[@102141] (2021) The efficacy of aducanumab for the treatment of AD is evaluated using outcomes from aducanumab’s phase I and phase III clinical trials. After supplementary data was incorporated following phase III trials being halted, Emerge met its primary goal (P = 0.01). An FDA advisory committee voted by majority that results from Emerge and Engage failed to demonstrate that aducanumab deserved FDA approval. The post hoc analyses for Engage and Emerge increase the likelihood of introduction of bias into data review and interpretation. Data from Emerge and Engage may not provide enough evidence to support FDA approval of aducanumab to outweigh the fact that both trials were halted for evidence of futility.
Avgerinos et al.[@102136] (2021) This meta-analysis and systematic review evaluated the risks and benefits associated with phase III clinical trials using monoclonal anti-Aß antibodies for the treatment of AD. Data from 17 studies (2 on gantenerumab, 3 on solanezumab, 6 on bapineuzumab, and 4 on aducanumab) involving 12 phase III clinical trials are included. Aducanumab was found to have the greatest risk of ARIA-E of any anti-Aß immunotherapeutic antibody developed. Aducanumab is the only monoclonal anti-Aß antibody that has been found to significantly reduce Aß PET SUVR (P < 0.05). Aducanumab improved patient CDR-SB and ADCS-ADL scores with an effect size of < 0.2. Aducanumab showed the most benefit in treating AD pathology and symptoms among the anti-Aß antibodies available based on biomarker and clinical symptom improvement.
Cummings et al.[@102139] (2021) Data from aducanumab’s Phase III Engage and Emerge trials are compared to findings from other phase III AD-modifying monoclonal antibody drug trials. Patients receiving high-dose aducanumab in the Emerge trial experienced an 87% decrease from baseline in NPI. High-dose patients in the Emerge trial also experienced a ~40% improvement in ADCS-ADL score relative to placebo patients. Trials for other anti-Aß monoclonal antibodies for the treatment of AD have shown dose-dependent effects like the pattern observed in the Emerge trial. The Emerge trial demonstrated clinical benefit in the treatment of AD, and its findings are supported by findings in similar studies.
Knopman et al.[@102138] (2021) The significance of findings from Engage and Emerge are evaluated. Both Emerge and Engage showed a dose-dependent reduction in size of Aß plaques relative to placebo based on PET SUVR (P < 0.001). After post-hoc analysis, Emerge met its primary target in reducing cognitive decline while Engage did not. Another Phase III clinical trial may be necessary to confirm the efficacy of high-dose aducanumab demonstrated in the Emerge trial.
Kuller and Lopez[@102140] (2021) The validity of findings from Engage and Emerge is determined. Further steps in verification of aducanumab as a therapy for AD are examined. Emerge is the first phase III clinical trial where an anti-Aß monoclonal antibody immunotherapy has been able to show slowing of cognitive impairment in patients suffering from AD or MCI. Possible confounding variables in Engage were identified including a lower number of high-dose patients and the presence of outliers. Patients from the Engage and Emerge trials should be evaluated long-term to observe the effects of aducanumab. Another phase III clinical trial using high-dose aducanumab is warranted.
Howard and Liu[@102137] (2020) The validity of interpretations from phase I and phase III trials regarding aducanumab for the treatment of AD is analyzed. To show significant clinical benefit, AD treatment must show an average difference in CDR-SB score of 1 point for patients with MCI and 2 points for patients with mild AD. Neither high-dose group from Engage nor Emerge reached a 1-point difference from placebo patients. Aducanumab’s efficacy at degrading Aß plaques was supported in both phase III trials. Phase III clinical trials for aducanumab did not show clinically significant benefit for AD patients in terms of CDR-SB score.
Tian Hui Kwan et al.[@102135] (2020) Findings from multiple Aß-targeted monoclonal antibody therapies that entered phase III clinical trials are compared. These drug therapies include crenezumab, gantenerumab, solanezumab, and aducanumab. Aducanumab was found to have positive dose-dependent clinical benefit in its Phase Ib study. Data from high-dose aducanumab patients in the Emerge and Engage trials showed an average improvement in CDR-SB of 23% (P = 0.010) and -2% (P = 0.825) respectively. The average score improvement in CDR-SB observed in patients in the Emerge trial was by a score of 0.4 points on an 18-point scale. Aducanumab’s Engage and Emerge trials show conflicting results, and the Emerge trial’s findings may be of little clinical significance.
Mo et al.[@102134] (2017) This meta-analysis and systemic review evaluates the safety and efficacy of monoclonal anti-Aß antibodies for the treatment of AD. ARIA-E was one of the most reported side effects, but no deaths were reported in the Phase Ib clinical trial for aducanumab. Aducanumab significantly improved MMSE scores in patients with MCI or mild AD relative to placebo in the Prime trial. Aducanumab was not found to significantly improve patients’ DAD or ADAS-cog13 scores. Aducanumab’s phase Ib clinical trial showed that aducanumab may help prevent cognitive decline in AD patients and significantly increase one’s risk of developing ARIA-E.
Gamage and Kumar[@102132] (2017) The role of calcium dysregulation in neurodegenerative disorders, such as AD, and how aducanumab may alter dysfunction. Aß plaques increase the clearance of NMDA receptors from neurons’ cell surfaces, which contributes to disruption in Ca2+ permeability. Aducanumab has been able to decrease Aß plaque size in human and mouse trials. Aducanumab was found to significantly recover SERCA pump regulation which was disrupted in transgenic mice with Aß plaques (P < 0.001). Aducanumab may improve neurological function in patients with neurodegenerative diseases caused by Aß plaques by restoring function of NMDA receptors and SERCA pumps.
Kastanenka et al.[@102131] (2016) Transgenic mice overexpressing amyloid precursor protein were grown and treated acutely with topical administration of an aducanumab analog directly to the brain (0.42-1 mg/ml) or were treated weekly with 10 mg/kg aducanumab for 6 months. Each mouse’s brain was imaged using fluorescent microscopy to tag Aß plaques, and biomarkers were measured before and after treatment. Acute topical treatment with aducanumab analog significantly reduced the number of Aß plaques at a greater rate than the reduction observed in control mice (P < 0.0001). Chronic treatment with aducanumab analog did not show significant reduction in the number of Aß plaques (P = 0.35). Mice that received chronic treatment had a lower incidence of calcium overload (P < 0.05) and increased calcium permeability relative to controls (P < 0.05). Aducanumab may decrease the rate of cognitive decline in AD patients not only by degradation of Aß plaques but by re-establishing physiological intracellular calcium levels.
Ferrero et al.[@102133] (2016) Aducanumab was studied in a single-dose-escalation, placebo-controlled, randomized, double-blind phase I clinical study. This study included 53 patients with mild or moderate AD who received placebo or 0.3, 1, 3, 10, 20, 30, or 60 mg/kg doses of aducanumab and were followed up to 24 weeks after receiving treatment. All 3 patients who received 60 mg/kg of aducanumab developed ARIA-E which ultimately resolved. Pharmacokinetic findings indicated that increasing dosage did not alter the rate of clearance, half-life, or volume of distribution of aducanumab. ARIA-E was the most severe adverse effect observed, with most other adverse effects being constitutional complaints. The only observed severe adverse effect in this study was ARIA-E which has been associated with other monoclonal anti-Aß antibody immunotherapies.
Sevigny et al.[@102124] (2016) Aducanumab was studied in a placebo-controlled, randomized, double-blind phase Ib trial including 165 patients. These participants with MCI or mild AD were administered 1, 3, 6, or 10 mg/kg of aducanumab monthly for 12 months. Aducanumab reduced cognitive decline in AD patients that received 3 or 10 mg/kg of aducanumab based on MMSE (P < 0.05). 41% of participants receiving 10 mg/kg aducanumab developed ARIA-E. PET SUVR score was lowered relative to baseline in patients that received 10, 6, and 3 mg/kg of aducanumab (P < 0.001). Aducanumab sufficiently crosses the BBB to aid in the degradation of Aß plaques in a dose-dependent manner in AD patients.