Alzheimer’s disease, commonly known as Alzheimer’s disease, is a neurodegenerative disease. Patients may experience memory loss, language problems, slow response, lost, mental behavior, etc., and even worse, they will not know their loved ones. According to the data, 50 million people in the world suffer from Alzheimer’s disease in 2018, and an average of three people are in this dilemma every three seconds.
At present, only a few drugs can partially alleviate the symptoms of the disease, there is no way to prevent the disease from happening, let alone cure the disease. Although academic researchers and the pharmaceutical industry have been working hard to develop effective treatments for Alzheimer’s disease, many drugs have failed in advanced clinical trials. From 2002 to 2012, the trial failure rate of this class of drugs was as high as 99.6%.
Recently, Biogen and Eisai announced that they will stop the phase III clinical trial of the β-amyloid lyase inhibitor elenbecestat due to the unfavorable benefit-risk ratio. This is the second drug study that Biogen and Eisai stopped in 2019; the clinical development plan for Aducanumab (a monoclonal antibody targeting Aβ) was stopped in March.
The challenge of treating Alzheimer’s disease
Alzheimer’s disease is a neurodegenerative disease characterized by the gradual deposition of extracellular β amyloid in the brain to form senile plaques and intracellular Tau protein hyperphosphorylation to form neurofibrillary tangles. It is divided into familial and sporadic. Familial Alzheimer’s disease is less than 5%, mainly caused by mutations in related genes such as APP, PS1 and PS2; the etiology of sporadic Alzheimer’s disease is still unclear, and is generally considered to be the result of a combination of genetic and environmental factors. . The prevalence and medical burden of this neurodegenerative disease is increasing, and the Alzheimer’s Association estimates that the global prevalence and burden of Alzheimer’s disease will increase by 68% by 2050.
The current treatment goal for Alzheimer’s disease is to maintain physical function and ability while slowing or delaying symptoms. Mild to moderate treatments for Alzheimer’s disease include the acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine. Donepezil is also indicated for the treatment of moderate to severe Alzheimer’s disease, either alone or in combination with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. These neurotransmitter-modulating drugs temporarily improve symptoms, but patients still experience progressive deterioration in cognitive ability, as well as mental illness, agitation, depression, and sleep disorders.
At present, the main hot spot in the development of new drug treatment for Alzheimer’s disease is inhibition of β-amyloid aggregation and clearance of β-amyloid. Some new targeted immunotherapeutics for β-amyloid or tau protein are undergoing in-depth clinical trials, but the validation of Alzheimer’s disease treatments is very difficult, and many drug candidates in advanced clinical trials have failed. Meet the primary endpoint. Researchers are turning their attention from treatment to prevention.
At present, the most important preventive method is vaccination; although some drug candidates have failed in the late 1990s and early 2000s, the theory that vaccination can prevent cognitive decline is receiving attention. The therapeutic beta-amyloid vaccine ACI-24 from AC Immune is currently undergoing Phase IB and Phase II clinical trials.
AC Immune CEO Andrea Pfeifer pointed out that Elan and Wyeth’s candidate vaccine AN-1792 failed in the early 21st century due to safety issues. The company’s Phase II clinical study of β-amyloid AN-1792 was in 2002. Participants were abandoned with meningitis and brain inflammation.
Researchers at the two companies identified the cause of inflammation in AN-1792 and published these findings at the Society for Neuroscience in New Orleans, USA, to allow others to learn from their failures.
The mechanism of action of ACI-24
Pfeifer explained that ACI-24 was developed using AC Immune’s superantigen technology, which anchors the antigen “on the liposome” and injects it into the patient.
The patient’s body produces antibodies that are “90% specific for pathological amyloid beta” and do not target normal beta amyloid peptides, thereby allowing “plaques to dissolve or inhibit plaque formation.”
Pfeifer continues: “This product is very effective in mice, it can completely restore the memory of transgenic mouse models.” At the same time, it significantly reduces plaque and restores memory in preclinical models, while ACI-24 has good safety. It has nothing to do with local inflammation because it targets pathological amyloid beta, does not activate the inflammatory pathways in the brain and activates T cells.”
Following this impressive success in mice, ACI-24 is undergoing Phase II clinical studies in patients with mild to moderate Alzheimer’s disease.
Pfeifer believes that the only way to treat Alzheimer’s disease is to “prematurely and safely” prevent it. The best way is to vaccinate “20, 30, 40 years ahead of time”, especially for people at high risk of developing Alzheimer’s disease.
She explained that risks can be identified by genes and biomarkers. An example of a risk gene is apolipoprotein E-e, which has been shown to affect approximately one in four cases of Alzheimer’s disease. The accumulation of tau in the brain seems to be a very high risk factor for these people to get sick.
ACI-24 in the Down Syndrome
In addition to studying the role of ACI-24 in patients with Alzheimer’s disease, ACIImmune also studied the role of ACI-24 in Down’s syndrome population, which has recently been shown to contain large amounts of amyloid beta protein. And plaques appear early in life, and their incidence of Alzheimer’s disease is three to five times that of the general population. This phenomenon has been unnoticed for many years due to the high mortality rate of Down syndrome patients. As the prognosis of patients with Down syndrome improves, the problem of Alzheimer’s disease becomes more apparent.
“At the age of 20, Down syndrome patients had Alzheimer’s disease signals. They had all the symptoms of Alzheimer’s disease at the age of 40, and most of them had Alzheimer’s disease at the age of 60,” Pfeifer said. “Previously Down syndrome patients died of heart disease 30 years of age or older, but now these patients live a normal life and can live to 60 years of age or older. Alzheimer’s disease becomes a real problem.”
The reason that Alzheimer’s disease is closely related to Down’s syndrome is genetically determined, because Down’s syndrome patients have three copies of chromosome 21 carrying the amyloid precursor protein gene. This gene plays a role in the formation of beta amyloid and plaque in the brain, which means that patients with Down syndrome have more beta protein production since birth.
Patients with Alzheimer’s disease and Down syndrome benefit at the same time
Pfeifer explained that being able to study vaccines in a “more homogeneous environment” based on genetic markers can help overcome the problems of finding and developing treatments for Alzheimer’s disease.
In addition to the difficulty of providing treatment before onset, these challenges include the mechanisms and timing uncertainties of disease-induced brain changes in Alzheimer’s disease, genetic and age-related variability, and other forms of dementia. The risk of the cause.
Pfeifer hopes that ACI-24 will “change the lives of patients with Down syndrome and Alzheimer’s disease.” She believes that if effective and safe, ACI-24 can be used early in the Down syndrome patients to prevent them from developing dementia; long-term treatment with existing Alzheimer’s drugs is expensive and “burdens the body” .
Initial data from the Phase Ib study showed that ACI-24 was well tolerated at all doses, no subjects withdrew due to serious adverse events, and had significant anti-beta amyloid immunoglobulin response. Currently, the vaccine is undergoing Phase II clinical trials.