Detailed data on how to understand new medicines for Alzheimer's disease

In a conference call on October 23rd, MrYan presented the results of an analysis of aducanumab's trial data in two Phase 3 clinical trials (EMERGE and ENGAGE), but the data has puzzled industry expertsBecause aducanumab obtained diametrically opposed results in two Phase 3 clinical trials with the same designWhat caused aducanumab to perform very differently in the two trials? The figures released on October 23rd do not give a convincing explanationToday, Yan Jian presented the results of the long-awaited and highly anticipated aducanumab trial in EMERGE and ENGAGE clinical trials at the 12th Alzheimer's Clinical Trials (12th Clinical Trials on Alzheimer's Disease, CTAD)In today's article, the Drug Ming-Conde Content team will share with readers an in-depth interpretation of the detailed data of aducanumab, in conjunction with media reports and PPT files from Yan Jian's reportwhy the different results of THE EMERGE and ENGAGE clinical trials are? In the data released byon October 23rd, perhaps the most surprising thing is that two theoretically identical clinical trials, EMERGE and ENGAGE, have produced completely different resultsIn THE EMERGE clinical trial, the CDR-SB score for measuring cognitive ability decreased by 22% in the patient group treated with high doses of aducanumab (a lower score meant that the disease symptoms worsened at a slower rate), while in the PATIENTs who also received high doses of aducanumab, the CDR-SB score increased by 2%So what is the difference between the treatments received by these two groups?major and secondary endpoint data for THE VIB and ENGAGE clinical trials, the red box scored changes for the high-dose group CDR-SB (Photo: Resources 1)this starts with the clinical design of both trialsPatients with AD who participated in clinical trials can be divided into two categories, one of which carries an allele called ApoE ?4 (ApoE 4 plus), while the other group does not carry the ApoE 4 allele (ApoE 4-)Allele encoding apoE protein has three main types in the population: ApoE , ApoE , and ApoE , and ApoE , respectivelyThe risk of AD was significantly higher in the group carrying ApoE 4At the same time, the results of pre-trial trials showed that patients with ApoE 4 plus were more likely to develop a side effect called ARIA when receiving aducanumab treatment ARIA's full name is amyloid associated imaging abnormality, which may be a sign of cerebral edema or micro-bleeding As a result of this side effect, the maximum dose of aducanumab was 6 mg/kg in the initial trial design for patients with ApoE 4 plus The maximum acceptable dose for patients who do not carry ApoE?4 is 10 mg/kg That is, in the same high-dose group, the aducanumab dose they received was different depending on whether the patient was carrying ApoE.4 THE "EMERGE AND ENGAGE DOSING PROCESS" (PHOTO: RESOURCES 1)
IN MARCH 2017, YAN JIAN MADE CHANGES TO THE TRIAL PROCESS, ACCORDING TO THE ARIA STUDY, YAN JIAN FOUND THAT THIS SIDE EFFECT HAS NOT HAD A SIGNIFICANT IMPACT ON THE PATIENT'S HEALTH, SO IN THE UPDATED TEST PROCESS (VERSION PROTOCOL 4, PV4), PATIENTS CARRYING APOE 4 CAN ALSO RECEIVE TREATMENT WITH A5 MG/KG ADUCANUM This means that in the high-dose group, the aducanumab dose received by patients carrying ApoE?4 is not uniform, with some patients likely to receive 6 mg/kg, while others receive 10 mg/kg changes to the trial process (Photo: Source: Resources 1) the rate at which patients were recruited in both THE EMERGE and ENGAGE trials resulted in a significant difference in the proportion of patients who actually received 10 mg/kg of aducanumab treatment in the high-dose group Prior to the change in the trial process, only 21% of patients in the HIGH-dose group of EMERGE were able to receive 14 treatments of 10 mg/kg In the high-dose group of ENGAGE, the proportion of this patient group dropped to 15% This is an important difference between the two groups of patients the treatment data graph received by patients in the EMERGE and ENGAGE high-dose groups prior to Pv4, blue represents the acceptance of 10 mg/kg of aducanumab injection (Photo: Source: Supplied) the patient group under the new trial process, THE EMERGE and ENGAGE test data are similar under the new trial process (Post test process) -PV4), the proportion of patients in the group who were able to receive 10 mg/kg of high-dose aducanumab treatment increased significantly, with 51% of patients in the EMERGE group receiving 14 treatments of 10 mg/kg throughout the clinical trial, and 47% of patients in the ENGAGE group receiving 14 treatments of 10 mg/kg If we focus on subgroups of patients who have a greater chance of receiving the highest dose of aducanumab, then data analysis finds that THE data for EMERGE and ENGAGE clinical trials are very similar In patients enrolled in the new trial process, CDR-SB scores decreased by 30% and 27% respectively in patients in high-dose groups in THE EMERGE and ENGAGE trials These data show that in the EMERGE and ENGAGE groups, patients who continued to receive aducanumab at a dose of 10 mg/kg were able to achieve consistent symptom relief for the disease many questions remain to be resolved
Aducanumab's detailed results show that patients' cognitive decline can be improved if they are able to continue to be treated with a high dose of aducanumab at 10 mg/kg This does not mean that the patient's cognitive ability has improved, but that the rate of decline slows down But for AD patients, this is very important "This means that for mild patients, they have more time to take care of themselves, and they can work, shop, travel.. The most worrying thing for AD patients is that life can't take care of itself, and I think this improvement is very important for our patients, far more than the change in the score on memory tests plans to submit a regulatory application to the FDA early next year, and the company will restart the discontinued Phase 3 clinical trial to allow patients participating in the EMERGE and ENAGE trials to resume treatment for aducanumab However, even if the detailed results of aducanumab are published, there are still many questions about aducanumab that have not yet been answered For example: how Aducanumab is effective for AD patients who do not carry ApoE?4? 's data are not classified according to whether or not the patient's efficacy is carried by ApoE Since the change in Pv4 allows patients carrying ApoE 4 to use a higher dose of aducanumab, this means that the positive effects of Pv4 may be due to improved symptoms in patients with ApoE 4 positive patients So does high-dose aducanumab have the same effect on patients who do not carry ApoE?4? From the point of view of FDA approval, this will determine the size of the patient population that aducanumab applies to will the side effects of Aducanumab affect its approval? ARIA is a common side effect of beta amyloid antibody drugs in clinical trials In the detailed data published by Yan Jian, 35% of patients treated with high doses of aducanumab had ARIA-related cerebral edema (ARIA-E) and 18% to 22.7% of patients with ARIA-related microhemorrhage (ARIA-H) Since the FDA will measure the efficacy-risk ratio of aducanumab when reviewing its regulatory application, the frequency and severity of ARIA events are also of concern However, most patients with ARIA did not show obvious symptoms and did not die as a result of ARIA, he said And as more clinical trials of these drugs progress, health care providers are now more sophisticated in their control over ARIA, so it may no longer be a limiting factor does need a new clinical trial? subgroup analysis of patients who had the opportunity to continue to receive 10 mg/kg dose aducanumab treatment showed consistent efficacy in EMERGE and ENGAGE clinical trials, but this was an after-the-fact analysis of a subgroup of the trial "We think this analysis should be seen as an exploration of a hypothesis," said Brian Skorney, an analyst at Baird To truly determine the efficacy of (high-dose aducanumab treatment), a new prospective clinical trial is needed in this regard, Yan Jian stated that the company will respect science and comply with the FDA's review mechanism and decisions But another clinical trial could take three to five years, which can be a long wait for patients eager to see new drugs improve the symptoms of the disease , the detailed data will not answer the most important question in everyone's mind, that is, whether the in-research treatment can be approved by the FDA to market 'It will be a top priority for the company to submit a regulatory application as soon as possible, ' Mr Yan said 'It remains to be seen what the outlook holds for aducanumab References: 1, EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Alzheimer's Disease Retrieved December 5, 2019 From Biogen Plans Filing filings for aducanumab in Early Alzheimer's Disease Retrieved December 4, 2019, from 3, BIOGEN REGULATORY FILING FOR ADUCANUMAB IN ALZHEIMER'S DISEASE SOURCE ON NEW ANALYSIS OF LARGER DATASET PHASE 3 FROMS Retrieved December 4, 2019, from 4 s 4 s 4's books key to making sense of new data on Biogen's resurrected Alzheimer's drug Retrieved December 4, 2019, from Retrieved December 4, 2019, from smh.com.au smh.com.au smh.com.au smh.com.au/instagram-aducanumab- Retrieved December 5, 2019, from s Origind December 5, 2019, from original title: Deep Interpretation! How can the detailed data of the new Alzheimer's disease drug be understood?