Remove starch protein
At the end of the last century, the theory of amyloid protein had already had many supporters, and Athena Neurosciences, a Los Angeles-based biotechnology company, took the lead in the process of targeting amyloid protein.
Their strategy is simple but also very bold: Develop a vaccine to clear the amyloid protein. The vaccine, named AN-1792, is capable of inducing an immune response and producing amyloid-specific antibodies through the synthesis of beta-amyloid protein. If a part of the antibody enters the brain, it will help remove the amyloid protein and the plaque formed in the brain.
Athena was acquired by Élan Corporation in 1996. From 1997 to 2000, they verified the effectiveness of the vaccine in a variety of animal models. Then Élan and Wyeth began clinical trials of AN-1792, which also made it the first clinically targeted amyloid protein. therapy. However, the results of the clinical trial were catastrophic: 16 patients had severe encephalitis in phase II clinical trials, so the trial was immediately suspended.
But even if the clinical trial was stopped, the follow-up of the patient was not over. Clinical data analysis found that although the proportion of patients with an immune response is very low, patients who can induce antibody production in vivo are superior to those who do not produce antibodies in terms of language, attention, memory and self-care.
So they changed their strategy and redesigned the new ‘vaccine’: Bapineuzumab. Unlike AN-1792, Bapineuzumab is a monoclonal antibody that can bind directly to amyloid without first inducing an immune response in the human body, thereby reducing the risk of encephalitis. However, this therapy has not been successful. In all phase III clinical trials, memory or other cognitive functions were not improved compared to placebo Bapineuzumab.
At the time, Eli Lilly also had a drug that targets the amyloid protein, Solanezumab, which has entered clinical trials to remove free beta-amyloid protein. Early clinical trials showed that the safety of Solanezumab was good.
After the two Phase III clinical EXPEDITION 1/2s recruited more than 2,000 patients in total, the results showed that Solanezumab did not improve the memory and other cognitive functions of mild to moderate patients, nor did it improve the daily diet of patients. And self-care ability.
Even if all the clinical trials of Bapineuzumab and Solanezumab failed at the time, researchers did not give up the amyloid hypothesis. AN-1792 and Dale Schenk, the main developer of Bapineuzumab, believe that the failure of a clinical trial may be due to a defect in the experimental design. For example, how the patient is diagnosed is the primary issue.
Autopsy was the only way to determine if a patient had the disease. And there was no strict distinction between early and mid-term patients, which may also have an impact on the results. In addition Bapineuzumab because of the side effects, resulting in low doses used in clinical trials may also be one of the factors leading to its failure. The scientists at Solanezumab seem to have more confidence that the benefits of patients with mild Alzheimer’s disease have provided a more reasonable basis for their choice of patients for further trial design.
After years of research, great progress has been made in the study of Alzheimer’s disease biomarkers. For example, the University of Pittsburgh reported on a radioactive dye PiB (Pittsburgh compound B) that binds to amyloid protein, providing a reliable basis for patient diagnosis.
Eli Lilly also began to verify the efficacy of Solanezumab in patients with mild Alzheimer’s disease. EXPEDITION 3 recruited more than 2,000 patients and completed the clinical study in October 2016. Although the industry has very high expectations for EXPEDITION 3, the experiment still failed: Compared to placebo, Solanezumab failed to improve its cognitive decline in mild patients.
However, the development of vaccines and monoclonal antibodies targeting amyloid proteins is not the only way to verify the amyloid hypothesis. As early as 1999, five research groups independently identified an APP cleavage enzyme BACE. BACE gene mutations can lead to increased activity, allowing it to shear beta-amyloid protein faster. So scientists began to try to reduce beta amyloid production by blocking the expression of BACE.
From 2003 to 2011, a large number of animal experimental studies showed that this strategy would have serious side effects. After knocking out the BACE gene, mice suffer from blindness, spine dysplasia and memory loss. But what happens if you inhibit enzyme activity?
Eli Lilly is one of the first companies to develop BACE inhibitors. Although the potential side effects of blindness have been the most worrying issue for scientists, after unremitting efforts scientists have finally developed a compound that has no obvious side effects in animal models and can reduce the formation of beta amyloid protein: LY2886721.
Eli Lilly quickly advanced the compound into clinical research. Perhaps you can also guess the outcome. The test is not going well. The study was immediately suspended due to liver injury in multiple patients. However, Merck did not delay, and quickly pushed Verubecestat into clinical research.
Early clinical studies did not find significant side effects, so Merck began to recruit a large number of patients to verify the effectiveness of the drug, and Verubecestat became the first BACE inhibitor to enter the phase III clinical. However, in February 2016, Merck suddenly announced that its phase III clinical APOCH experiment was prematurely terminated due to lack of effectiveness.
In fact, the clinical tests for verifying the amyloid hypothesis are far more than these, such as high taurine that binds to free beta-amyloid protein, and Semagacestat, a gamma secretase inhibitor developed by Eli and Elan. However, none of these drugs successfully passed clinical trials. At this point, should we have a reason to say that the theory of amyloid protein is finally dead?