Professor Lu Shen: Progress in anti-β-amyloid therapy for Alzheimer's disease NCN2021

On September 24, the 24th National Neurology Conference of the Chinese Medical Association was in full swing in Zhuhai
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This academic session sincerely invites Professor Zhang Wei from Beijing Tiantan Hospital, Capital Medical University, as the host of the conference, and invites Professor Shen Lu from Xiangya Hospital of Central South University to discuss "Alzheimer's disease (AD) anti-β-amyloid protein" "Treatment Progress" made a wonderful theme report
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This article will briefly summarize the wonderful content for readers
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Amyloid plaques caused by Aβ aggregation is one of the pathological features of AD, Xiangya Hospital of Central South University Professor Shen Lu Amyloid plaques caused by Aβ aggregation is one of the pathological features of AD
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From a biological point of view, AD is defined as two hallmark protein lesions: extraneuronal β-amyloid (Aβ) plaques and intraneuronal neurofibrillary tangles (consisting of hyperphosphorylated tau protein)
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The pathological changes caused by Aβ in the brain include inflammation, synaptic dysfunction, and neurofibrillary tangles (see Figure 1)
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Figure 1 FDA accelerated the approval of Aducanumab as the world's first and only treatment for AD with a clear pathological mechanism.
On August 7, 2020, the U.
S.
FDA announced that the Aducanumab Biologics License Application (BLA) has received priority review
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On June 7, 2021, the FDA approved Aducanumab for the treatment of AD patients through an accelerated approval route, and updated the Aducanumab instructions on July 8, 2021, restricting the drug users to AD-derived MCI and mild AD patients
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Aducanumab is a recombinant human antibody expressed in a Chinese hamster ovary cell line (41-3D17), purified to obtain high purity, and made into a liquid preparation
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The research and development of Aducanumab utilizes the patented technology platform of Reverse Transformation Medicine™ (Neurimmune, Switzerland, Zurich), which collects memory B cells of healthy and slow cognitive decline, and reversely recognizes that it has the potential for Aβ aggregates.
Reactive antibody clone, and finally recombinant expression to form Aducanumab
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Aducanumab can eliminate Aβ oligomers, fibers and amyloid plaques according to the pathological mechanism of AD, thereby slowing down the progression of the disease (see Figure 2)
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Figure 2 Aducanumab clinical development process 1.
PRIME study-exploring the optimal dose of Aducanumab PRIME study is a 12-month randomized, multi-center, double-blind, placebo-controlled study, the study mainly evaluates Aducanumab in AD patients Safety, tolerability, pharmacokinetics and pharmacodynamic effects
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The primary endpoint of the study is to evaluate the safety and tolerability of Aducanumab.
The secondary endpoints are serum PK, immunogenicity, and changes in amyloid PET at week 26.
The exploratory endpoints include CDR-SB score, MMSE score, and the first Changes of amyloid PET at 54 weeks
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The results of this study show that Aducanumab can effectively reduce amyloid plaques in a dose- and time-dependent manner (see Figure 3)
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The fixed-dose analysis of the extended 48-month study showed that Aducanumab can effectively and stably remove Aβ plaques for a long time (see Figure 4) and can significantly delay the clinical decline of cognitive function (see Figure 5)
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Figure 3 Figure 4 Note: The ordinate represents the effect of Aducanumab on Aβ plaques-based on PET SUVR measurement results Figure 5 Note: The ordinate represents the effect of Aducanumab on clinical decline-based on the CDR-SB measurement results 2.
ENGAGE and EMERGE studies ——Design optimization based on PRIME to increase the probability of success of Phase III studies.
Aducanumab's two Phase III studies—ENGAGE and EMERGE studies—are randomized, double-blind, placebo-controlled studies and last for 18 months
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The study included 20 countries, 348 research centers, and 3285 patients with early Alzheimer's disease (MCI due to Alzheimer's disease + mild Alzheimer's disease dementia).
The primary end point of the study was 18 months The secondary endpoints are MMSE, ADAS-Cog13, ADCS-ADL-MCI scores, and the sub-study endpoints are amyloid PET, tau protein PET, and CSF disease-related biomarkers
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3.
Effectiveness results of the ENGAGE and EMERGE studies The results of the EMERGE study show that the high-dose Aducanumab group can reach the clinical endpoints of cognitive function, functional independence, and neuropsychiatry in the 78th week (see Figures 6 and 7), β starch The PET test of Aducanumab showed that the beta amyloid in the high-dose Aducanumab group was reduced by 71% compared to the baseline (see Figure 8), which confirmed the dose-dependent targeted binding effect of Aducanumab
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Both EMERGE and PRIME studies show that the reduction in Aβ is strongly correlated with slowing down clinical deterioration (see Figure 9)
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Fig.
6 Fig.
7 Fig.
8 Note: The ordinate represents the corrected mean of the changes from baseline in the Aducanumab group by β-amyloid PET detection.
The levels of Aβ1-42 in the high-dose group increased, and the levels of p-tau and t-tau decreased, especially in the high-dose group (see Figure 10), suggesting that Aducanumab treatment improved the levels of AD CSF A/T/N biomarkers.

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Figure 10 Although the ENGAGE study did not reach the primary and secondary clinical endpoints, a dose-dependent decrease in brain amyloid in the treatment group was still observed under PET (see Figure 11)
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The reasons for the inconsistency of the two phase III results are the lower overall exposure of the ENGAGE high-dose group at 10 mg/kg (caused by the modification of the study protocol), and the number and number of patients with rapidly progressing Alzheimer’s disease Uneven distribution is related
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Figure 11 In addition, in the subgroup analysis of the ENGAGE study, patients who received ≥10 infusions of 10 mg/kg without interruption in the steady state had a slower decline in CDR-SB than the placebo group, which is consistent with the results of the EMERGE study (See Figure 12), suggesting that Aducanumab infusion delayed the patient's disease progression
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Figure 124.
Safety results of the ENGAGE and EMERGE studies During the ENGAGE and EMERGE studies, the incidence of AREA-E in the Aducanumab treatment group was higher than that of placebo, but most patients (74% in the Aducanumab 10 mg/kg group) ARIA-E did not Symptoms
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The most common symptoms of ARIA-E are headache, confusion, dizziness, and nausea.
The clinical severity of most symptoms is mild (67.
7%) or moderate (28.
3%), and 98% were relieved during the study (see Figure 13)
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Figure 13 Long-term health outcomes of Aducanumab treatment The latest results of the long-term health outcomes of Aducanumab treatment predicted by the model show that compared with standard treatment alone, the addition of Aducanumab treatment may not only reduce the proportion of patients who progress to more severe stages of AD or are hospitalized (see Figure 14) It may also delay the progression of dementia in MCI patients (see Figure 15)
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Figure 14 Figure 15 Summary ➤ Amyloid plaque caused by Aβ aggregation is a key factor in the formation and development of AD
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➤ Aducanumab is currently the world's first and only human IgG1 anti-Aβ monoclonal antibody with a clear pathological mechanism for AD approved by the FDA
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➤PRIME research shows: Aducanumab can reduce the amyloid in patients with prodromal AD and mild AD, delay the decline of cognitive function, and extend the data for 48 months to further confirm its long-term stable effectiveness
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➤ENGAGE and EMERGE research shows: Aducanumab can effectively slow down the clinical deterioration of AD-derived MCI and mild AD patients in multiple dimensions of cognitive function, functional independence and neuropsychiatry, reduce plaque load, and is well tolerated
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➤The long-term health outcomes of Aducanumab treatment predicted by the model show that Aducanumab may delay the progression of dementia in MCI patients up to 2.
82 years
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