Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019
Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justif...
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| Published in | Alzheimer's & dementia Vol. 17; no. 4; pp. 696 - 701 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.04.2021
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| Online Access | Get full text |
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| Abstract | Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high‐dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes. |
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| AbstractList | Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high-dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes.Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high-dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes. Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high‐dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes. |
| Author | Jones, David T. Greicius, Michael D. Knopman, David S. |
| Author_xml | – sequence: 1 givenname: David S. surname: Knopman fullname: Knopman, David S. email: knopman@mayo.edu organization: Department of Neurology, Mayo Clinic – sequence: 2 givenname: David T. surname: Jones fullname: Jones, David T. organization: Mayo Clinic – sequence: 3 givenname: Michael D. surname: Greicius fullname: Greicius, Michael D. organization: Stanford University School of Medicine |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33135381$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2020 The Authors. published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association. |
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| License | Attribution 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association. |
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| PublicationTitle | Alzheimer's & dementia |
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| References | 2019 2014; 370 1999; 400 2016; 537 2018; 10 2019; 380 2020 2017; 9 2017; 88 2019; 15 2018; 14 2018; 378 e_1_2_4_11_1 e_1_2_4_12_1 e_1_2_4_3_1 e_1_2_4_13_1 e_1_2_4_2_1 e_1_2_4_5_1 e_1_2_4_4_1 e_1_2_4_7_1 e_1_2_4_6_1 e_1_2_4_9_1 e_1_2_4_8_1 Dujardin S (e_1_2_4_10_1) 2020 33135288 - Alzheimers Dement. 2021 Apr;17(4):702-703 |
| References_xml | – volume: 370 start-page: 311 year: 2014 end-page: 321 article-title: Phase 3 trials of solanezumab for mild‐to‐moderate Alzheimer's disease publication-title: N Engl J Med – volume: 378 start-page: 321 year: 2018 end-page: 330 article-title: Trial of Solanezumab for mild dementia due to Alzheimer's disease publication-title: N Engl J Med – volume: 9 start-page: 95 year: 2017 article-title: A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease publication-title: Alzheimers Res Ther – volume: 88 start-page: 1751 year: 2017 end-page: 1758 article-title: Randomized controlled trials in mild cognitive impairment: sources of variability publication-title: Neurology – volume: 15 start-page: 73 year: 2019 end-page: 88 article-title: A critical appraisal of amyloid‐beta‐targeting therapies for Alzheimer disease publication-title: Nat Rev Neurol – volume: 14 start-page: 869 year: 2018 end-page: 879 article-title: Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease publication-title: Alzheimers Dement – volume: 400 start-page: 173 year: 1999 end-page: 177 article-title: Immunization with amyloid‐beta attenuates Alzheimer‐disease‐like pathology in the PDAPP mouse publication-title: Nature – volume: 10 start-page: 96 year: 2018 article-title: Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti‐amyloid‐beta antibody double‐blind, placebo‐controlled, randomized phase II study in mild‐to‐moderate Alzheimer's disease (BLAZE) publication-title: Alzheimers Res Ther – year: 2020 article-title: Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease publication-title: Nat Med – year: 2019 – volume: 380 start-page: 1408 year: 2019 end-page: 1420 article-title: Randomized trial of Verubecestat for prodromal Alzheimer's disease publication-title: N Engl J Med – volume: 537 start-page: 50 year: 2016 end-page: 56 article-title: The antibody aducanumab reduces Abeta plaques in Alzheimer's disease publication-title: Nature – ident: e_1_2_4_11_1 doi: 10.1212/WNL.0000000000003907 – ident: e_1_2_4_12_1 doi: 10.1056/NEJMoa1812840 – ident: e_1_2_4_6_1 doi: 10.1186/s13195-017-0318-y – ident: e_1_2_4_8_1 doi: 10.1056/NEJMoa1705971 – ident: e_1_2_4_2_1 doi: 10.1038/22124 – ident: e_1_2_4_7_1 doi: 10.1186/s13195-018-0424-5 – ident: e_1_2_4_5_1 doi: 10.1038/nature19323 – ident: e_1_2_4_9_1 doi: 10.1056/NEJMoa1312889 – year: 2020 ident: e_1_2_4_10_1 article-title: Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease publication-title: Nat Med doi: 10.1038/s41591-020-0938-9 – ident: e_1_2_4_13_1 doi: 10.1016/j.jalz.2018.01.012 – ident: e_1_2_4_3_1 doi: 10.1038/s41582-018-0116-6 – ident: e_1_2_4_4_1 – reference: 33135288 - Alzheimers Dement. 2021 Apr;17(4):702-703 |
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| Title | Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019 |
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