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    Home > Active Ingredient News > Study of Nervous System > 18 years later, the FDA finally approved a new drug for Alzheimer’s

    18 years later, the FDA finally approved a new drug for Alzheimer’s

    • Last Update: 2021-06-17
    • Source: Internet
    • Author: User
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    *Only for medical professionals' reference to read Alzheimer's disease, which has a huge patient population and urgent needs, but effective drugs are quite scarce.
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    On June 7, local time (Monday), the US FDA adopted accelerated approval channels Approved the first new drug for Alzheimer's disease since 2003-Aducanumab (trade name Aduhelm)
    .

    The approval of this drug is not only a super heavyweight in the treatment of Alzheimer’s disease in the past 20 years, but also a major controversy over the FDA’s drug approval standards, so that the US biomedical industry media STAT published on the front page of today There were three related reports, and the front page headline was a harshly worded comment, with the headline stating that the FDA’s move was "changing its own rules, with huge risks
    .
    "
    (The front page of the famous American biomedical industry media STAT today) Alzheimer's disease is known informally as "Alzheimer's disease".
    The main clinical features are memory loss, delayed thinking and reasoning, and changes in personality and behavior.

    .

    It is an irreversible progressive neurological disease
    .

    That is, once the disease damage occurs, it cannot return to a healthy state, and at the same time, it will continue to progress
    .

    As the disease progresses, patients will experience more and more serious symptoms and complications, including various mood disorders and psychotic symptoms—such as anxiety, depression, persecutory delusions, and even the decline of basic body perception—not only for patients The body and spirit are a huge burden, and it is also a problem for the family and society responsible for caring for the patient
    .

    A statistical study published in The Lancet Public Health in December 2020 shows that among the elderly in China, there are approximately 15.
    07 million patients with dementia, of which 9.
    83 million are patients with Alzheimer's disease
    .

    Around the world, about 40 million people over the age of 60 suffer from Alzheimer's disease, and the number of cases is increasing, doubling every 20 years
    .

    For such a disease with a huge patient population and urgent needs, effective drugs are quite scarce
    .

    What is even more thought-provoking is that the drugs that have been on the market in recent years, such as the current Aducanumab and the GV-971 of the previous two years, are full of controversy.
    Why is this? There is no new medicine in the past 20 years, why? One of the fundamental reasons for the difficulty in developing anti-Alzheimer's disease drugs is that the pathogenic mechanism of Alzheimer's disease has not yet been determined
    .

    At present, Alzheimer's disease has a variety of hypothetical mechanisms, and a large number of clinical studies mainly rely on different hypotheses to find solutions for treatment or alleviation of the disease
    .

    In 2019, a retrospective review published by Nature’s journal Signal Transduction and Targeted Therapy gave a statistical chart.
    The analysis showed that as of 2019, 2173 clinical studies on Alzheimer’s disease rely on hypotheses.
    More than 10 kinds of.
    .
    .
    (Schematic diagram of the relationship between clinical trials and various hypotheses of Alzheimer's disease) As can be seen from this picture, in the field of clinical trials of Alzheimer's disease, the main popular ones are: β-amyloid Hypothesis (22.
    3%), neurotransmitter hypothesis (19.
    0%), Tau protein hypothesis (12.
    2%), mitochondrial cascade hypothesis and related hypotheses (17.
    0%), neurovascular hypothesis (7.
    9%), exercise hypothesis (6.
    6%), and Inflammation hypothesis (4.
    6%) and so on
    .

    It can be seen that about 70% of clinical trials are invested in the first four hypotheses.
    Even if the scope is limited to the main hypotheses, Alzheimer’s disease has often been based on different hypotheses in the past 20 years, whether basic or clinical.
    The results are inconsistent with other hypotheses, so the contradictory situations that lead to controversy are studied
    .

    At the same time, since there is no one hypothesis that can perfectly explain the overall condition of Alzheimer's disease, treatment methods that rely on a single hypothesis path are often ineffective and difficult to inhibit the progression of the disease, which makes it difficult for new treatment drugs and treatment options.
    Pass the effective test endpoint and expert review
    .

    What kind of medicine is Aducanumab? The Aducanumab produced by Biogen, which was approved by the FDA this time, relies on the β-amyloid hypothesis
    .

    This hypothesis believes that β-amyloid protein, as a metabolite, is cleared by normal metabolic processes in the brains of healthy people.
    Pathological observations have found that β-amyloid protein in the brains of Alzheimer’s disease patients cannot be normalized.
    Cleared, will form amyloid plaques.
    This theoretical hypothesis is that the accumulation of beta amyloid that cannot be normally metabolized and the formation of plaques will eventually lead to the death of nerve cells and cause diseases
    .

    From this hypothetical theory alone, we can find that even if the statement that “beta amyloid is the main cause of Alzheimer’s disease” is adopted, to fundamentally solve the problem, it is actually necessary to restore the patient’s brain metabolism to normal.
    Allow patients to clear beta amyloid protein normally
    .

    Aducanumab is a monoclonal antibody that targets β-amyloid protein and selectively binds to β-amyloid protein to clear the accumulation of β-amyloid protein in the brain of patients
    .

    This mechanism sounds quite interesting, and Biogen also claims that Aducanumab is the only drug that can inhibit the development of the disease rather than just improve the symptoms
    .

    In other words, Biogen believes that, without exception, several drugs approved in the past have only the effect of improving symptoms.
    Even if the medication is taken, the patient's condition will continue to progress.
    Only Aducanumab has managed to stop the patient's condition from progressing.

    .

    Why does Aducanumab's approval cause controversy? Before it was approved, Aducanumab was on the cusp of public opinion in the pharmaceutical industry because of the ups and downs in clinical trials
    .

    Biogen has initiated two clinical trials, called 221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (ENGAGE) and 221AD302 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (EMERGE)
    .

    Since the FDA previously allowed Biogen to skip the clinical phase II trial, and the phase II trial can be used to study the optimal dose and adverse reaction balance, Biogen lacking this step has the problem of titrating the safe dose and effective dose in the phase III trial.
    , It also caused some adverse reactions such as cerebral hemorrhage in patients with APOE4 gene
    .

    The "medical community" once introduced this situation in the report "The neurologist has Alzheimer's disease and sent his case to the SCI paper"-the doctor in question happened to be involved in the clinical practice of Aducanumab After the trial, cerebral hemorrhage and other serious problems occurred after the medication, and he was admitted to the ICU
    .

    Adverse reactions are only one of them.
    The situation that triggered greater public opinion is the analysis of the data results of the ENGAGE and EMERGE trials showing that the drug is futile
    .

    On May 30th, three experts jointly published an opinion article on JAMA to evaluate Aducanumab, using the word Futility in the title
    .

    The term that the term describes clinically is that certain treatments, medications, and nursing care are of no more benefit to the patient
    .

    Simply put, the two trials of ENGAGE and EMERGE were sentenced to negative results, causing the stock price to fall by one-third
    .

    It was said to be "once" because three months before the data was locked and the negative results were to be qualitatively determined, data of 318 patients who completed clinical trials were entered
    .

    Therefore, the data was re-analyzed.
    In the EMERGE study, patients who used high-dose Aducanumab had better cognitive function than the placebo group, which is a positive result
    .

    However, in the ENGAGE study, this difference was not observed
    .

    In any case, this positive result caused the stock price to rise and finally allowed it to obtain FDA approval
    .

    In fact, the FDA's internal opinions on the over-approval of this drug are not consistent.
    In November last year, the expert committee voted to reject Aducanumab's over-approval and criticized the approval process
    .

    However, considering the severity of the disease, the urgent needs of patients and other factors, the FDA finally over-approved Aducanumab using the fast-track approval channel without discussion by the expert committee
    .

    Due to the huge controversy, the FDA issued an explanatory note specifically for this over-approval
    .

    (FDA's description of the approval of Aducanumab) In the description, the FDA explained that they understand the "complexity" of Aducanumab clinical trial data and the expert committee's clear opposition to it.
    The approval is based on the principle that Aducanumab can reduce beta amyloid plaques.
    It is estimated that this mechanism can bring "important benefits" to patients
    .

    In the last part of the above statement, the FDA also pointed out that it will continue to monitor the situation of Aducanumab in the future, and requires Biogen to provide a post-approved clinical trial certificate to illustrate the clinical effect of the drug
    .

    If the drug is not as effective as expected, the FDA will step in and remove it from the market
    .

    (Screenshot of the corresponding part of the original FDA instructions) This operation is somewhat familiar.
    In the conditional approval of China’s new anti-Alzheimer’s disease drug “GV-971”, the State Food and Drug Administration of China made a very similar explanation, only However, the FDA added a guarantee to "let it out of the market
    .
    "
    (Screenshot of the official website of the Food and Drug Administration) How is Aducanumab clinically evaluated in China? In addition to medical experts who went to JAMA to publicly express detailed objections, there are also clinicians who went to the media to publicly express their views-"If the FDA over-approves Biogen's Alzheimer's disease treatment, I will not use it to prescribe it
    .

    " This A doctor stated in the article that not only would he not prescribe the drug, but his colleagues around him were also unwilling to prescribe it
    .

    He also pointed out that this potentially ineffective drug will cause patients to stop participating in more new drug research and development, and only content with taking this "new drug
    .
    "
    This is a relatively stern attitude, and some doctors commented sarcastically under the JAMA article, "You wrote really well, please show it to the FDA and tell them to'follow the science'.
    "
    .

    Of course, in the face of huge patient demand, not all doctors hold such an opposing attitude
    .

    At present, Aducanumab has not been approved for marketing in China, but Aducanumab is also undergoing phase III clinical trials in China
    .

    The "medical community" learned from the neurology department of one of the top three hospitals undertaking clinical trials that due to the long-term lack of medicines available, doctors and patients are very eager and expecting new drugs.
    The doctors who participated in and in charge of some clinical trials told the "medical community" that he I think the test results will be better, and the drug is effective
    .

    At the same time, the doctor told the "medical community" that he also believes that GV-971 is effective and is actively used clinically
    .

    GV-971 is a sensational Chinese original research and development new drug at the end of 2019.
    On November 2, 2019, the National Medical Products Administration of China conditionally approved "Phase Nine One" as a national Class I new drug for mild to moderate use.
    Alzheimer's disease, which improves the cognitive function of patients, was officially launched in China on December 29
    .

    If Aducanumab relies on a single hypothetical mechanism, the mechanism of GV-971 can be more "comprehensive.
    " According to its researchers, "GV-971 reshapes the balance of the intestinal flora and inhibits the abnormality of specific metabolites of the intestinal flora.
    Increase, reduce peripheral and central inflammation, reduce β-amyloid protein deposition and Tau protein hyperphosphorylation, thereby improving cognitive dysfunction"-inflammation hypothesis, β-amyloid hypothesis and Tau protein hypothesis, covered in popular hypotheses There are three kinds, and the mechanism of Aducanumab only depends on the "district" one of the β-amyloid hypothesis
    .

    The “medical community” visited the neurological memory clinic of the hospital and learned that patients and their families were really eager for GV-971.
    GV-971 was out of stock at that time.
    After the prescription was issued, the medicine was not available immediately due to lack of stock.
    The desire for medicine is more intense
    .

    At present, there are not many drugs available for Alzheimer's disease clinically, and the improvement of the disease is also very limited.
    Many mood disorders and psychotic symptoms need symptomatic drugs to control
    .

    Many patients in the later stage of the disease do not even recognize their family members, do not know whether they are warm or cold, are naked in cold weather, do not know whether they are hungry or full, and if they eat on their own, they will continue to eat because they do not feel full, which is life-threatening
    .

    A doctor told the “medical community” that Alzheimer’s disease has progressed to the later stage.
    For the patient, every day is spent in loneliness, panic, and pain, regardless of how the outside world takes care of him/her.
    For the patient, what he always feels is unfamiliarity (caused by forgetting), fear (symptoms such as persecution delusions) and physical pain
    .

    Therefore, it is not difficult to imagine that in the face of such a long and immense pain, any new medicine, even if it only has some erratic effects, is also the hope of patients and their families, making them like drowning people, trying their best to grasp this.
    Life-saving straw-this is also the problem that the hard-working American doctor is worried about
    .

    Since the conditional approval of GV-971 in China at the end of 2019, on the one hand, the clinical supply is in short supply and a lot of profits have been made.
    On the other hand, there has been a big battle in the academic world.
    The main inventor of GV-971 is even more closely related to the current incumbent.
    Rao Yi, the president of Capital Medical University, started a two-line confrontation in journals and the media, and the debates between the two sides have come back and forth
    .

    (One of Rao Yi’s public doubts originally published in cell research) Regrettably, the doubts about GV-971 from the medical academia and industry do not seem to reach patients and family members.
    When taking medicine, the people who need to know the truth most cannot get the information of interest.
    To solve this problem, the key point is still in the hands of the approval agency: whether science is respected, and whether there are sufficient scientific and evidence-based experts to review it
    .

    After all, it is the examination and approval agency that holds the door to "science" for patients
    .

    Otherwise, it is useless for experts to question it loudly outside the gate of approval.
    According to the information on the official website of Green Valley Pharmaceuticals, in May 2020, the FDA has approved its application for an international multi-center phase III clinical trial in the United States
    .

    In November 2020, 971 completed the first patient screening of the international phase III clinical trial.
    It is expected to end the clinical trial in 2025 and be marketed in Europe and the United States
    .

    I don’t know how the FDA will judge this drug, which is more “sweet” than Aducanumab from a mechanism point of view, by then.
    .
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    At the end of the article, let’s take a small survey~References: [1]https://news.
    stcn .
    com/sd/202102/t20210202_2799223.
    html.
    [2]http://zhishifenzi.
    com/depth/depth/9741.
    html.
    [3]https:// 4]https:// GC,Emerson S,Kesselheim AS.
    Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility.
    JAMA.
    2021;325(17):1717-1718.
    doi:10.
    1001/jama.
    2021.
    3854.
    [6]Du X,Wang X,Geng M .
    Alzheimer's disease hypothesis and related therapies.
    Transl Neurodegener.
    2018;7:2.
    Published 2018 Jan 30.
    doi:10.
    1186/s40035-018-0107-y.
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