The phase III clinical study of AD new drugs obtained positive results, which can significantly alleviate cognitive decline

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All key secondary endpoints were also met, demonstrating highly statistically significant results
.

Lecanemab is a humanized anti-Aβ fibrillary monoclonal lgG1 antibody that targets the removal of toxic Aβ from the brain parmorandum by microglia for the treatment of Alzheimer's disease (AD) mild dementia and AD-derived mild cognitive dysfunction (MCI) (collectively known as early AD).


Today, Eisai and Biogen jointly announced important positive results from Lecanemab's large, global, confirmatory Phase III Clarity AD clinical study[1].

Figure 1: Article

Primary endpoints and critical secondary endpoints

All are statistically significant

       

The Phase III Clinical Clarity AD Study is a global randomized, double-blind, parallel, placebo-controlled study evaluating the clinical efficacy of new agents in 1795 patients with early-stage AD, with the primary endpoint being the clinical dementia score
of the Cognitive and Functional Scale (CDR-SB) at 18 months of treatment.
The treatment group was given 10 mg/kg lecanemab every two weeks, and subjects received either placebo or lecanemab
in a 1:1 ratio.
The baseline features of the placebo and lecanemab groups were similar and well-balanced
.

Studies have shown that Lecanemab treatment reached the primary endpoint, with a 27% reduction in CDR-SB score in the lecanemab group compared to placebo at 18 months (p=0.
00005).

In fact, from 6 months onwards, the CDR-SB score of the lecanemab group had a significant statistical change from baseline (all p-values were less than 0.
01)
compared to the placebo group.

It is worth noting that the results of all key secondary endpoints were highly statistically significant compared to the placebo group (p<0.
01<b17>).
Key secondary endpoints were changes in amyloid levels by positron emission tombosis (PET), AD assessment scale-cognitive subscale 14 (ADAS-cog14), AD composite score (ADCOMS), and AD collaborative study-ADCS-ADL-MCI score for people with mild cognitive impairment at 18 months of treatment compared with placebo group
.

In terms of safety, amyloid-associated imaging abnormalities-brain swelling (ARIA-E) are adverse events
associated with amyloid-targeted therapy.
Studies have shown that the incidence of lecanemab ARIA-E is 12.
5%, compared with 1.
7%
in the placebo group.
The incidence of symptomatic ARIA-E was 2.
8% in the lecanemab group and 0.
0%
in the placebo group.

The rate of ARIA-H (ARIA-microhemorrhage) was 17.
0% in the lecanemab group and 8.
7%
in the placebo group.
The incidence of symptomatic ARIA-H was 0.
7% in the lecanemab group and 0.
2%
in the placebo group.
In addition, there was no difference
in isolated ARIA-H between lecanemab (8.
8%) and placebo (i.
e.
, ARIA-H patients did not develop ARIA-E).

Overall, the total incidence of ARIA (ARIA-E and / or ARIA-H) was 21.
3% in the lecanemab group and 9.
3% in the placebo group, and the incidence of ARIA in lecanemab was within the expected range
.

In addition, Lecanemab's detailed findings will be published in a peer-reviewed medical journal
in November this year.

It is reported that the US FDA has accepted the drug Biological Product Licensing Application (BLA) and granted priority review qualifications, and is expected to make a decision
before January 6, 2023.
If the results are positive, the company will also file a traditional approval application with the FDA by March and will apply for approval
in Japan and Europe.

Review of previous studies

       

The results of the Lecanemab Phase II clinical study showed that at 12 months, 10 mg/kg was treated every two weeks, and the ADCOMS showed that 64% of patients achieved clinically significant efficacy (at least 25% better than placebo).

And after the Core, the reduction in amyloid after Lecanemab treatment remained unchanged during an average of about two years of discontinuation (Figure 2
).

Figure 2: Detailed information
Lecanemab Phase II extended phase clinical trial results show that the 18-month core phase (18 months) and open extended period (up to 60 months) plasma Aβ42/40 ratios can track the effect of Lecanemab on brain Aβ clearance, or correlated with clinical outcomes (Figure 2), and the findings support the use of plasma Aβ42/40 ratios to monitor the
。
It can also be seen that during the gap period (discontinuation of the drug for an average of 24 months), the difference between the treatment group and the placebo group persisted
.
The results also suggest that continued administration is beneficial in maintaining the effectiveness of Lecanemab therapy[2].


Figure 3: Average changes in the Aβ42/40 ratio of Lecanemab treatment core phase, open extension period and discontinuation period[2]
★ Experts comment that


the total number of Alzheimer's disease (AD) patients worldwide exceeds 50 million, if there is no effective treatment, That number could rise to 139 million
by 2050.
At present, the AD drugs used in clinical practice are mainly cholinesterase inhibitors for the whole process of AD dementia and NMDA receptor antagonists in the middle and severe stages of dementia, although these drugs can partially improve symptoms, but can not delay the course of
the disease.
Therefore, disease modification drugs that delay the course of AD are the focus of
AD drug development in recent years.

The pathological changes in the AD core are β-amyloid (Aβ) deposition leading to the formation of age spots and tau protein hyperphosphorylation leading to nerve fiber tangles, while Aβ occurs first, more upstream
throughout the pathological process.

Although there are many hypotheses about the onset of AD, the Aβ cascade waterfall hypothesis is still dominant
.
Therefore, the development of AD disease modulation drugs is mainly based on this pathogenesis hypothesis, trying to delay the course
of AD by clearing the abnormal deposition of Aβ in the early brain of AD.

Lecanemab, jointly developed by Eisai and Bojian, is a humanized anti-Aβ fibrillary monoclonal antibody that can selectively neutralize and remove soluble and toxic β-amyloid (Aβ) aggregates that cause AD neuropathy, which may have a positive effect on the pathological process of AD and slow down the disease progression
.

Today, Lecanemab's Phase III Clarity AD clinical study results are published, the primary endpoint and all key secondary endpoints have reached the results, and the results are statistically significant, which is another epoch-making new achievement
in the field of AD treatment.

It should be emphasized here that this study was for early AD including mild AD dementia and AD-derived mild cognitive dysfunction (MCI), and is not suitable for patients with AD dementia at all stages
.
At the same time, the success of this research also puts forward a more urgent need
for early and accurate diagnosis of biomarker-based AD in the future.

Other similar drugs for the early Aβ clearance of AD include Roche's Gantenerumab and Eli Lilly's Donanemab, whose previous clinical trials have also shown very good results, and have also been recognized as breakthrough therapies by the US FDA, and are conducting global multi-center phase III clinical trials, and the results are also very much worth looking forward to
.

Expert profile

Yu Jintai

• Professor of Neurology, Chief Physician and Doctoral Supervisor of Huashan Hospital Affiliated to Fudan University

• Executive Deputy Director of Institute of Neurology, Fudan University

• Leader of the subspecialty of cognitive impairment

• He is a member of the Behavioral Medicine Branch of the Chinese Medical Association

• Deputy Leader of the Neuropsychology and Behavior Group of the Neurology Branch of the Chinese Medical Association

• Editor-in-chief of Brain Disorders Journal, Youth Vice Chairman of the Neurology Branch of the Chinese Medical Association, and Associate Editor of Ann Transl Med Journal

• He has presided over a number of national natural science foundation and major program projects, led the development of international guidelines for evidence-based prevention of Alzheimer's disease, and published many academic papers in top journals such as Lancet Neurology and Alzheimers Dement

• He is good at the clinical diagnosis and treatment of memory loss, brain atrophy, walking instability, various dementias, and Parkinson's syndrome

Reference source:

[1] lecanemab-confirmatory-phase-3-clarity-ad-study-met-primary-endpoint-showing-highly-statistically-significant-reduction-of-clinical-decline-in-large-global-clinical-study-of-1-795-participants-with-early-alzh eimers-disease-301634888.
html

[2] Akihiko Koyama.
Plasma Aβ42:40 Ratio Tracks with Changes in Brain Amyloid PET SUVr in the Core and Open Label Extension of the Phase Proof of Concept Study BAN2401-G000-201 Following Treatment with Lecanemab in Subjects with Early Alzheimer’s Disease.
Data Presentation at Alzheimer's Association International Conference 2021.
Retrieved Aug 11,2021,fromhttps://alz.
confex.
com/ alz/2021/meetingapp.
cgi/Paper/57760.

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Source of this articleMedical Neurology Channel Xizi This article reviewYu Jintai Responsible editor of Huashan Hospital
affiliated to Fudan University Mr.
Lu Li Xiang Yu

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