Cognitive decline slowed down by 35%, Alzheimer's treatment "inflection point" has arrived?

Behind the frequent emergence of new drugs for Alzheimer's disease

China Newsweek reporter: Niu He

Published in the 2023nd issue of China Newsweek magazine on May 5, 22

Recently, Eli Lilly announced the positive results of the phase III clinical trial of the Alzheimer's disease drug donazumab. Compared to placebo, donasumab slowed cognitive decline by 35% in Alzheimer's patients.

Eli Lilly said it will submit a marketing application for donakimab to the U.S. Food and Drug Administration (FDA) this quarter. If approved, donagumab would be the third monoclonal antibody in the United States to treat Alzheimer's disease. The first two, adducamimab and lencanezumab, received marketing approval from the FDA in June 2021 and January this year, respectively.

"Donasumab does not cure Alzheimer's disease, but along with two other drugs previously approved by the FDA, it could be a turning point in the long and frustrating exploration of Alzheimer's disease treatment." The New York Times report reads.

According to WHO data at the end of 2020, Alzheimer's disease and other forms of dementia are among the top <> causes of death worldwide. However, because the pathogenesis of Alzheimer's disease is not clear, the failure rate of drug development remains high.

James Luo, professor of cognitive neurology at the University of Cambridge in the United Kingdom and co-head of dementia at Cambridge University Hospital, told China Newsweek that the main impact of the clinical trials of donasumab and lencanezumab is "optimistic", that is, people not only see Alzheimer's disease as a disease, but also as a disease that can and must be treated.

Has the "inflection point" arrived?

Commonly known as "Alzheimer's," Alzheimer's disease is a progressively worsening brain disorder caused by damage to neurons in the brain.

The first part of the brain that is damaged by this disease is the part responsible for memory, language and thinking. As nerve cell damage spreads to parts of the brain that support basic functions such as walking and swallowing, it results in patients being bedridden and requiring round-the-clock care. Studies have shown that people aged 65 and above can survive an average of 4~8 years after being diagnosed with Alzheimer's disease, but some patients can survive for 20 years.

While the specific cause of Alzheimer's disease is not fully understood, it is characterized by changes in the brain, including tangles of nerve fibers caused by β-amyloid (Aβ) deposition and overphosphorylation of tau protein, resulting in the loss of neurons and their connections. Among the many hypotheses on the pathogenesis of Alzheimer's disease, the "Aβ hypothesis" is the most mainstream. This hypothesis believes that β-amyloid that accumulates in the brain is the "culprit" that causes Alzheimer's disease, and donazumab was developed based on the "Aβ hypothesis".

The aforementioned phase III clinical trial of Eli Lilly included nearly 1200 patients with early Alzheimer's disease aged 60~85, and their tau protein levels were moderate. For 18 months, participants received either donakimab or placebo intravenously every two weeks. Based on the Alzheimer's Disease Rating Scale, the rate of clinical decline in cognitive function slowed by 35% compared to placebo.

Based on the more commonly used Clinical Dementia Rating Scale, the results showed a 36% reduction in cognitive decline in patients over the same period. 1% of users with no decline in scores within 47 year were more than double the placebo group. The data also showed that donakinumab cleared β-amyloid in 6% of patients at 34 months of use, and this clearance increased to 12% at 71 months. The Alzheimer's Disease Rating Scale, which assesses participants' cognition and activity in their daily lives, is the primary endpoint of donakimab measurement. The clinical dementia rating scale evaluates six aspects of participants' memory, orientation, judgment and problem-solving ability, and personal self-care ability.

According to the US Consumer News and Business Channel on May 5, Maria Carrillo, chief scientific officer of the Alzheimer's Association, said in a statement, "This is the strongest phase III data for Alzheimer's disease treatment to date, further highlighting the inflection point we are at in the field of Alzheimer's disease." ”

Zhou Lingyun is a pharmaceutical company worker who has been following up drug research and development related projects for a long time. He told China Newsweek that donakimab mainly targets early Alzheimer's disease and achieves the result of slowing progression. In layman's terms, it is that the speed of dementia is not so fast, but the disease progression is still irreversible.

Like donazumab, adducamimamab developed by Biogen Corporation (Biogen) and lencaneizumab jointly developed by Eisai Co., Ltd. (hereinafter referred to as Eisai) and Biogen are also amyloid drugs.

On January 1 this year, the FDA quickly approved lencanezumab, which also caused a huge sensation in the industry. The results of a phase III clinical trial of lencanezumab were published in the New England Journal of Medicine. Christopher, director of the Alzheimer's Laboratory at Yale School of Medicine, is the paper's first author.

In the phase III clinical trial of lencaneizumab, a total of 1795 participants aged 50~90 with early Alzheimer's disease were enrolled, and the experimental group was injected with lencaneizumab every two weeks, and the evaluation standard used was the clinical dementia rating scale. The results showed that the drug slowed the rate of cognitive decline by 18% over 27 months. As reported by NBC on January 1, Eisai announced that it has submitted an application for full approval to the FDA. The head of the company has said that the FDA may make a decision within six months.

From the data, Lillydonamab is more effective than lencanezumab. However, a number of experts at home and abroad told China Newsweek that based on the clinical data disclosed by both sides, it is not enough to judge which drug is more effective.

"These drugs are equivalent to confirming the 'Aβ hypothesis' from the side." Yu Jintai, chief physician of the Department of Neurology at Huashan Hospital affiliated to Fudan University, told China Newsweek that the efficacy of the two drugs needs to be concluded through "head-to-head" clinical trials. A "head-to-head" clinical trial, in which all else is the same, divides subjects into three groups, one with two drugs and one placebo.

Richard Casselli, deputy director and clinical core director of the Alzheimer's Disease Center at the Mayo Clinic in Arizona, USA, said in an interview with China Newsweek that the clinical effects of amyloid clearance are quite mild, and the available evidence is still insufficient to prove the authenticity of the "Aβ hypothesis". Amyloid has been shown to be toxic, so its removal is beneficial, but the disease continues to progress at a slightly lower rate.

In order to collect more data, Eli Lilly's clinical trial also evaluated the efficacy of 552 patients with high levels of tau, meaning that they were patients with advanced disease. It was found that donakimab showed positive results when participants with high TAU were combined with moderate TAU populations. The Alzheimer's Disease Rating Scale and the Clinical Dementia Rating Scale showed a 29% and 22% slowdown in the progression of Alzheimer's disease symptoms, respectively.

On May 5, Deke, director of Yale University's Alzheimer's Disease Research Laboratory, told China Newsweek that participants in the Lilly drug trial had predominantly moderate levels of tau protein, which maximized their chances of drug success. But whether high-level TAU participants benefited, or benefited less, "should be the message to focus on after the data is fully disclosed." said.

Alzheimer's disease drugs are also known as the "black hole" of research and development because of the high failure rate. In September 2021, in a study published online by Alzheimer's Disease and Dementia, the official journal of the Alzheimer's Association and a top international academic journal, researchers collected clinical trials of Alzheimer's disease conducted between January 9, 1995 and June 1, 1 by integrating multiple databases. "The failure rate of Alzheimer's drug development is close to 2021%." Researchers analyzed that in the 6 years from 21~100, in all therapeutic areas, the FDA approved 1995 drugs, of which only 2021 were suitable for Alzheimer's disease.

Michael Wiener, a professor of psychiatry and neurology at the University of California, San Francisco, told China Newsweek that all drug development is difficult, but drug development for brain diseases is particularly challenging because they are difficult to diagnose and therapeutic drugs must be able to cross the blood-brain barrier to enter the brain. Wiener is also the principal investigator of the Alzheimer's Disease Neuroimaging Program, the world's largest observational study of Alzheimer's disease.

Zhou Lingyun analyzed that all drug research and development is usually "natural" after the pathogenesis is clear, which is why the difficulty of developing Alzheimer's disease drugs has increased geometrically. According to his understanding, many Alzheimer's disease drugs with good results in phase II clinical trials failed as soon as they reached the stage III stage of expanding the subject population. "That's why donasumab and lencanemab are so precious." He said.

These three drugs have not yet been approved in China. Sun Yongan, vice chairman of the Alzheimer's Disease Branch of the Chinese Geriatric Health Care Association and chief physician of the Department of Neurology of Peking University First Hospital, said that now adukamamab has begun clinical trials in Boao, Hainan, and 5 Alzheimer's disease patients have been enrolled in China. Based on lencanezumab has been approved by the FDA, this drug may also be approved in China in the future.

The risks of medication are questionable

How expensive is it to develop Alzheimer's disease drugs? The aforementioned research analysis published in "Alzheimer's Disease and Dementia" in 2021 found that in 1995~2021, the cumulative expenditure on the research and development of Alzheimer's disease in the clinical stage was estimated to be 425.240 billion US dollars, of which the R&D cost of phase III clinical trials was the highest, reaching 65.57 billion US dollars, accounting for 2014%. According to a 57 analysis, the total cost of developing a treatment specifically for Alzheimer's disease from the non-clinical stage to FDA approval was estimated at $13.<> billion and would take more than <> years to complete, the study said.

The high cost of research and development determines that the price of such drugs is not cheap.

According to Biogen's official website, after its launch in June 2021, according to a 6 mg/kg dose of intravenous injection once a month, the average cost of adducamimab per person per year is 10,5 US dollars, about 6,39 yuan. Eisai issued a document in January 2023 that according to the 1 mg/kg dose of intravenous injection every two weeks, lencanezumab costs an average of 10,2 US dollars per person per year, about 65,18 yuan. The fast-approved lencanezumab did not result in revenue growth for Biogen. Biogen's first-quarter earnings report released on April 4 showed that its Alzheimer's disease revenue was negative $25 million.

In April 2022, the U.S. Centers for Medicare and Medicaid Services (CMS) issued a decision that would prevent Medicare from covering FDA-approved Alzheimer's disease drugs for β-amyloid, including adducamab, lencanezumab, and other monoclonal antibodies that could be approved by the FDA in the coming months. In February 4, the center said in a statement that the decision had not changed as of that date. The center noted that in order to provide coverage nationwide, CMS needs to check whether drugs are reasonable and necessary.

Currently, both adaducamimab and lencanezumab are approved by the FDA expeditiously, which means that additional studies are needed to confirm the expected clinical benefit.

The safety of Alzheimer's monoclonal antibodies cannot be ignored. In the data released by Lilly, the incidence of brain swelling and cerebral hemorrhage in donakimab was 24% and 31%, respectively, exceeding the 13% and 17% of Biogen and Eisai lencanezumab.

"Targeting amyloid drug candidates can slow cognitive decline in some people, but questions about their potential side effects remain." On May 5, Nature published an article saying. The article noted that the incidence of amyloid-related imaging abnormalities (ARIA) was several times higher in patients treated with donazumab than in the placebo group, and 4 patients in the trial died after experiencing this condition. "Whether there is a causal relationship between the three deaths in the clinical trial of donalizumab and the drug remains to be confirmed." Yu Jintai said. ARIA is a common side effect of immunotherapy for Alzheimer's disease, with the most common symptoms being brain swelling and microbleeding in the brain.

"It is extremely important to recognize that these drugs have serious adverse effects, and donazumab is no exception." Peminde Sachidev, a professor of neuropsychiatry at the University of New South Wales in Sydney and co-director of the Australian Dementia Network, told China Newsweek that Eli Lilly said the adverse reactions were mostly "mild to moderate" and could be stabilized after "proper management", but that 1.6 per cent still had "serious" side effects. Details of the deaths of the three trial patients are not yet disclosed.

On January 1 this year, the FDA issued the approval notice of lencanezumab and mentioned that the most common side effects of the drug were infusion-related reactions, headaches and ARIA.

In clinical trials of lencanezumab, 3 patients died. An autopsy analysis released on the same day showed that a 2023-year-old woman suffered a stroke while receiving the trial lencanezumab treatment and received emergency treatment with a thrombus-destroying agent, resulting in fatal brain hemorrhage and blood vessel rupture, Reuters reported in January 1. "In the clinical trial of lencainemab, three deaths were associated with the use of anticoagulants or acute thrombolytics." Alzforum, an internationally renowned academic forum for Alzheimer's disease, revealed in a May 65 article.

The main side effect of adducamamab is also ARIA. In addition, adducamimab has been questioned due to differences in clinical data.

In March 2021, two phase III clinical trials of the drug were terminated because one of them was unlikely to meet its primary goal upon completion, CNN reported in June 6. In November 2019, the FDA's Advisory Committee on Peripheral and Central Nervous System Drugs was asked to vote on evidence of the drug's effectiveness. In the committee's briefing paper, Biogen noted that in one clinical trial, patients treated with high-dose drugs for 3 months experienced a 2019 percent reduction in clinical decline in cognitive health compared to the placebo group, meaning that adulcumimab delayed its early Alzheimer's progression.

However, the members of the Committee did not agree with the result. In response to a question "whether it is reasonable to consider data from a positive study as the primary evidence for the effectiveness of adulcummab in treating early Alzheimer's disease," none of the 11 committee members voted in favor.

In Yu Jintai's view, the drug benefits patients, and the risk of side effects is small enough to be approved for marketing. He said that the elderly themselves have a relatively high incidence of cerebral hemorrhage. After administration, amyloid deposits on the blood vessel wall are removed, which may cause local bleeding or swelling in the area where it was removed. The vast majority of side effects are very mild, and those who have in-brain lesions or microbleeding are more likely to experience these side effects. Patients with significant side effects will gradually relieve the side effects after stopping the drug.

James Rowe believes that people want safe and effective drugs, but all drugs used in clinical practice have potential side effects. The degree to which doctors and patients are willing to take the risk of this side effect depends on the severity and reversibility of the side effect, which in turn depends on the transparency of pharmaceutical companies and clinical trials.

Caselli told China Newsweek that the safety risks of such drugs are also affected by the apolipoprotein E (APOE) genotype, and that APOE E4 gene carriers have a high risk of adverse reactions, and those who carry two copies of the APOE gene are particularly at high risk of developing the disease. While only 2 percent of Americans carry homozygous for the APOE E4 gene, in Alzheimer's disease, that percentage reaches 10 percent. He recommends that APOE genotyping be performed in patients who plan to receive this treatment to better predict the likelihood of potentially serious adverse effects.

What should future treatments look like?

The number of Alzheimer's patients is increasing. WHO's 2019 Global Public Health Situation Report on the Dementia Response shows that at that time, more than 5500 million people were living with dementia, including 65.8% of women over 1 years old and 5.4% men. This number is expected to increase to 2030 million in 7800 and 2050 million in 1.

Yu Jintai said that patients and their families did not pay much attention to this disease before, doctors did not pay attention to it, and there were fewer patients in hospitals. In recent years, the number of Alzheimer's patients visiting outpatient clinics has increased significantly. On the afternoon of May 5, at least 10 of the 53 patients he saw were Alzheimer's patients. "Patients in their forties and fifties are more common." He said.

"The most important thing for Alzheimer's disease treatment is prevention." Yu Jintai analyzed. Recently, a study on the risk factor map of Alzheimer's disease published by Yu Jintai's team found that if the risk factors are actively intervened, 47%~72% of dementia can be prevented.

Alzheimer's disease is a type of dementia. According to the Mayo Clinic, a world-renowned medical institution, about 5500 million dementia patients in the world, it is estimated that 60%~70% have Alzheimer's disease. In Wiener's view, prevention seems feasible, such as blood tests and scans of normal people without symptoms to determine if they have early-stage Alzheimer's disease.

Zhou Lingyun said that one of the difficulties in the prevention and treatment of Alzheimer's disease lies in early diagnosis. Usually many patients are diagnosed with the disease in the middle or advanced stages. At this time, this type of monoclonal antibody drug has a limited effect or is basically ineffective. At present, Alzheimer's disease is detected more by a scale test, similar to the way depression is diagnosed. However, if normal elderly people only have a slight memory loss, they are unlikely to take the initiative to go to the hospital for such tests.

Yu Jintai analyzed that many patients with memory loss who come to the hospital do not suffer from Alzheimer's disease. Nearly 20% of the dementia patients admitted to the dementia ward of Huashan Hospital under his charge are dementia that can cure and stop the progression of the disease.

What will be the future of drug treatment for Alzheimer's disease? Yu Jintai analyzed that in the future, you can try to take drugs that improve symptoms and drugs that improve the hyperphosphorylation of tau protein, and patients may benefit more. In addition, non-pharmacological interventions such as magnetic stimulation, electrical stimulation, and cognitive training can be tried.

Zhou Lingyun analyzed that in theory, if the pathogenesis of Alzheimer's disease can be clarified, it is possible to create a "miracle drug" once and for all. When the pathogenesis is not well understood, a more likely treatment is a combination of drugs.

James Rowe believes that the "Aβ hypothesis" is more complex in the research community than it was 20 years ago. Amyloid, Tau and inflammation are linked, forming a "toxic alliance" that damages the brain. Once you develop Alzheimer's disease and start showing symptoms, many other important factors such as tau protein also drive the disease to progress. These problems may not be the cause of the onset of the disease, but they determine the symptoms of the disease and the rate of cognitive deterioration, so treating these problems could have a significant impact on slowing down Alzheimer's disease symptoms.

Peminde said that for a complex disease, it is often difficult to find a panacea. The end result of combining drugs is often to control the disease rather than cure it completely. "Alzheimer's disease is not an easy enemy to conquer, but we can eliminate it little by little and make it less frightening than it is now." He said.

"There are now at least a few promising drugs, and this is the beginning, not the end, of the drug race against dementia." James Luo told China Newsweek that there are currently more than 170 phase II and III clinical trials for Alzheimer's disease worldwide, testing more than 140 different drugs, of which only a few are anti-amyloid. He reminded that the current long-term goal in the field of Alzheimer's disease drug development is to treat early Alzheimer's disease well, even before symptoms appear, to prevent advanced Alzheimer's disease. However, for patients with early Alzheimer's disease, patients will progress to advanced stages sooner or later, so clinical trials for advanced Alzheimer's disease symptoms such as agitation, psychosis, and apathy are also very important and cannot be ignored.

(Zhou Lingyun is a pseudonym in the text)

China Newsweek, Issue 2023, 18

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