Recently, Eli Lilly and Company announced that the Phase III clinical trial of the Alzheimer’s disease drug donamumab has achieved positive results. Donatumab slowed the rate of cognitive decline in Alzheimer’s patients by 35 percent compared to a placebo.
Lilly said it will submit a marketing application for donamumab to the U.S. Food and Drug Administration (FDA) this quarter. If approved, donamumab will become the third monoclonal antibody drug for the treatment of Alzheimer’s disease in the United States. The first two are aducanumab and lencanezumab, which were approved by the FDA in June 2021 and January this year, respectively.
”Donatuzumab is not a cure for Alzheimer’s disease, but it, along with two other drugs previously approved by the FDA, could represent a turning point in the long and frustrating search for a treatment for Alzheimer’s disease.” According to the New York Times report.
Alzheimer’s disease and other forms of dementia are among the top 10 causes of death globally, according to WHO data at the end of 2020. 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 and co-head of dementia at Cambridge University Hospital, said in an interview with China News Weekly that the main impact of the clinical trials of donerumab and lencanezumab is “optimism.” “, that is, people not only regard Alzheimer’s disease as a disease, but also think that it is a disease that can and must be treated.
Has the “turning point” arrived?
Alzheimer’s disease, commonly known as “senile dementia”, is a progressive brain disease caused by damage to neurons in the brain.
The disease damages, above all, the parts of the brain responsible for memory, language and thinking. As nerve cell damage spreads to parts of the brain that support basic functions like walking and swallowing, it can leave patients bedridden and require round-the-clock care. Studies have shown that people 65 and older live an average of four to eight years after an Alzheimer’s diagnosis, but some patients can live as long as 20 years.
Although the exact cause of Alzheimer’s disease is not fully understood, it is characterized by changes in the brain, including β-amyloid (Aβ) deposits and neurofibrillary tangles caused by hyperphosphorylation of tau protein, leading to neuronal and Its connection is lost. Among the many hypotheses on the pathogenesis of Alzheimer’s disease, the “Aβ hypothesis” is the most mainstream. This hypothesis believes that the β-amyloid protein accumulated in the brain is the “culprit” that causes Alzheimer’s disease, and donamumab was developed based on the “Aβ hypothesis”.
The aforementioned Eli Lilly phase III clinical trial included nearly 1,200 early Alzheimer’s disease patients aged 60 to 85 with moderate levels of tau protein. For 18 months, participants received either donarumab or a placebo intravenously every two weeks. Patients experienced a 35 percent slower rate of clinical decline in cognitive function compared to placebo, based on the Alzheimer’s Disease Rating Scale.
Based on the more commonly used Clinical Dementia Rating Scale, the results showed a 36 percent reduction in the rate of cognitive decline in patients over the same period. 47% of drug users had no decline in score within 1 year, more than double that of the placebo group. The data also showed that donamumab cleared beta-amyloid in 34% of patients at 6 months, increasing to 71% at 12 months. The Alzheimer’s Disease Rating Scale, which assesses participants’ cognition and activities of daily living, was the primary endpoint of the donamumab measurement. Clinical Dementia Rating Scale, which evaluates participants in six aspects including memory, orientation, judgment and problem-solving ability, and personal self-care ability.
”This is the most powerful treatment for Alzheimer’s disease to date,” Maria Carrillo, chief scientific officer of the Alzheimer’s Association of America, said in a statement. Phase III data further underscores the inflection point we are at in the field of Alzheimer’s disease.”
Zhou Lingyun is a staff member of a pharmaceutical company and has been following up drug research and development related projects for a long time. He told “China News Weekly” that donamumab is mainly aimed at early Alzheimer’s disease, and what it achieves is the result of slowing down the progress. In layman’s terms, it means that the speed of dementia in patients is not so fast, but the progress of the disease is still irreversible.
Like donerumab, aducanumab developed by Biogen Corporation of the United States (hereinafter referred to as Biogen), and lencanezumab jointly developed by Eisai Co., Ltd. of Japan (hereinafter referred to as Eisai) and Biogen also belong to the Drugs targeting amyloid.
On January 6 this year, the FDA quickly approved lencanezumab, which also caused a huge sensation in the industry. The results of phase III clinical trials of lencanezumab were published in the New England Journal of Medicine. Christopher Decker, director of the Alzheimer’s Disease Research Unit at the Yale School of Medicine, is lead author of the paper.
In the phase III clinical trial of lencanezumab, a total of 1795 participants with early Alzheimer’s disease aged 50 to 90 were enrolled, and the test group was injected with lencanezumab every two weeks. The evaluation criteria used is the Clinical Dementia Rating Scale. The drug slowed the rate of cognitive decline by 27 percent over 18 months, the results showed. According to a report by NBC on January 10, Eisai announced that it has submitted an application to the FDA for full approval. The relevant person in charge of the company has said that the FDA may make a decision within six months.
From the data point of view, Eli Lilly’s doranumab is more effective than lencanezumab. However, many experts at home and abroad told China News Weekly that based on the clinical data disclosed by both parties, 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, Huashan Hospital Affiliated to Fudan University, told China News Weekly, but the efficacy of the two drugs needs to be tested “head-to-head”. Only clinical trials can draw conclusions. “Head-to-head” clinical trial, that is, in a clinical trial carried out, other conditions are the same, the subjects are divided into three groups, and the two drugs and the placebo are used respectively.
Richard Caselli, deputy director and clinical core director of the Mayo Clinic Alzheimer’s Disease Center in Arizona, USA, said in an interview with China News Weekly that the clinical impact of amyloid clearance is quite mild, and the existing 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 reduced rate.
In Lilly’s clinical trial, in order to collect more data, the drug effect was also evaluated in 552 patients with high levels of tau, which means that they are patients with advanced disease. It found that when high-tau participants were pooled with the medium-tau population, donamumab showed positive results. The Alzheimer’s Disease Rating Scale and the Clinical Dementia Rating Scale showed a 29% and 22% reduction in the rate of progression of Alzheimer’s disease symptoms, respectively.
On May 15, Deck, director of Yale University’s Alzheimer’s Disease Research Office, told China News Weekly that participants in Eli Lilly’s drug trials mainly had moderate levels of tau protein, which maximized the chances of their drug’s success. However, whether participants with high levels of tau benefited, or benefited less, “this should be the information that should be focused on after the data is fully disclosed.” Dyke said.
Drugs for Alzheimer’s disease are also known as “black holes” in research and development due to their high failure rate. In September 2021, in a study published online in Alzheimer’s Disease and Dementia, the official journal of the American Alzheimer’s Association and the top international academic journal, the researchers collected data from January 1995 by integrating multiple databases. Alzheimer’s disease clinical trials conducted between June 1 and June 21, 2021. “The failure rate of drug development for Alzheimer’s disease is close to 100%.” The researchers analyzed that in the 26 years from 1995 to 2021, in all therapeutic areas, the FDA approved 878 drugs, of which only 6 were suitable for Alzheimer’s disease .
Michael Weiner, a professor of psychiatry and neurology at the University of California, San Francisco, told China News Weekly that all drug development is difficult, but drug development for brain diseases is particularly challenging because they are difficult to diagnose and difficult to treat. Drugs must be able to cross the blood-brain barrier to enter the brain. Weiner is also the principal investigator of the Alzheimer’s Disease Neuroimaging Program, the world’s largest observational study of Alzheimer’s disease.
According to Zhou Lingyun’s analysis, all drug research and development is usually “successful” after the pathogenesis is clear, which is why the difficulty of research and development of Alzheimer’s disease drugs increases geometrically. As far as he knows, many Alzheimer’s disease drugs with good results in phase II clinical trials have failed when they reached the phase III phase of expanding the subject population. “That’s why donanumab and lencanezumab are so valuable,” he said.
These three drugs have not yet been approved in China. Sun Yongan, deputy director of the Alzheimer’s Disease Branch of the China Association for the Elderly Care and chief physician of the Neurology Department of Peking University First Hospital, said that now aducanumab has started clinical trials in Boao, Hainan, and 5 Alzheimer’s patients have been enrolled in the country. patients with Haimer’s disease. Since lencanezumab has been approved by the FDA, this drug may also be approved in China in the future.
Doubtful drug risk
How expensive is Alzheimer’s drug development? The above-mentioned research analysis published in “Alzheimer’s Disease and Dementia” in 2021 found that from 1995 to 2021, the cumulative expenditure on Alzheimer’s disease research and development in the clinical stage is estimated to be 42.5 billion US dollars, of which the research and development cost of phase III clinical trials is the highest , reaching 24.065 billion US dollars, accounting for 57%. According to a 2014 analysis, the estimated total cost of developing a treatment specifically for Alzheimer’s disease from the nonclinical stage to FDA approval is $5.7 billion and would take more than 13 years to complete, according to a 2014 analysis.
The high cost of research and development determines that the price of such drugs is not cheap.
According to the information on Biogen’s official website, after it goes on the market in June 2021, it will be injected intravenously once a month at a dose of 10 mg/kg. The average cost of aducanumab per person per year will be US$56,000, or about RMB 390,000. Eisai issued a document in January 2023, according to the intravenous injection of 10 mg/kg every two weeks, the average cost of lencanezumab per person per year is 26,500 US dollars, about 180,000 RMB. Fast-track approval of lencanezumab did not generate revenue growth for Biogen. Biogen’s first-quarter financial report released on April 25 showed that its Alzheimer’s disease revenue was negative US$18 million.
In April 2022, the Centers for Medicare and Medicaid Services (CMS) issued a decision that would prevent Medicare from covering FDA-approved Alzheimer’s drug treatments targeting beta-amyloid, including Aducan Matumab, lencanezumab, and other monoclonal antibodies likely to receive FDA approval in the coming months. In February 2023, the center stated in a statement that as of that date, the aforementioned decision had not changed. The center noted that in order to provide coverage nationwide, CMS needs to check that drugs are reasonable and necessary.
Currently, aducanumab and lencanezumab are fast-tracked by the FDA, which means that additional studies are needed to confirm the expected clinical benefit.
The safety of Alzheimer’s disease monoclonal antibodies cannot be ignored. According to the data released by Eli Lilly, the incidences of brain swelling and cerebral hemorrhage of Donatuzumab were 24% and 31%, respectively, exceeding the 13% and 17% of Biogen and Eisai Luncanezumab.
”Candidate drugs targeting amyloid can slow cognitive decline in some people, but questions about their potential side effects remain.” On May 4, “Nature” published an article. The article pointed out that the incidence of amyloid-related imaging abnormalities (ARIA) was several times higher in patients receiving donamumab than in the placebo group, and three patients in the trial died after experiencing this condition. “Whether there is a causal relationship between the 3 deaths in the clinical trial of donamumab and the drug remains to be confirmed,” Yu Jintai said. ARIA is a common side effect of immunotherapy for Alzheimer’s disease, and the most common symptoms are brain swelling and microbleeds in the brain.
”It is extremely important to realize that this type of drug has serious adverse reactions, and donamumab is no exception.” Pei Mingde Saqidev, a professor of neuropsychiatry at the University of New South Wales in Sydney and co-director of the Australian Dementia Network, told “China Newsweek said Lilly said most of these adverse reactions were “mild to moderate” and stabilized with “appropriate management,” but “serious” side effects remained in 1.6 percent of people. No further details of the deaths of the three trial patients were disclosed.
On January 6 this year, when the FDA released the approval notice of lencanezumab, it mentioned that the most common side effects of the drug were infusion-related reactions, headache and ARIA.
In clinical trials of lencanezumab, 3 patients died. Reuters reported in January 2023 that a 65-year-old female patient suffered a stroke while being treated with the experimental lencanezumab and received emergency treatment with a clot-busting agent, an autopsy analysis released on the same day showed. treatment, which resulted in a fatal cerebral hemorrhage and a ruptured blood vessel. “In the clinical trial of lencanezumab, 3 deaths were related to the use of anticoagulants or acute thrombolytics.” Alzforum, an internationally renowned academic forum on Alzheimer’s disease, disclosed in an article on May 4.
The main side effect of aducanumab is also ARIA. In addition, aducanumab has been questioned due to discrepancies in clinical data.
In March 2019, 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 2021. In November 2019, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee was asked to vote on the drug’s evidence of effectiveness. In a meeting briefing document for the committee, Biogen noted that in a clinical trial, patients treated with high doses of the drug for 18 months experienced a 22% reduction in clinical decline in cognitive health compared with a placebo group, This means that aducanumab delayed the progression of early Alzheimer’s disease.
However, the aforementioned committee members did not agree with this result. None of the 11 committee members voted in favor of the question “whether it is reasonable to consider data from one positive study as the primary evidence of efficacy of aducanumab in early-stage Alzheimer’s disease.”
In Yu Jintai’s view, the drug will be approved for marketing only when it benefits patients and the risk of side effects is small enough. He said that the elderly themselves have a relatively high incidence of intracerebral hemorrhage. After administration, the amyloid deposited on the blood vessel wall is removed, which may cause localized bleeding or swelling at the removed site. Most of the side effects are very mild, and those with brain lesions or microbleeds are more prone to these side effects. For patients with obvious side effects, the side effects will gradually relieve after stopping the drug.
James Rowe believes that people want safe and effective drugs, but all drugs in clinical use have potential side effects. The degree to which doctors and patients are willing to take the risk of such side effects depends on the severity and reversibility of the side effects, which in turn depends on the transparency of pharmaceutical companies and clinical trials.
Caselli told China News Weekly that the safety risk of this type of drug is also affected by the genotype of apolipoprotein E (APOE). Carriers of the APOE E4 gene have a high risk of adverse reactions, and those who carry two copies of the APOE gene Humans are at particularly high risk. While only 2 percent of Americans are homozygous for the APOE E4 gene, that number reaches 10 percent in Alzheimer’s disease. He suggested that APOE genotyping be performed in patients planning to receive this treatment to better predict the likelihood of potentially serious adverse effects.
What should the future of treatment look like?
The number of Alzheimer’s patients is increasing. According to the “Global Public Health Response to Dementia Status Report” released by WHO in 2019, as of then, more than 55 million people were living with dementia, of which 8.1% were women over the age of 65 and 5.4% were men. This number is expected to increase to 78 million in 2030 and 139 million in 2050.
Yu Jintai said that patients and their families did not pay much attention to this disease before, and doctors did not pay much attention to it, and there were fewer patients in the hospital. In recent years, the number of patients with Alzheimer’s disease who come to the clinic to see a doctor has increased significantly. On the afternoon of May 10, among the 53 patients he received, at least 30 were Alzheimer’s patients. “Patients in their 40s and 50s are more common,” he said.
”For the treatment of Alzheimer’s disease, the most important thing is prevention.” Yu Jintai analyzed. Recently, a study published by Yu Jintai’s team on the risk factor map of Alzheimer’s disease found that if the risk factors are actively intervened, 47% to 72% of dementia can be prevented.
Alzheimer’s disease is a type of dementia. According to the Mayo Clinic, a world-renowned medical institution, among the approximately 55 million dementia patients worldwide, it is estimated that 60% to 70% suffer from Alzheimer’s disease. In Weiner’s view, prevention seems feasible, such as blood tests and scans of normal people without symptoms to determine whether they have early 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 when many patients are diagnosed, the disease has developed to the middle and late stage. At this time, the effect of such monoclonal antibody drugs is very limited, or basically ineffective. At present, the detection of Alzheimer’s disease is more through 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 memory loss patients who came to the hospital for treatment did not suffer from Alzheimer’s disease. Nearly 20% of the dementia patients admitted to the Cognitive Impairment Ward of Huashan Hospital in charge of him belong to dementia that can be cured and prevent the progression of the disease.
What does the future hold for drug treatments for Alzheimer’s disease? Yu Jintai analyzed that in the future, drugs that improve symptoms and drugs that improve tau protein hyperphosphorylation can be tried together, and patients may benefit more. In addition, non-drug interventions such as magnetic stimulation, electrical stimulation, and cognitive training can also be tried.
Zhou Lingyun analyzed that theoretically, if the pathogenesis of Alzheimer’s disease can be clarified, it is possible to create a “miracle medicine” once and for all. When the pathogenesis has not been clarified, the more likely treatment is a combination of multiple drugs.
James Rowe believes that compared with 20 years ago, the research community has a more complicated view on the “Aβ hypothesis”. Amyloid, tau and inflammation are linked, forming a ‘toxic alliance’ that damages the brain. Once you have Alzheimer’s disease and start showing symptoms, many other important factors, such as tau proteins, are also driving the disease. These issues may not be the cause of the disease in the first place, but they determine disease symptoms and the rate of cognitive decline, so treating these issues could have a significant impact on slowing Alzheimer’s symptoms.
For a complex disease, it’s often difficult to find a panacea, Perminder said. Combination drugs often end up controlling the disease rather than curing it completely. “Alzheimer’s disease is not an easy foe to conquer, but we can take it away little by little so that it’s not as scary as it is now,” he said.
”Now there are at least a few promising drugs. This is the beginning of the drug race against dementia, not the end.” James Luo told “China News Weekly”. At present, there are more than 170 drugs targeting Alzheimer’s disease worldwide. More than 140 different drugs were tested in phase II and III clinical trials of silent disease, only a few of which were anti-amyloid. He reminded that in the field of Alzheimer’s disease drug development, the long-term goal is to treat early Alzheimer’s disease well, even before symptoms appear, so as to prevent advanced Alzheimer’s disease. However, for patients with early Alzheimer’s disease, the patients will progress to the late stage sooner or later. Therefore, clinical trials for late-stage Alzheimer’s disease symptoms such as restlessness, psychosis, and apathy are also very important and cannot be ignored.