New Beijing News (Reporter Zhang Zhaohui) Recently, the Medicines Committee of the European Medicines Agency stated that it does not recommend the marketing authorization application for the Alzheimer's disease drug lencanavir monoclonal antibody from Eisai and Bojian.
The European Medicines Agency's Committee for Medicinal Products for Human Use believes that although lencanazumab may delay cognitive decline, its benefits are not sufficient to compensate for the potential risks of serious side effects, especially the frequent occurrence of amyloid related imaging abnormalities, which involve brain swelling and possible bleeding.
No related side effects have been detected domestically
Lenvatinib is the world's first AD drug to receive full approval from the US Food and Drug Administration (FDA) in 20 years. It is an anti beta amyloid (A β) drug that reverses the pathological progression of AD and delays clinical progress by clearing toxic A β proteins in the brain. On January 9, 2024, lencanavir monoclonal antibody was approved by the National Medical Products Administration. Currently, there are four countries worldwide that have approved the drug for marketing.
However, since its approval in the United States, the drug has also been under review. The US FDA requires a warning about the side effects associated with the use of this drug and brain diseases.
On June 26th of this year, Lenvatinib monoclonal antibody was prescribed as the "first prescription" in China by Professor Yu Jintai from the Department of Neurology at Huashan Hospital affiliated with Fudan University. The first batch of 6 patients diagnosed with early-stage Alzheimer's disease (AD) at Huashan Hospital will receive a treatment cycle of 18 months, with two infusions of lencanavir monoclonal antibody per month. Yu Jintai told the media that among the dozens of patients who have already taken medication, no related brain swelling side effects have been detected.
The Alzheimer's disease drugs currently used in clinical practice are symptomatic treatments that improve symptoms such as insomnia and depression in patients. And lencanavir monoclonal antibody directly targets the etiology in terms of mechanism, that is, it can clear the amyloid deposition in the brain, the culprit of Alzheimer's disease. According to Phase III clinical data, the use of this drug can delay disease progression by an average of 3 to 5 years. However, experts remind that the use of this drug must be diagnosed with "Alzheimer's disease" through PET-CT, cerebrospinal fluid puncture testing, and other examinations, and must be in the early stage without contraindications such as cerebral hemorrhage.
The EU regulatory authorities believe that there are three main issues with lencanazumab. Firstly, the 18 point scale used to measure functions such as memory and problem-solving in the trial showed that there was very little absolute difference between patients receiving lencanazumab treatment and those receiving placebo treatment; Secondly, there have been cases of brain swelling and cerebral hemorrhage in clinical trials, leading to hospitalization of some patients; The third is that people with two copies of the APOE4 gene have a higher risk of brain swelling and bleeding, and the APOE4 gene is also associated with a higher risk of developing Alzheimer's disease.
Eisai and Bojian stated that they will seek to re-examine the proposal, but did not disclose what information will be provided to regulatory agencies.
Eli Lilly monoclonal antibody entering Europe or affected
Currently, there are very limited Alzheimer's disease drugs available on the market. From 1993 to 2003, only 5 AD drugs were approved (excluding the combination of Meverine/Donepezil), namely Tacrine (delisted), Donepezil, Kabardine, Galantamine, and Meverine Hydrochloride, which can only improve clinical symptoms. Global pharmaceutical companies have invested hundreds of billions of dollars in research and development for Alzheimer's disease, with the vast majority ending in failure, including projects laid out by well-known multinational pharmaceutical companies such as Eli Lilly, Takeda, Merck, Pfizer, and Roche.
According to data from the American Society for Drug Manufacturing and Research, the global cumulative R&D investment in AD has exceeded $600 billion, with over 300 failed clinical drugs and a failure rate of 99.6%.
On July 3rd, Lilly's Alzheimer's drug, Kisunla, received approval from the US FDA, while the A β monoclonal antibody Kisunla is believed to be a strong competitor to lencanavir monoclonal antibody in the industry.
Kisunla's approval in the United States has also gone through ups and downs, with regulatory agencies concerned about the serious side effects of the drug, including brain swelling and bleeding. Lilly first submitted a marketing application for Kisunla to the FDA in October 2021, seeking accelerated approval, but was rejected by the FDA in January 2023 on the grounds of insufficient sample size. In the second quarter of 2023, Lilly once again submitted a new drug application for Kisunla to the US FDA. Domestically, in January 2023, Kisunla has also been proposed by the Drug Evaluation Center of the National Medical Products Administration to be included as a breakthrough therapy. In October 2023, Eli Lilly submitted a marketing application for Kisunla injection and was accepted by the National Medical Products Administration.
Clinical data shows that 24% of patients in the donenumab treatment group experienced brain swelling, and 31% of patients receiving donenumab treatment experienced cerebral hemorrhage. These side effects have resulted in the death of three patients receiving treatment. In contrast, the incidence of this symptom in patients receiving placebo treatment is about 14%. The latest decision by the European Union may also affect the prospects of Eli Lilly's drug entering Europe. The drug is still under review by European regulatory agencies.
The number of AD drugs developed in China ranks second in the world
GlobalData predicts that driven by new therapies, the AD drug therapy market will grow rapidly at a compound annual growth rate of 20%. By 2030, the market size of eight major countries is expected to total $13.7 billion. In addition to Eisai and Eli Lilly, this field also attracts well-known multinational pharmaceutical companies such as Roche, Pfizer, GlaxoSmithKline, Novartis, Sanofi, AstraZeneca, Johnson&Johnson, Lingbei Pharmaceutical, AbbVie, Merck, etc.
According to the Wisdom Bud Global New Drug Database, clinical trial data for AD drug development shows that there are 857 drugs under development for Alzheimer's disease indications worldwide, but more than half are still in the preclinical stage. A total of 259 individuals have entered Phase I-III clinical trials, of which only 33 have entered Phase III clinical trials.
From a national/regional perspective, China ranks second only to the United States in terms of the number of drugs developed for AD indications. Anti A β, neural regulation, stem cells, and traditional Chinese medicine therapy have been the main exploration directions in China in recent years.
In 2019, China conditionally approved Green Valley Pharmaceuticals' Ganlute Sodium (trade name: Phase 9, Phase 1) for marketing, which is used to treat mild to moderate Alzheimer's disease and improve patients' cognitive function. Unlike the mainstream research and development mechanism for AD drugs worldwide, Ganlute Sodium focuses on the brain gut axis mechanism.
In the development of mainstream A β targeted AD drugs, according to the Dingxiangyuan Insight database, only A β monoclonal antibodies developed by Hengrui Pharmaceutical and Conova have entered the clinical stage in China. Among them, SHR-1707 from Hengrui Pharmaceutical is currently undergoing phase II clinical trials and is expected to complete its main indicators by April next year. According to the information disclosed by Hengrui Pharmaceutical on April 30 for the 2023 annual shareholders' meeting, the clinical trial of SHR-1707 in Australia is proceeding smoothly. Konya's CM383 has just completed the first subject enrollment for Phase I clinical trials earlier this month.
According to a search by a reporter from the Beijing News on the drug clinical trial registration and information disclosure platform, among other targets and mechanisms, the domestically developed Class 1 new drug QD202 for injection by Quetedi Biotechnology is currently under development for mild to moderate AD indications. This drug achieves the effect of treating AD by increasing the release of neurotransmitters and enhancing lysosomal function. According to the official disclosure information from Quitdy Biotech, QD202 tablets have demonstrated good efficacy and safety in preclinical trials and were approved for clinical trials in November 2023. On March 14th of this year, Quietdi Biotechnology announced the launch of Phase I clinical trials. Zhuokai Biotechnology's 50561 tablets are the world's first new drug for treating Alzheimer's disease from a forgetting perspective and are currently undergoing Phase IIa clinical trials.
In terms of traditional Chinese patent medicines and simple preparations, Shenqi Xingnao Granules of Beijing Hengqingtang Pharmaceutical Technology Co., Ltd. and Yangxue Qingnao Pills of Tianshili are also conducting phase II clinical research on mild Alzheimer's disease. According to Tianshi Li's response to investors on May 21st, Yangxue Qingnao Wan has increased indications for AD and is currently undergoing phase II clinical trials. The important innovative drug Wujia Yizhi Granules of Jishengtang Pharmaceutical, a wholly-owned subsidiary of Kanghong Pharmaceutical, is also developing indications for mild to moderate Alzheimer's disease (spleen and kidney deficiency syndrome) and has entered phase IIb clinical trials.
New Beijing News reporter Zhang Zhaohui