The "Waterloo Battlefield" for new drug development is undoubtedly Alzheimer's disease, with a clinical failure rate of 99.6%. Several major pharmaceutical giants have failed here.
One of the few survivors, Biogen's new drug Aduhelm, received an explosive response this year. However, Aduhelm’s sales were only $300,000 more than three months after it was approved, and there were just over 100 patients, which was far from Wall Street’s projection of about 10,000 patients starting treatment by the end of this year.
Shortly after the announcement of Aduhelm's approval, in a paper in "Nature-Aging", researchers announced the results of a clinical trial of an Alzheimer's disease vaccine, AADvac1, saying that it seemed to safely clear abnormal tau protein in the brain. . But the trial has not been able to detect that the vaccine can save brain function, the paper notes.
The Alzheimer's disease vaccine seems to have become a helpless choice after the development of new drugs has repeatedly hit a wall. Currently, there are more than 140 immunotherapy trials targeting amyloid-beta (hereinafter referred to as Aβ) and more than 25 trials targeting Tau protein, but the FDA has not approved any Alzheimer's so far. Hymer's Disease Vaccine.
Is an Alzheimer's Vaccine Really Possible?
Clinical translation brings new hope
According to the World Health Organization's Global Status Report on the Public Health Response to Dementia this year, it is estimated that more than 55 million people (8.1% of women and 5.4% of men over the age of 65) are currently living with dementia. . That number is estimated to rise to 78 million by 2030 and 139 million by 2050.
In 2019, the global cost of dementia was estimated at $1.3 trillion. That cost is expected to rise to $1.7 trillion by 2030, or $2.8 trillion when the increase in care costs is factored in.
In my country, there are currently 10 million Alzheimer's patients, and this number is still rising. It is estimated that by 2050, there will be more than 40 million Alzheimer's patients in my country.
For decades, scientists have been experimenting with various hypotheses in an attempt to find and solve the disease. In addition to the currently well-studied beta-amyloid and au proteins, another strategy is to treat Alzheimer's disease with anti-neuroinflammatory therapies.
Recently, the Institute for Molecular Medicine (IMM), one of the research parties, announced that it has licensed MultiTEP, a universal vaccine platform technology, to its incubated startup Nuravax. Similar to the flu vaccine or the new crown vaccine, the purpose of this technology is also to stimulate the system's extremely high immune response to "invaders" (amyloid and tau proteins).
The company is taking an uncommon approach by inducing therapeutically effective concentrations of antibodies against pathological proteins associated with Alzheimer's and Parkinson's disease, such as amyloid and tau.
The immune system of the elderly is deficient in naive T helper cells, but it is full of memory T helper cells. Based on these principles, Nuravax is designing vaccines to stimulate these helper T cells to interact with B cells to produce large amounts of antibodies. These antibodies can prevent the formation of amyloid plaques and Tau tangles, thereby delaying or stopping the disease.
The vaccine carries 12 protein fragments (epitopes) that the average person would acquire through vaccination or previous infection. These protein fragments are sufficient to clear the antibody titer of the blood-brain barrier.
The MultiTEP technology route is relatively new, but there are many companies that also use the concept of eliminating harmful proteins to prevent and treat Alzheimer's disease and other neurologically driven diseases.
For example, AXONNeuroscience mentioned above is conducting Phase II clinical trials of AADvac1.
Another company called Vaxxinity (formerly UnitedNeuroscience) is developing an endosome vaccine for UB-311. In 2019, the company announced positive results from a Phase IIa clinical study of a novel synthetic peptide vaccine for mild-to-moderate Alzheimer's disease, saying it had met its primary goals of safety and immunogenicity, with a 96% efficacy rate .
The progress of the above companies means that the Alzheimer's disease vaccine has begun to enter the clinical transformation stage. If it goes well, the first Alzheimer's disease vaccine will be available soon.
Dr. Michael Agadjanyan, head of the Department of Molecular Immunology at IMM, believes that under normal circumstances, amyloid can be seen in the brain of people between the ages of 35 and 40, so vaccinations should be given at a young and healthy age to suppress amyloid as soon as possible. Protein and Tau protein aggregation.
A maintenance dose of 10 mg/kg of Biogen Aduhelm for a typical patient would cost $5.6 per year. Although the monoclonal antibody does attack some amyloid and tau proteins, Michael Agadjanyan believes that the drug should not be used as a treatment, but should also be used in conjunction with preventive measures.
The first Alzheimer's disease vaccine is about to be born?
The progress of the above companies offers new hope that an Alzheimer's vaccine is at least technically feasible, although it is too early to know whether such a vaccine will actually work.
Not only because there is a huge difference between mouse experiments and human experiments, like walking a tightrope, on the other hand, the more central reason is that the exact underlying pathology of Alzheimer's disease is still controversial. In this process, if Alzheimer's disease is treated as a single disease for prevention and treatment, it will inevitably lead to failure.
In addition, some of the previous drugs failed because they caused dangerous side effects, such as brain swelling in patients. Live vaccines also face a huge risk of side effects.
In clinical trials, novel interference prevention protocols are needed. The fundamental purpose of vaccines is not to revive neurons, but to prevent them from aging. Therefore, clinical trial designs must adapt to this new treatment paradigm, rather than following the procedures of previous drug testing. In this regard, regulatory authorities, the pharmaceutical industry, and the scientific community should all discuss together.
Ramon Cacabelos, a well-known scientist in the field of international neuroscience, believes that to achieve the success of clinical trials, the following problems still need to be solved:
Development of multi-targeted Alzheimer's disease immunotherapy: APP/MAPT dual targets are not enough to prevent Alzheimer's disease Disease progression in the early stages of Haimer's disease, other targets must be addressed interacting with APP processing to produce amyloid deposition and neurodegenerative disease;
optimization of antibody titers and epitopes through improved immune programming and vaccineomics;
immune programming Pharmacogenetic/epigenetic validation;
preventive treatment of patients with genetic disorders in the presymptomatic stage: each patient's genomic background modulates disease progression and may produce differential immunotherapy responses to Alzheimer's disease vaccines;
based on Definition of objective/multifactorial biomarkers for prevention of primary focus: new biomarkers should include genomic, epigenetic and proteomic signatures in humoral or functional neuroimaging; of particular importance are epigenetic and proteomic markers, These markers can change with disease progression and are highly sensitive to presymptomatic therapeutic intervention.
Overall, it will be years, if not decades, before an Alzheimer's vaccine is finally on the market.
