This article was transferred from WeChat public account:Pharmaceutical Pharmacy (ID: WuXiAppTecChina),The original title “Alzheimer’s disease new drug is back to life! Can it usher in a “shocking reversal”? 》, Cover: Oriental IC
“Stunning” (shocking), “amazing reversal” (stunning reversal)… These are the descriptions of the US media’s news of the company’s (Biogen) . Today, Yu Jian and Eisai (Eisai) company announced that after discussing with the FDA and external experts, plans to submit treatments for Alzheimer next year. (AD) The new drug application for the new drug aducanumab (BLA) .
In March of this year, the two companies announced that they would terminate Phase 3 clinical trials of aducanumab, as recommended by the Independent Data Oversight Committee. If aducanumab is finally approved, it will not only hope to benefit tens of millions of Alzheimer’s patients, but also bring new life to the “amyloid hypothesis” that was once “sentenced to death.”
This news came out and immediately caused widespread public debate. However, for this unexpected reversal, everyone has a lot of doubts in mind? What happened to the company’s aducanumab changed from “invalid” to “effective”? Does this mean that drugs for treating AD are expected to come out? Has the “amyloid hypothesis” come back to life? Today, the WuXi PharmaTech content team will share with readers an in-depth interpretation of this news.
Aducanumab changed from “invalid” to “effective” timeline
Ajiananumab, a human monoclonal antibody that binds to amyloid β(β-amyloid) . It selectively binds to amyloid deposits in the brains of AD patients and then clears the deposited proteins out of the brain by activating the immune system.
In August and September 2015, Yu Jian launched two Phase 3 clinical trials, named ENGAGE and EMERGE. These clinical trials enrolled early patients with mild cognitive impairment in AD, and confirmed by PET scans that these patients had elevated levels of beta amyloid in their brains. They received three different doses of aducanumab treatment (3mg/kg, 6mg/kg, 10mg/kg).
An important change in the trial occurred in March 2017, when the researchers modified the protocol. For AD patients with the APOE4 allele, the dose of aducanumab they received could be increased to 10 mg/kg. The highest dose of aducanumab.
The progress timeline for two phase 3 trials of ENGAGE and EMERGE (Source: Reference [2])
In March 2019, the Independent Data Oversight Committee completed an invalidity analysis of the mid-term data of the trial What is the difference between invalidity analysis and the latest data analysis?
So, why is the Invalidity Analysis of the Independent Data Oversight Committee and the data analysis of Jianjian a big difference in the effectiveness of aducanumab? This is due to the fact that the patient population for the two analyses is very different.
The experimental data published by Yu Jian showed that the cognitive ability score of patients with AD who received high-dose aducanumab in a clinical trial called EMERGE -SB) was reduced by 23% compared to the control group, and a statistically significant improvement was obtained. However, although the CDR-SB scores of AD patients receiving low-dose aducanumab treatment improved, they did not reach statistically significant levels.
EMERGE clinical trial primary endpoint data (Source: Reference [2])
In a clinical trial called ENGAGE, the therapeutic effect of aducanumab is quite different from that of EMERGE. Aducanumab did not statistically improve the patient’s cognitive ability scores, either high-dose or low-dose, and the cognitive scores were worse in patients receiving high-dose aducanumab.
Although the two trials were designed identically, the patient’s characteristics were very similar, but the effect of aducanumab was quite different.
Primary and secondary clinical endpoint data for ENGAGE clinical trials (Source: Reference [2])
The Independence Data Surveillance Committee’s Invalidity Analysis, which targets a patient population including all patients receiving low-dose and high-dose aducanumab in two clinical trials, EMERGE and ENGAGE. Because only patients who received high doses of aducanumab in the EMERGE trial showed significant cognitive improvement in all patients treated, the performance of these patients was significantly diminished in all patients including ineffectiveness analysis. The invalidity analysis resulted in an “invalid” result.
The performance of two subgroups of different patients in Phase 3 trials (Source: WuXi PharmaTech Content Team Mapping)
With the latest data analysis, the patients were divided into different subgroups according to the participating clinical trials and the doses of aducanumab received, and it was found that aducanumab was significantly improved in the subgroup of patients receiving high doses of aducanumab in the EMERGE trial. Cognitive ability score.
New hope for Alzheimer’s patients?
After the latest data analysis, the high dose of aducanumab can provide a statistically significant improvement in cognitive ability for specific patient subgroups in Phase 3 clinical trials.
For these patients, the improvement in cognitive ability is not only a change in the CDR-SB score. Use other scoring systems that assess cognitive ability (MMSE,ADAS-Cog13,ADCS-ADL-MCI) The assessment of these patients also demonstrated an improvement in patient cognitive ability.
EMERGE Clinical Trial Secondary Endpoint Data (Source: Reference [2])
Moreover, PET scans showed that high doses of aducanumab were able to significantly reduce beta amyloid levels in the brains of these patients.
The level of cerebral amyloid in PET scans (Source: Reference [2])
Next, Minjian plans to submit a BLA in early 2020, which will include data from Phase 1/1b studies as well as complete data from Phase 3 clinical trials. At that time, the FDA will evaluate the BLA.
Since 2003, no new drugs have been approved in the AD field. The FDA will need to weigh the urgent needs of AD patients and the assessment of the safety and efficacy of this therapy. What is the FDA’s response to this application? Everyone can look forward to it.
Is the amyloid hypothesis coming back to life?
渤健aduThe latest reversal of canumab has undoubtedly added a new firewood to the discussion of the “amyloid hypothesis”.
The “amyloid hypothesis” can be said to be a very controversial hypothesis in the field of AD research and development. It believes that the development of AD disease is caused by the accumulation of amyloid in the brain. This hypothesis is still the theory of AD onset that is supported by the most scientific evidence. However, a number of in-situ therapies targeting amyloid have been smashed in phase 3 clinical trials, raising doubts about the credibility of the amyloid hypothesis. Recent statistics on clinical trials have also shown that therapies for the treatment of AD are shifting to treatment modalities that are not based on amyloid and Tau proteins.
β amyloid hypothesis icon (Source: Reference [4])
The success of Aducanumab may raise questions about why aducanumab can improve cognitive performance in Phase 3 clinical trials, while other antibodies that target amyloid or BACE inhibitors have no effect. Does the success of Aducanumab mean that the “amyloid hypothesis” is about to revive?
It is worth noting that although a variety of research-based therapies target amyloid proteins, they work in different ways. For example, the primary role of BACE inhibitors is to inhibit amyloid precursors from being cleaved by BACE to produce amyloid. There is no direct effect on the amyloid deposition that has been produced.
And, often overlooked is that although BACE is named beta-amyloid precursor protein lyase (Beta-Site APP Cleaving Enzyme), but the protein it can cut is not just an amyloid precursor. BACE inhibitors also affect BACE’s cleavage of other important proteins and are therefore not identical to amyloid antibodies.Security features.
Even amyloid proteins are targeted by even antibodies that target amyloid. Some antibodies target soluble amyloid monomers, and some antibodies target the aggregation form of amyloid. Here, what needs to be pointed out in particular is the way in which aducanumab is discovered. It was originally discovered by Neurimmune under the reverse transformation medical technology platform.
The researchers compared the B cell bank from healthy elderly people with no cognitive impairment and elderly people with abnormally slow cognitive decline and found this monoclonal antibody. It can be said that it is an amyloid antibody found by “natural test” verification. It differs from other drug discovery processes for the amyloid antigen, which is a monoclonal antibody produced by humanization of mouse antibodies. The success of aducanumab does not necessarily predict the success of other amyloid-based therapies because of the subtle differences between the different therapies.
A recent review published in the top scientific journal Cell showed that while existing evidence supports the role of amyloid in the pathogenesis of AD, the mechanism by which amyloid triggers AD may not be advanced. The imagination is so direct, this is still a question that researchers need to clarify.
Proving the causal relationship between amyloid and cognitive decline in AD patients will remain the key to the resurgence of the amyloid hypothesis.
References:
[1] BIOGEN PLANS REGULATORY FILING FOR ADUCANUMAB IN ALZHEIMER’S DISEASE BASED ON NEW ANALYSIS OF LARGER DATASETFROM PHASE 3 STUDIES. Retrieved October 22, 2019, from http://investors.biogen.com/news-releases/news-release-details/biogen-plans-regulatory-filing-aducanumab-alzheimers-disease< /p>
[2] Biogen Aducanumab Update. Retrieved October 22, 2019, from http://investors.biogen.com/static-files/5a31a1e3-4fbb-4165-921a-f0ccb1d64b65
[3] Long and Holtzman. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell, https://doi.org/10.1016/j.cell.2019.09.001
[4] Reitz et al., (2012). Alzheimer’s Disease and the Amyloid Cascade Hypothesis: A Critical Review. International Journal of Alzheimer’s Disease. Doi: 10.1155/2012/369808
This article was transferred from WeChat public account:Pharmaceutical Kanto (ID: WuXiAppTecChina), Cover: Oriental IC