Shanghai prescribes the first targeted new drug in China, precise treatment of Alzheimer's disease to delay progression

On the 26th, the highly anticipated new drug for targeted treatment of Alzheimer's disease, Lencanetumab, was officially prescribed for the first time at the National Center for Neurological Diseases - Huashan Hospital Affiliated to Fudan University. The first six patients diagnosed with early AD at Huashan Hospital will receive a treatment cycle of 18 months, with two monthly infusions of Lencanetumab. This progress marks a new stage in my country's precision treatment of AD, and indicates that more efficient and personalized treatment plans will benefit more people with early AD.

my country is one of the countries with the largest number of AD patients in the world. According to the "2022 China Alzheimer's Disease Report", there are 38.77 million people aged 60 and above with mild cognitive impairment and approximately 15.07 million patients with dementia, of which 13 million are patients with AD-related mild cognitive impairment and 9.83 million are patients with AD dementia.

Precision targeted therapy, currently approved for marketing in four countries

Lencanicumab is the world's first new AD drug fully approved by the U.S. Food and Drug Administration in 20 years. It is an anti-β-amyloid protein drug that removes toxic Aβ protein from the brain, reverses the pathological progression of AD, and delays the clinical course. On January 9 this year, Lencanicumab was approved by my country's National Medical Products Administration. Currently, there are four countries in the world that have approved the drug for marketing.

According to the clinical staging of international guidelines, the course of AD can be divided into three stages: preclinical stage, mild cognitive impairment stage and dementia stage. The current clinical indication of Lencanermab is early-stage AD patients, mainly including patients with mild cognitive impairment caused by AD and early-stage AD dementia patients.

Yu Jintai, chief physician and head of the cognitive impairment subspecialty of the Department of Neurology at Huashan Hospital, said that the etiology of AD is complex and the pathogenesis is not yet fully understood, but the "amyloid cascade hypothesis" is currently the most recognized mainstream hypothesis in the scientific community. The hypothesis holds that due to excessive production or untimely removal of Aβ amyloid protein, soluble Aβ oligomers and insoluble amyloid protein are deposited in the brain to form amyloid plaques, which in turn leads to the pathological expansion of tau protein and ultimately neuronal dysfunction and death. Based on this hypothesis, the core of Aβ targeted therapy is to reduce the level of Aβ in the brain to non-pathogenic levels, thereby bringing clinical benefits.

In recent years, the successful clinical trials of several new Aβ targeted biological agents, including lencanel and donetumab, have further confirmed the correctness of the "amyloid cascade hypothesis" and brought breakthrough progress in the field of AD treatment.

Data from the Phase III clinical trial of lencanezumab published in the New England Journal of Medicine at the end of 2022 showed that after 18 months of medication, the rate of decline in cognitive and memory function in the lencanezumab group was 27% slower than that in the placebo group. Simulation model evaluation data published in Neurology and Therapy in April 2023 showed that the combined use of lencanezumab and cholinesterase inhibitors can delay the progression of AD patients by an average of 2 to 3 years.

In addition, ARIA is a common side effect of current Aβ antibody drugs, which may cause adverse reactions such as cerebral edema and cerebral hemorrhage. Phase III clinical trial data showed that the incidence of ARIA-E of lencanezumab was 12.6%, the incidence of symptomatic ARIA-E was 2.8%, and the incidence of ARIA-H was 17.3%. Therefore, patients need to undergo regular MRI examinations after treatment to monitor risks in real time.

Which patients are suitable for lencanezumab? Yu Jintai said that the following four steps are needed to assess whether a patient is suitable for use:

1. The patient has symptoms of cognitive decline and is confirmed to be an early-stage patient through neuropsychological assessment;

2. Medical history, physical examination, blood and brain MRI tests suggest that cognitive impairment may be caused by AD, and other contraindications are excluded;

3. AD was diagnosed by brain positron emission tomography or cerebrospinal fluid testing;

4. APOE genotype testing is used to assess the risk of side effects.

He also emphasized that AD is a chronic disease that gradually worsens, and the use of new drugs is only for early AD patients who have been accurately diagnosed with biomarkers, that is, patients who only have mild clinical symptoms but whose ability to take care of themselves in daily life is not affected or is only slightly affected.

It is understood that with the introduction of lencanezumab, the cognitive impairment team of Huashan Hospital will also launch a new clinical study to explore the "cure both the symptoms and the root causes" effect of the combined use of beta-amyloid antibody drugs and symptom-improving drugs.

In order to improve the early detection rate and overall diagnosis and treatment efficiency of AD patients, relying on the major project of "Brain Science and Brain-like Research" under the Science and Technology Innovation 2030 led by Professor Yu Jintai, a community brain health aging cohort has been established nationwide to build an integrated "community-outpatient-ward" full-service system to solve bottleneck problems such as early screening, early diagnosis and early intervention. As early as 2020, the team took the lead in formulating the world's first international evidence-based prevention guideline for AD, which proposed that at least 40% of AD cases can be prevented through 21 methods including vascular risk factor control and healthy lifestyle.

"The clinical use of new drugs for targeted precision treatment of AD is just the beginning. With theoretical breakthroughs in basic research, precise diagnosis and continuous deepening of targeted drug research and development, this field is full of infinite possibilities. AD has every hope of becoming a disease that can be conquered in the future," the expert concluded.