Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Biogen, Neurimmune
BIIB037 is a high-affinity, fully human IgG1 monoclonal antibody against a conformational epitope found on Aβ. It was originally derived by the biotech company Neurimmune in Schlieren, Switzerland, from healthy, aged donors who were cognitively normal. The rationale was that these donors' immune systems had successfully resisted Alzheimer’s disease, and that the operative antibodies could be turned into therapeutics by a process called "reverse translational medicine." BIIB037 binds aggregated forms of Aβ, not monomer. In the brain, BIIB037 preferentially binds parenchymal over vascular amyloid. Thirteen-week chronic dosing in old APP-transgenic mice reduced plaques of all sizes; vascular amyloid stayed unchanged. Brain-exposure studies in mice suggest that microhemorrhages start at 500 mg/kg, more than 100 times the minimally effective dose for plaque clearance, 3 mg/kg (Apr 2013 conference news).
A Phase 1 safety and pharmacokinetics study began with a single-ascending-dose trial of 0.3 mg/kg to 30 mg/kg intravenous BIIB037 in 56 people with mild to moderate AD. Participants were assessed at 10 time points up to two years after dosing. Amyloid-related imaging abnormalities (ARIAs) were monitored with four MRI scans, read both locally and by a central reader at an imaging CRO. Side effects included headache, diarrhea, and dizziness. They were mild or moderate, some possibly related to the study drug but not to the dose. No new ARIA developed during the trial beyond age- and AD-related baseline ARIA. In dose-ranging studies, a new dose is given once the safety-monitoring board has deemed the previous dose safe. Because BIIB037 seemed safe at 30 mg/kg, 60 mg/kg was added. This amounts to 4 grams in a 150-pound person. (For comparison, the multiple sclerosis antibody natalizumab [Tysabri®] is administered as a 300-mg infusion.) BIIB037 exposure changed in a linear fashion across doses, with little variability from person to person. Consistent with preclinical work, the antibody generated no plasma spike.
In summer 2012, Biogen Idec started PRIME, a multicenter, multiple-dose study in 166 people with prodromal or mild AD. Besides aducanumab, this trial evaluates the performance of proposed research diagnostic criteria (see Dubois et al., 2010; Albert et al., 2011). Prospective participants must score more than 19 on the MMSE, between 0.5 and 1 on the Clinical Dementia Rating, and 27 or lower on the Free and Cued Selective Reminding Test (FCSRT). They then undergo amyloid PET and MRI scans; a positive amyloid scan is required for entry.
Nineteen imaging centers using 12 different scanner models participate in the aducanumab prodromal trial and send the scan data to a central reading CRO, where a binary classification method and quantitative standardized uptake value ratios (SUVRs) are compared to establish best methods of interpreting an amyloid scan. Of the first 80 patients scanned, 44 had been diagnosed as prodromal, 36 as mild AD. Of those, the visual read confirmed the clinical diagnosis in 60 percent and the quantitative analysis confirmed the diagnosis in 55 percent of the subjects. The visual read produced no false positives. The false negatives were prodromal cases with a mean MMSE of 27 and an SUVR near the cutoff (Apr 2013 conference news).
In December 2014, Biogen announced it would move into Phase 3 based on interim data suggesting target engagement and a cognitive benefit (Bloomberg news).
In March 2015, an interim analysis of the first data cut prespecified in the protocol was reported at the AD/PD conference (Mar 2015 conference news). Aducanumab dose-dependently reduced amyloid deposition in six cortical regions of the brain. The effect was large: After one year, the highest dose appeared to have reduced cortical amyloid close to the cut point of positivity. ARIA-E occurred with increasing dose and ApoE4 genotype; about a third of cases were symptomatic, with mild headache and confusion reported in retrospect. Two exploratory signals were reported, as well: Aducanumab appeared to reduce decline on the MMSE and CDR-SB in dose-dependent fashion, although only the 1, 3, and 10 mg/kg doses were reported at AD/PD. The PRIME study will continue collecting data until 2016.
In July 2015, one-year data for the 6 mg/kg dose were presented to have reduced brain amyloid levels and, in exploratory analyses, to have slowed decline on the CDR-SB in accordance with a dose-dependent effect. On the MMSE, the 6 mg/kg group numerically was closer to the 1 mg/kg than the 3 or 10 mg/kg group, but overall dose dependence remained significant. Instances of ARIA-E increased with dose and ApoE4 carriage, up to 55 percent among ApoE4 homozygotes on 10 mg/kg. Most instances occurred early in the trial, about a third were symptomatic; all resolved (Aug 2015 conference news).
In May 2015, development began in Japan with a Phase 1 study of increasing doses up to 6 mg/kg in 25 patients with mild to moderate AD.
In August 2015, Phase 3 began with two efficacy trials. The 221AD301 ENGAGE study planned to enroll 1,350 people with MCI due to AD or mild AD as ascertained by a positive amyloid PET scan. It aimed to compare monthly infusions of one of three doses of aducanumab or placebo over an 18-month treatment course; the primary outcome measures were cognitive and functional decline per the CDR-SB; secondary outcomes include the MMSE, ADAS-cog13, and the ADCS-ADL mild cognitive impairment version. The trial is set to run until 2022, in 150 centers in North America, Europe, Australia, and Asia. The 221AD302 EMERGE study is identical to ENGAGE; it was conducted in 1,350 additional patients at 131 other sites in North America and Europe.
In 2016, Biogen formally published the PRIME data (Sevigny et al., 2016), presented data suggesting that a dose titration schedule mitigated ARIA-E, and announced it would be used in Phase 3 (Dec 2016 conference news).
In 2017 and spring 2018, two- and three-year data from the long-term open-label extension phase of the PRIME study were being reported at conferences as continuing to show dose-dependent amyloid removal by up to 70 centiloids, and also as slowing cognitive decline as per exploratory analysis. ARIA in the open-label extension was reported to be similar to ARIA in the placebo-controlled phase of the trial (Dec 2017 and May 2018 conference news).
On March 21, 2019, Biogen and Eisai announced they would terminate all currently ongoing aducanumab trials, following an interim analysis that predicted EMERGE and ENGAGE would miss their primary endpoints (see Mar 2019 news). On April 24, 2019, Biogen announced it would not initiate an anticipated Phase 3 secondary prevention program with aducanumab (Biogen Q1 Update), and removed it from its pipeline (May 2019 conference news).
On October 22, 2019, Biogen announced that the interim futility analysis was wrong, and that subsequent analysis of a larger data set instead showed EMERGE had met its primary endpoint. People on the highest dose, 10 mg/kg, had a significant reduction in decline on the primary endpoint, the CDR-SB. This group also declined less on secondary endpoints MMSE, ADAS-Cog, and ADCS-ADL-MCI. The low-dose group had some slowing of progression, but the differences were not statistically significant from placebo.
The ENGAGE trial did not meet the primary endpoint; however, an exploratory analysis suggested that a subgroup of people who had received 10 or more 10 mg/kg doses declined more slowly, similar to comparable EMERGE participants.
In substudies to these trials, aducanumab caused a dose-dependent reduction in brain amyloid and some CSF phospho-Tau reduction. As in prior trials, the most common adverse events were ARIA-E and headache.
Based on interactions with the FDA, Biogen announced plans to apply in early 2020 for regulatory approval for aducanumab in the U.S. The company will also ask eligible patients from EMERGE, ENGAGE, and PRIME, to return for renewed dosing and observation (see Oct 2019 news and commentary).
At CTAD in December 2019, Biogen attempted to link cumulative exposure to efficacy with a subgroup analysis of participants who enrolled after a protocol amendment that allowed higher doses for ApoE4 carriers. Post-amendment enrollees received a median cumulative dose of 153 mg/kg, versus 116 mg/kg for pre-amendment enrollees. Later enrollees in both trials were reported to have declined more slowly on the CDR-SB, by 30 percent in EMERGE and by 27 percent in ENGAGE. Secondary outcomes were said to have followed a similar pattern, but data were not shown. Results from a tau PET imaging substudy in 36 patients were shown to suggest a dose-dependent decline in MK6240 tracer uptake in medial temporal brain regions after 14 months of treatment, suggesting aducanumab reduced tangle pathology. The incidence of ARIA was high. One-quarter of participants in the 6 mg/kg dose group and one-third of those receiving 10 mg/kg developed ARIA-E, compared with 10 percent in the placebo group. Seventeen percent of people on drug developed ARIA-H microhemorrhages, compared with six percent of controls (Dec 2019 conference news and commentary).
On January 27, 2020, Biogen listed a Phase 3b open-label study for 2,400 previous aducanumab trial participants, who will receive monthly injections of 10/kg for two years. The trial lists only safety and tolerability parameters as primary outcomes. Called EMBARK, the study is projected to run through September 2023. At the November 2020 CTAD virtual meeting, the company presented more detail on secondary and exploratory endpoints related to long-term efficacy and biomarkers. Endpoints for efficacy will to be the same as in EMERGE and ENGAGE, with the addition of the CGIC every six months. Biomarker endpoints will include amyloid-PET, tau-PET and CSF in a subset of participants, and volumetric MRI in all. As of September 2020, the study had screened 880 participants and enrolled 531.
On July 8, 2020, Biogen submitted a biologics license application to the U.S. Food and Drug Administration for aducanumab, requesting priority review (July 2020 news), and later in the year, filed for approval in the European Union and Japan.
On November 6, 2020, an FDA advisory committee voted against approval, citing weaknesses in the efficacy data, and recommended a confirmatory trial (see Nov 2020 news and Nov 2020 news for commentary). On November 9, Public Citizen lodged a complaint.
To view all clinical trials on aducanumab, see clinicaltrials.gov.
Clinical Trial Timeline
Last Updated: 23 Dec 2020
- Safe at 4 Grams? No ARIA at High Dose of Human Aβ Antibody
- Biogen Antibody Buoyed by Phase 1 Data and Hungry Investors
- Aducanumab, Solanezumab, Gantenerumab Data Lift Crenezumab, As Well
- Much ‘Adu’ About a Little: Phase 1 Data Feeds the Buzz at CTAD
- 10th CTAD: Finally, Alzheimer’s Field Is Serious About Prevention Trials
- New Alzheimer’s and Parkinson’s Immunotherapy Data at AAN
- Biogen/Eisai Halt Phase 3 Aducanumab Trials
- Keep Your Enthusiasm? Scientists Process Brutal Trial Data
- ‘Reports of My Death Are Greatly Exaggerated.’ Signed, Aducanumab
- Exposure, Exposure, Exposure? At CTAD, Aducanumab Scientists Make a Case
- Biogen Asks FDA To Approve Aducanumab
- FDA Advisory Committee Throws Cold Water on Aducanumab Filing
- Aducanumab Still Needs to Prove Itself, Researchers Say
- Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27. PubMed.
- Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. Epub 2011 Apr 21 PubMed.
- Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.
- Frost CV, Zacharias M. From monomer to fibril: Abeta-amyloid binding to Aducanumab antibody studied by molecular dynamics simulation. Proteins. 2020 Dec;88(12):1592-1606. Epub 2020 Aug 3 PubMed.
- Budd Haeberlein S, O'Gorman J, Chiao P, Bussière T, von Rosenstiel P, Tian Y, Zhu Y, von Hehn C, Gheuens S, Skordos L, Chen T, Sandrock A. Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease. J Prev Alzheimers Dis. 2017;4(4):255-263. PubMed.
- Selkoe DJ. Alzheimer disease and aducanumab: adjusting our approach. Nat Rev Neurol. 2019 Jul;15(7):365-366. PubMed.
- Arndt JW, Qian F, Smith BA, Quan C, Kilambi KP, Bush MW, Walz T, Pepinsky RB, Bussière T, Hamann S, Cameron TO, Weinreb PH. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018 Apr 23;8(1):6412. PubMed.
- Ferrero J, Williams L, Stella H, Leitermann K, Mikulskis A, O'Gorman J, Sevigny J. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease. Alzheimers Dement (N Y). 2016 Sep;2(3):169-176. Epub 2016 Jun 20 PubMed.
- Kastanenka KV, Bussiere T, Shakerdge N, Qian F, Weinreb PH, Rhodes K, Bacskai BJ. Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice. J Neurosci. 2016 Dec 14;36(50):12549-12558. Epub 2016 Nov 3 PubMed.
- Gamage KK, Kumar S. Aducanumab Therapy Ameliorates Calcium Overload in a Mouse Model of Alzheimer's Disease. J Neurosci. 2017 Apr 26;37(17):4430-4432. PubMed.
- Chiao P, Bedell BJ, Avants B, Zijdenbos AP, Grand'Maison M, O'Neill P, O'Gorman J, Chen T, Koeppe R. Impact of Reference/Target Region Selection on Amyloid PET Standard Uptake Value Ratios in the Phase 1b PRIME Study of Aducanumab. J Nucl Med. 2018 May 18; PubMed.
- Schneider L. A resurrection of aducanumab for Alzheimer's disease. Lancet Neurol. 2020 Feb;19(2):111-112. Epub 2019 Dec 4 PubMed.
- Kaplon H, Muralidharan M, Schneider Z, Reichert JM. Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. PubMed.
- Vaillancourt DE. Aducanumab reduces Aβ plaques in Alzheimer's disease. Mov Disord. 2016 Nov;31(11):1631. Epub 2016 Oct 14 PubMed.