On September 24th, the 24th National Conference on Neurology of the Chinese Medical Association was in full swing in Zhuhai. This academic session is cordially invited
Professor Zhang Wei of Beijing Tiantan Hospital affiliated to Capital Medical University served as the moderator of the conference, and invited Professor Shen Lu of Xiangya Hospital of Central South University to make a wonderful keynote speech on "Progress in The Treatment of Alzheimer's Disease (AD) Anti-β Amyloid"
。 This article will provide a brief summary of the highlights for the benefit of the reader.
Professor Shen Lu, Xiangya Hospital, Central South University
Amyloid plaques caused by Aβ aggregation are one of the pathological features of AD
Amyloid plaques caused by Aβ aggregation are one of the pathological features of AD. Biologically, AD is defined as two signature protein lesions: extraneural β-amyloid (Aβ) plaques and intraneuronal nerve fiber tangles (composed of overphosphorylated tau proteins). Pathologies caused by Aβ pathology in the brain include inflammatory responses, synaptic dysfunction, and nerve fiber tangles (see Figure 1).
Figure 1
The FDA accelerates approval of Aducanumab as the world's first and only treatment for defining the pathological mechanism of AD
On August 7, 2020, the U.S. FDA announced that the Aducanumab Biologics Licensing Application (BLA) was given priority review. On June 7, 2021, the FDA approved Aducanumab for the treatment of AD patients through an expedited approval channel, and updated the instructions for Aducanumab on July 8, 2021, limiting the drug to AD-derived MCI and mild AD patients.
Aducanumab is a recombinant human antibody expressed in the Chinese hamster ovarian cell line (41-3D17), purified to obtain high purity, and made into a liquid preparation. Aducanumab's development utilizes a patented technology platform for reverse-transformative drugs ™ (Neurimmune, Switzerland, Zurich), which reverses the identification of antibody clones that are reactive to Aβ aggregates by collecting memory B cells from healthy older adults and elderly people with abnormally slow cognitive decline, and finally recombinant expression to form Aducanumab. Aducanumab slows the progression of the disease by removing Aβ oligomers, fibrous, and amyloid plaques against the pathological mechanisms of AD (see Figure 2).
Figure 2
Aducanumab clinical development history
1. PRIME study – exploring the optimal dosage of Aducanumab
The PRIME study was a 12-month randomized, multicenter, double-blind, placebo-controlled study that assessed the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of Aducanumab primarily in patients with AD. The primary endpoints of the study were to assess the safety and tolerability of Aducanumab, the secondary endpoints were serum PK, immunogenicity, and changes in week 26 amyloid PET, and exploratory endpoints included CDR-SB score, MMSE score, and changes in amyloid PET at week 54.
The results of this study show that Aducanumab can be effective in reducing amyloid plaque, showing dose and time dependence (see Figure 3). Fixed dose analysis of the 48-month extended study showed that Aducanumab was effective in long-term stable clearance of Aβ plaque (see Figure 4) and significantly delayed clinical decline in cognitive function (see Figure 5).
Figure 3
Figure 4
Note: The ordinate coordinate represents the effect of Aducanumab on Aβ plaques – based on PET SUVR measurements
Figure 5
Note: The ordinate represents the effect of Aducanumab on clinical decline – based on CDR-SB measurements
2. ENGAGE and EMERGE study – DESIGN OPTIMIZATION BASED ON PRIME TO IMPROVE THE PROBABILITY OF SUCCESS OF PHASE III STUDIES
Two phase III studies in Aducanumab—ENGAGE and EMERGE studies—were randomized, double-blind, placebo-controlled studies for 18 months. A total of 3285 patients with early-stage Alzheimer's disease (MCI + mild Alzheimer's disease dementia) from 20 countries, 348 research centers were enrolled, and the primary endpoint of the study was CDR-SB score at 18 months, the secondary endpoint was MMSE, ADAS-Cog13, ADCS-ADL-MCI score, and the sub-study endpoint was amyloid PET, tau protein PET, CSF disease-related biomarkers.
3. Results of the ENGAGE and EMERGE studies
The RESULTS of the EMERGE study showed that the Aducanumab high-dose group achieved multiple clinical endpoints of cognitive function, functional independence, and neuropsychiatric dimensions at week 78 (see Figures 6 and 7), and β amyloid PET testing showed a 71% reduction in β amyloid in the Aducanumab high-dose group compared to baseline (see Figure 8), which confirmed the binding effect of Aducanumab's dose-dependent targeting. Both EMERGE and PRIME studies have shown that the magnitude of Aβ reduction is strongly associated with slowing clinical exacerbations (see Figure 9).
Figure 6
Figure 7
Figure 8
Note: The ordinate indicates that the amyloid PET detection β shows the corrected mean of the Aducanumab group that has changed from baseline
Figure 9
CSF biomarker detection in the EMERGE study showed that Aducanumab treatment for 78 weeks increased Aβ1-42 levels compared to baseline levels, low-dose and high-dose groups, and p-tau and t-tau levels decreased, especially in the high-dose group (see Figure 10), suggesting that Aducanumab treatment improved A/T/N biomarker levels in AD cerebrospinal fluid across the board.
Figure 10
Although the ENGE study did not reach primary and secondary clinical endpoints, a dose-dependent decrease in amyloid in the brain of patients in the treatment group was observed under PET (see Figure 11). The reasons for the incomplete consistency of the results of the two phase III are related to the low overall exposure of 10 mg/kg administered in the ENGAGE high-dose group (caused by modification of the study protocol) and the uneven number and distribution of patients with rapidly progressive Alzheimer's disease.
Figure 11
In addition, in the subgroup analysis of the ENGAGE study, patients who received ≥ 10 non-disruptive 10 mg/kg dose infusions in a steady state had a slower decline in CDR-SB than in the placebo group, which was consistent with the results of the EMERGE study (see Figure 12), suggesting that Aducanumab infusion delayed disease progression in patients.
Figure 12
4. Safety findings of engage and EMERGE studies
During the ENGAGE and EMERGE studies, the incidence of AREA-E in the Aducanumab-treated group increased compared with placebo, but the majority of patients (74% in the Aducanumab10 mg/kg group) ARIA-E were asymptomatic. The most common ARIA-E symptoms were headache, confusion, dizziness, and nausea, with most symptoms being mild (67.7%) or moderate (28.3%) in clinical severity and 98% relieved over the course of the study (see Figure 13).
Figure 13
Aducanumab treatment results for long-term healthy outcomes
The latest results of long-term health outcomes for Aducanumab treatment predicted by the model show that the addition of Aducanumab treatment may not only reduce the proportion of patients who progress to a more severe stage or be hospitalized (see Figure 14), but may also delay the progression of dementia in MCI patients compared with standard therapy alone (see Figure 15).
Figure 14
Figure 15
summary
➤ Amyloid plaques caused by Aβ aggregation are key factors in the formation and development of AD.
➤ Aducanumab is currently the world's first and only FDA-approved IgG1 anti-Aβ monoclonal antibody against humans with a defined pathological mechanism of AD.
➤PRIME study showed that Aducanumab was able to reduce amyloid in patients with AD prodromal and mild AD, delay cognitive decline, and extend the data by 48 months to further confirm its long-term stable effectiveness.
➤ENGAGE and EMERGE studies have shown that Aducanumab can effectively slow down the clinical deterioration of cognitive function, functional independence and neuropsychiatric multi-dimensional aspects of AD in patients with AD-derived MCI and mild AD, reduce plaque load, and be well tolerated.
➤ Long-term health outcomes predicted by the model for Aducanumab treatment suggest that Aducanumab may delay the progression of dementia in patients with MCI up to 2.82 years.