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Aducanumab - Biogen/Eisai Co/Neurimmune Therapeutics

Drug Profile

Aducanumab - Biogen/Eisai Co/Neurimmune Therapeutics

Alternative Names: Aducanumab-avwa; ADUHELM; Anti-beta amyloid monoclonal antibody - Biogen/Neurimmune Therapeutics; BART; BIIB 037; NI-10

Latest Information Update: 19 Nov 2021

At a glance

  • Originator Neurimmune Therapeutics; University of Zurich
  • Developer Biogen; Eisai Co Ltd
  • Class Antibodies; Antidementias; Monoclonal antibodies
  • Mechanism of Action Amyloid beta-protein inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Alzheimer's disease

Most Recent Events

  • 17 Nov 2021 Biogen and Eisai expects a formal opinion form Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on Marketing Authorization Application in Alzheimer's disease
  • 11 Nov 2021 Pooled efficacy data from the phase III EMERGE and ENGAGE trials in Alzheimer's disease released by Biogen
  • 28 Oct 2021 No recent reports of development identified for phase-I development in Alzheimer's-disease(In volunteers) in USA (SC, Injection)

Development Overview

Introduction

Aducanumab is a monoclonal antibody directed against amyloid beta developed by Biogen and Eisai, under a license from Neurimmune, for the treatment of Alzheimer's disease. Alzheimer's disease is caused by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Aducanumab selectively targets soluble oligomers and insoluble fibrils embedded in the beta amyloid plaque, in the brains of patients and reduce soluble and insoluble Aβ in a dose-dependent manner. Aducanumab was discovered by Neurimmune Therapeutics using their Reverse Translational Medicine (RTM) technology platform together with a team of researchers at the University of Zurich. The technology translates antibody-encoding genetic information obtained from human white blood cells into therapeutic antibodies. A de-identified library of B cells collected from healthy elderly participants without cognitive impairment was used for the discovery of aducanumab. The drug is available in the US for the treatment of Alzheimer's disease. Aducanumab is under regulatory review in the EU, Japan, Australia, Canada, Brazil, and Switzerland. Clinical development is ongoing in multiple countries.

In March 2015, Biogen Idec changed its name to Biogen [1] .

As at October 2021, no recent reports of development had been identified for phase-I development in Alzheimer's-disease (In volunteers) in USA (SC, Injection).

Company Agreements

In October 2017, Eisai Co Ltd and Biogen Idec expanded their agreement, with Eisai exercising its option to co-develop and co-promote Biogen’s aducanumab. Under the terms of the agreement Biogen would continue to lead the phase III development of aducanumab and will remain solely responsible for all development costs until April 2018. Eisai will then reimburse Biogen for 15% of expenses from April 2018 through December 2018, and 45% from January 2019 onwards. Neither company is making any upfront payments associated with the exercise of the aducanumab option. Furthermore, Eisai’s and Biogen’s respective milestone payments under the original agreement for aducanumab and BAN 2401 were eliminated. The companies will continue to jointly develop elenbecestat and BAN 2401.Previously in March 2014, Eisai and Biogen entered into a collaboration to develop and commercialise Eisai's drug candidates for the treatment of Alzheimer's disease, BAN 2401 and E 2609 (elenbecestat) [see ADIS Insight drug profile800034837]. Both companies will co-develop and co-market the products in major markets, including Japan, the US and the EU. Eisai and Biogen will share research and development costs with Eisai booking all sales and with profits to be split between the companies. [2] [3] [4] [5] [6] [7]

In May 2018, Biogen and Neurimmune announced that Biogen has exercised its option to further reduce the royalty rates payable on potential future sales of aducanumab. As per the option, Neurimmune will receive $US50 million payment from Biogen in exchange for a 5% reduction in the original royalty rates on potential commercial sales of aducanumab, which follows the 15% reduction in royalty rates announced in October 2017 as a part of their amended agreement from 2017. Previously, in December 2010, Biogen Idec and Neurimmune Holding AG announced that Biogen Idec had acquired a subsidiary of Neurimmune, which includes the world-wide rights to three pre-clinical immunotherapy programs. The three programs are focused on the discovery and development of novel human antibodies that address three central nervous system targets: alpha-synuclein, tau and TDP 43. Biogen Idec will make an initial payment of $US32.5 million and up to $US395 million in contingent payments. This acquisition builds on a 2007 agreement between the two companies to explore human antibodies against beta-amyloid for the treatment and prevention of Alzheimer's disease. Biogen Idec will be responsible for the development of the pre-clinical candidates and the commercialisation of all products. Neurimmune will be responsible for additional scientific activities with respect to the lead candidates as well as the discovery of back-up candidates, utilizing its Reverse Translational Medicine™ technology platform. Neurimmune retains the right to use its platform for creating therapeutic antibody products outside the scope of its agreement with Biogen Idec. [8] [9] [10] [11]

Key Development Milestones

As of August 2021, aducanumab (ADUHELM™) has been launched in the US for the treatment of Alzheimer’s disease [12] .

In June 2021, the US FDA granted accelerated approval for aducanumab (ADUHELM™), for the treatment of Alzheimer’s disease. The approval was based on data from the phase III EMERGE, ENGAGE and PRIME clinical trials [see trials below], demonstrating the effect of the drug on reducing amyloid beta plaques. Under the accelerated approval provisions, Biogen needs to conduct a new randomised, controlled clinical trial to verify the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug. Earlier, in January 2021, the US FDA extended the review period by three months for the Biologics License Application (BLA) for aducanumab and granted new Prescription Drug User Fee Act (PDUFA) action date of June 7, 2021. The US FDA, in August 2020, accepted for priority review, and granted a Prescription Drug User Fee Act (PDUFA) action date of March 7, 2021, for. The FDA also stated that there may be a possibility of early action on the application, under an expedited review. In November 2020, data were presented and opinions were expressed for the review process at the FDA Advisory Committee meeting. Earlier, in July 2020, following a pre-BLA meeting, Biogen completed the rolling BLA submission, which was initiated in April 2020. The submission package included data from the phase III EMERGE and ENGAGE studies, and the phase Ib PRIME study [13] [14] [15] [16] [17] [18] [19] [20] [21] .

In the first quarter of 2021 Biogen submitted a marketing authorisation application (MAA) to Agência Nacional de Vigilância Sanitária (ANVISA), Brazil for aducanumab for Alzheimer’s disease treatment. The application is in queue for review [22] [23] .

In the first quarter of 2021, Biogen submitted marketing authorisation applications for aducanumab to Health Canada, the Therapeutic Goods Agency in Australia, and Swissmedic in Switzerland, all of which are subject to agency validation of whether the applications are accepted [22] [23] .

In December 2020, Biogen has submitted Japanese New Drug Application (J-NDA) to the Ministry of Health, Labor and Welfare (MHLW) for aducanumab in the treatment of Alzheimer’s disease [24] .

In October 2020, Biogen announced that European Medicines Agency (EMA) accepted Marketing Authorization Application (MAA) of Aducanumab for the treatment of Alzheimer's Disease for review, following a standard timetable. The MAA was submitted in the same month [25] [26] . In November 2021, Biogen and Eisai announced that following an oral explanation held at the November meeting of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), Biogen received a negative trend vote on the aducanumab Marketing Authorization Application for aducanumab 100 mg/mL concentrate solution for infusion for the treatment of Alzheimer’s disease. The CHMP may adopt a formal opinion on the Marketing Authorization Application at its December meeting (December 13-16, 2021). Biogen intends to continue to engage with the EMA and CHMP as it considers next steps towards the goal of providing access to aducanumab to patients in Europe [27] .

In April 2017, the Japanese MHLW granted SAKIGAKE designation system to aducanumab for the treatment of Alzheimer’s disease in Japan [28] .

In August 2016, Biogen reported that aducanumab was granted fast track designation by the US FDA, for treatment of early Alzheimer's disease [29] .

In June 2016, the EMA granted the PRIME (priority medicines) designation to aducanumab for the treatment of Alzheimer’s disease. The PRIME status was granted based on the results of the phase Ib PRIME trial [see below] [30] .

In October 2019, Biogen reported that after consulting with the US FDA, the company intends to pursue regulatory approval for aducanumab, based on a new analysis conducted by Biogen, of a larger dataset from the phase III clinical studies that were discontinued in March 2019 following a futility analysis. Significant benefits on measures of cognition and function such as memory, orientation, and language were reported in patients who received aducanumab. The analysis includes additional data available after the pre-specified futility analysis demonstrating that aducanumab is pharmacologically and clinically active. The BLA submission will also include data from the phase I/Ib [see below] and phase III [see below] studies. Biogen also intends to offer access to aducanumab to eligible patients previously enrolled in the phase III studies, the long-term extension study for the phase Ib PRIME [see below] study, and the EVOLVE [see below] safety study [31] .

In October 2019, the Alzheimer's Association reported that Biogen will pursue regulatory approval from the US FDA for aducanumab based on phase III trial results from the EMERGE and ENGAGE studies. The company plans to offer access to aducanumab to eligible patients previously enrolled in the phase III studies, the long-term extension of the phase Ib study, and a safety study [32] .

As of April 2019, aducanumab was no longer reflecting on Biogen's pipeline and Neurimmune Therapeutics' pipeline, and based on the results of phase III ENGAGE and EMERGE trials, it seemed that the drug development was discontinued (Neurimmune Therapeutics pipeline and Biogen pipeline, April 2019).

In July 2021, Biogen and Eisai released pooled results of the PRIME, EMERGE and ENGAGE trials [33] . In June 2021, pooled efficacy data for aducanumab in Alzheimer's disease from three clinical trials was released by Biogen [14] . In the same month, pooled safety and pharmacodynamics results from the phase III EMERGE and ENGAGE trials were presented at the Alzheimer's Association International Conference 2021 (AAIC-2021) [34] [35] . Later, n November 2021, updated pre-specified pooled analysis from the two pivotal phase III trials namely; EMERGE and ENGAGE trials [see below] were released by Biogen [36]

In March 2020, Biogen initiated phase IIIb EMBARK trial to evaluate the long-term safety and tolerability of aducanumab after a wash-out period imposed by discontinuation of feeder studies in participants who had previously received aducanumab (previously treated patients) or who had previously received placebo (treatment-naïve patients) (participated in the aducanumab studies PRIME, EVOLVE, EMERGE and ENGAGE; or 221AD103, 221AD301, 221AD302 and 221AD205) (221AD304; EudraCT2019-004368-22; NCT04241068). The first patient was dosed in the same month. The open-label, single group assignment trial intends to enrol 2400 participants in the US, Australia, Austria, Belgium, Denmark, Canada, Finland, France, Germany, Italy, Japan, South Korea, Netherlands, Poland, Portugal, Spain, Sweden, Switzerland, Taiwan, United Kingdom. In November 2020, study design of the ongoing trial was presented at the 2020 Clinical Trials on Alzheimer's Disease digital conference [37] [38] .

In October 2019, Biogen reported that the phase III EMERGE trial that assessed the efficacy and safety of two dosages of aducanumab in patients with early Alzheimer's disease met its primary endpoint showing a significant reduction in clinical decline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores (221AD302; NCT02484547; EudraCT2015-000967-15) [31] . The double-blind, randomized trial was initiated in July 2015 and completed enrolment of 1 683 patients in the second quarter of 2018, in the US, Belgium, Canada, Finland, France, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, Switzerland [39] . Earlier, in March 2019, Biogen and Eisai terminated the trial based on analysis by an independent data monitoring committee which indicated that the trial was unlikely to meet the primary endpoint upon completion. There were no safety concerns regarding the study drug. In March 2021, efficacy data from the trial was Biogen [40] [41] [42] [43] [44] . In July 2021, Biogen and Eisai released updated results of the trial. The results were presented at the Alzheimer's Association International Conference (AAIC-2021) [45] [33] .

In October 2019, Biogen reported that the phase III ENGAGE trial that assessed the efficacy and safety of two dosages of aducanumab in patients with early Alzheimer's disease did not meet the primary endpoint (221AD301; NCT02477800; EudraCT2015-000966-72). The trial was discontinued in March 2019, based on analysis by an independent data monitoring committee which indicated that the trial was unlikely to meet the primary endpoint upon completion. There were no safety concerns regarding the study drug. The double-blind, randomised trial was initiated in June 2015 and completed enrolment of 1 605 patients in the second quarter of 2018, in the US, Australia, Austria, Canada, Denmark, France, Germany, Italy, Japan, Portugal, South Korea, Spain, Taiwan, and the United Kingdom [46] . The first patient was enrolled in September 2015, thereby triggering a $US60 million milestone payment to Neurimmune [31] [41] [42] [47] [48] [43] .

In March 2019, Biogen and Eisai announced that the initiation of the aducanumab phase III secondary prevention trial will be assessed while the data from ENGAGE and EMERGE are further evaluated [41] .

In March 2019, Biogen and Eisai terminated the phase II EVOLVE trial intended to evaluate the safety of aducanumab dosing in asymptomatic amyloid-related imaging abnormalities (ARIA) in patients with mild cognitive impairment due to Alzheimer's disease or with mild AD dementia, based on futility analysis and not based on safety concerns (EudraCT2018-002102-31; 221AD205; NCT03639987). The decision was taken following discontinuation of phase III trials EMERGE and ENGAGE [see above]. The randomised, double-blind, placebo-controlled trial was initiated in December 2018 and intended to enrol approximately 500 patients in the US, the UK, France, Italy and Spain [41] [49] .

In October 2021, Biogen in collaboration with Eisai Co Ltd, completed a phase I trial of aducanumab (NCT04924140; 221HV103). The primary objective of the study is to evaluate the absolute bioavailability of a single, fixed subcutaneous (SC) dose of aducanumab, compared with a single weight-based intravenous (IV) dose of aducanumab, in healthy volunteers. The secondary objectives of the study are to assess the safety and tolerability of aducanumab, administered SC in healthy volunteers, and to characterise additional pharmacokinetic (PK) parameters of a single, fixed SC dose of aducanumab and a weight-based IV dose of aducanumab in healthy volunteers. The randomised, open-label, parallel-arm study was initiated in June 2021 and enrolled 30 volunteers, aged 40 to 70 years, in the US [50] .

In December 2016, Biogen completed a randomised, double-blind, placebo-controlled phase I trial that assessed the safety, tolerability, pharmacokinetics and immunogenicity of single and multiple ascending doses of aducanumab in patients with mild to moderate Alzheimer's disease (NCT02434718; 221AD104). The trial was initiated in May 2015 and enrolled 21 patients aged 55 to 85 years, in Japan [51] .

In November 2016, Biogen completed a phase I trial which evaluated the absolute bioavailability, safety and tolerability of a single, fixed subcutaneous (SC) dose of aducanumab compared with a single, weight-based intravenous (IV) dose in healthy volunteers and to characterise the pharmacokinetics of aducanumab (221HV102; NCT02782975). The randomised, open-label trial initiated in May 2016, enrolled 28 volunteers in the US [52] .

In August 2013, Biogen Idec completed a phase I trial, which investigated the safety, tolerability and pharmacokinetics of single ascending doses of aducanumab in patients with mild to moderate Alzheimer's disease (NCT01397539). The randomised, double-blind trial was initiated in June 2011 and enrolled 53 patients in the US [53] . Interim results were presented at the 2013 Alzheimer's Association International Conference in July 2013 [54] [55] . Biogen Idec submitted the IND for the trial in April 2011 [56] .

In In March 2019, the long-term extension phase of the randomised, double-blind, placebo-controlled phase Ib PRIME trial was discontinued which was planned to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of aducanumab in patients with Alzheimer's disease, based on futility analysis and not safety concerns (NCT01677572; EudraCT2012-000349-10). The trial was initiated in October 2012. The primary endpoint is tolerability, assessed from baseline to 30 weeks. Enrolment of 197 patients aged 50 to 90 years was completed in the US in August 2015 [57] . Patients completing the one-year placebo-controlled portion of the study had a long-term extension further. Positive interim results were reported in December 2014 and March 2015. Updated results from the trial were reported in March 2018 [58] [59] [44] . Positive results from a phase Ib study of aducanumab (BIIB037) analysis were presented at the Alzheimer’s Association International Conference in July 2015 (AAIC-2015) [60] . In December 2016, interim results from the titration cohort as well as data from the first year of the long-term extension (LTE) study were released by the company [61] . Updated results from the LTE study for patients treated with aducanumab up to 24 months in the titration cohort and up to 36 months in the fixed-dose cohorts were reported in August 2017 [28] . In November 2017, Biogen released new efficacy data from the phase Ib long-term extension trial. Safety data from the LTE was reported in March 2018. Additional safety data was released in August 2018 [62] [58] [63] . The decision was taken following discontinuation of phase III trials EMERGE and ENGAGE [see above] [41] . In May 2019, data from the long term extension trial were released at the American Academy of Neurology (AAN- 2019) [64] .

In August 2016, Biogen released results from structural analysis designed to understand the epitope targeted by aducanumab and its binding profile relative to other therapies that showed less efficacy. The study demonstrated that aducanumab was highly selective for aggregated forms of beta-amyloid, including soluble oligomer and insoluble fibril and that non-binding to monomer was critical [65] .

Drug Properties & Chemical Synopsis

  • Route of administration IV, SC
  • Formulation Infusion, Injection
  • Class Antibodies, Antidementias, Monoclonal antibodies
  • Target Amyloid beta-protein
  • Mechanism of Action Amyloid beta-protein inhibitors
  • WHO ATC code

    N06DX03 (Aducanumab)

  • EPhMRA code

    N7D9 (All other anti-Alzheimer products)

  • Chemical name Immunoglobulin G1, anti-(human beta-amyloid) (human monoclonal BIIB037 heavy chain), disulfide with human monoclonal BIIB037 kappa-chain, dimer
  • Molecular formula C6472 H10028 N1740 O2014 S46
  • CAS Registry Number 1384260-65-4

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

Alzheimer's disease

Eligibility Criteria

ApoE

4

Biomarker

Drug Name Biomarker Name Biomarker Function
Aducanumab - Biogen/Eisai Co/Neurimmune Therapeutics ApoE Eligibility Criteria
Hydrocortisone Outcome Measure
Interleukin-6 (IL-6) Outcome Measure
MAMLD1 Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Alzheimer's disease accelerated approval - Marketed USA IV / Infusion Biogen 23 Aug 2021
Alzheimer's disease - - Preregistration Australia, Brazil, Canada, European Union, Japan, Switzerland IV / Infusion Biogen 31 Mar 2021
Alzheimer's disease - - Phase III South Korea, Taiwan IV / Infusion Biogen 16 Oct 2015
Alzheimer's disease - In volunteers Phase I USA IV / Infusion Biogen, Eisai Co Ltd 30 Jun 2021
Alzheimer's disease - In volunteers No development reported (I) USA SC / Injection Biogen 28 Oct 2021

Priority Development Status

Type Region Indication
PRIME European Union Alzheimer's disease

Commercial Information

Involved Organisations

Organisation Involvement Countries
Neurimmune Therapeutics Originator Switzerland
University of Zurich Originator Switzerland
University of Zurich Owner Switzerland
Neurimmune Therapeutics Owner Switzerland
Biogen Licensee World
Eisai Co Ltd Sub-licensee Japan

Brand Names

Brand Name Organisations Indications Countries
ADUHELM Biogen Alzheimer's disease USA

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Alzheimer's ex US Biogen, Eisai Filed 2021 40 2035 - 01 Feb 2021
Alzheimer's US Biogen, Eisai Filed 2021 85 2035 - 01 Feb 2021

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Alzheimer's ex US 0 0 0 0 0 0 1944 4363 4855 5366 01 Feb 2021
Alzheimer's US 0 0 0 0 0 1936 4444 4785 5138 6027 01 Feb 2021
Total 0 0 0 0 0 1936 6388 9148 9993 11393

Scientific Summary

Pharmacokinetics

Aducanumab indicated pharmacokinetic activity and exposure linear with dosage, during the phase I PRIME study in patients with Alzheimer's disease. The pharmacokinetics of aducanumab was not affected by transient treatment-related immunogenicity, which was seen in 3% of patients. The interim results were reported from the randomised, double-blind trial that enrolled 165 patients in the placebo, 1 mg/kg, 3 mg/kg and 10 mg/kg and 6 mg/kg cohorts [44] .

Ascending doses of aducanumab demonstrated a predictable pharmacokinetic profile in patients with mild-to-moderate Alzheimer's disease in a phase I trial in 56 patients with Alzheimer's disease. The aducanumab exposures (AUC) were linear throughout the dosage range of 0.3-30 mg/kg. The mean serum t1/2 was approximately 18 days, and was consistent between 1 and 30 mg/kg doses. The coefficient of variance for both AUC and t1/2 was generally less than 30% [55] .

Adverse Events

Phase III:

The results form the phase III EMERGE and ENGAGE trials showed that amyloid-related imaging abnormalities-edema (ARIA-E) and headache were the most commonly reported adverse events. The majority of patients with ARIA-E did not experience symptoms during the ARIA-E episode, and ARIA-E episodes generally resolved within 4 to 16 weeks, typically without long-term clinical sequel. In the 10-mg/kg group (n=1029 with 1 postbaseline MRI), ARIA-E was the most common adverse event (35.2%), with a higher incidence in apolipoprotein e4 carriers compared with noncarriers (43.0% versus 20.3%, respectively). ARIA-E typically occurred within the first 32 weeks of treatment with aducanumab and were mostly asymptomatic (74.0%). The majority of symptoms during ARIA were characterized as mild (67.7%) or moderate (28.3), the most common symptoms were headache (46.6%), confusion (14.6%), dizziness (10.7%) and nausea (7.8%). ARIA-E were transient but recurred in 10.6% of participants in the 10-mg/kg group. ARIA-H microhemorrhage and superficial siderosis were typically asymptomatic and more common in participants who had ARIA-E (40.3% and 38.7%, respectively), compared with participants without ARIA-E (7.6% and 1.6%, respectively) [34] [31] .

Phase I:

Aducanumab indicated an acceptable safety and tolerability profile during the phase I PRIME study in patients with Alzheimer's disease. The most commonly reported adverse events were amyloid-related imaging abnormalities (ARIA). The incidence of ARIA edema was observed early in the course of treatment and was asymptomatic or with mild, transient symptoms and led to dose-reduction. ApoE4 carriers indicated 5% incidence of ARIA oedema in the 1 mg/kg and 3 mg/kg groups, 43% in the 6 mg/kg group and 55% in the 10 mg/kg group, of which 5%, 10% and 35% patients discontinued treatment in the 1 mg/kg, 6 mg/kg an 10 mg/kg cohorts. In the titration arm the incidence of ARIA-E in ApoE4 carriers was 35%. ApoE4 non-carriers indicated ARIA oedema incidence of 0%, 9%, 11% and 17% in the 1 mg/kg, 3 mg/kg, 6 mg/kg and 10 mg/kg groups, respectively, of which 11% and 8% patients discontinued treatment in the 6 mg/kg and 10 mg/kg cohorts. Headache was seen in 22% patients receiving aducanumab, relative to 5% patients receiving placebo. Three deaths were reported in the study, two in the placebo group and one in the aducanumab 10 mg/kg group, none of which were related to the study. Other observed adverse and serious adverse events were consistent with those seen in the study population. The interim results were reported from the randomised, double-blind trial that enrolled 165 patients in the placebo, 1 mg/kg, 3 mg/kg and 10 mg/kg and 6 mg/kg cohorts. In the phase Ib LTE, the most commonly reported adverse events were headache, fall and amyloid-related imaging abnormalities (ARIA). Of the 185 patients dosed with aducanumab in the study, 46 patients experienced ARIA-E (oedema) and 61% were asymptomatic. Eight patients experienced more than one episode of ARIA-E. No new cases of ARIA-E were found in patients initially randomised to aducanumab 3, 6 or 10 mg/kg who were treated up to 24 months. The incidence of ARIA events in patients switching from placebo to aducanumab was consistent with the incidence reported in placebo-controlled portion of phase Ib [64] [28] [61] [59] [44] [57] .

Aducanumab (at dosages of 0.3-30 mg/kg) was generally well tolerated in a phase I trial in 56 patients with mild-to-moderate Alzheimer's disease. To date, 21 patients reported 43 treatment-emergent adverse events. All the events reported were either mild or moderate in intensity, with 15 (all mild) considered possibly related to aducanumab. The most common events reported were headache (15%), diarrhoea (8%), and dizziness (8%). The incidence and severity of the adverse events were not related with the dosage. No cases of amyloid-related imaging abnormalities (ARIA) were reported [54] .

In the long-term extension of phase Ib study, the most commonly reported adverse events were headache, fall, and amyloid-related imaging abnormalities (ARIA). Of the 185 patients dosed with aducanumab, 46 patients experienced ARIA-E (oedema). There were no new cases of ARIA-E in patients who continued on the same dose of aducanumab. Eight patients experienced more than one ARIA events, mild in nature, in the early course of treatment, which got resolved or stabilised within 4-12 weeks. Most common AEs were headache, fall and ARIA. The trial enrolled patients with prodromal or mild Alzheimer's disease [62] [58] [57] .

Pharmacodynamics

Summary

Phase III:

Pooled results form the phase III EMERGE and ENGAGE trials demonstrated that the amyloid positron emission tomography (PET) composite standard uptake value ratio (SUVR) subgroup analysis revealed a consistent dose- and time-dependent Aß reduction advantage of high-dose and low-dose aducanumab over placebo in each of the prespecified 13 subgroups. Also, these results were consistent with the overall results of the amyloid PET biomarker substudies in which the aducanumab treatment was associated with robust dose-dependent reduction in brain Aß levels. The results were obtained from participants that were randomised (1:1:1) to receive high-dose aducanumab, low-dose aducanumab, or placebo, via intravenous injection, every 4 weeks, for 18 months and the longitudinal amyloid PET imaging using 18F-florbetapir was performed in a subset of patients (n=488 in EMERGE; n=585 in ENGAGE) at screening, Week 26 and Week 78 [35] [39] [46] .

Pooled analysis

Pooled group-level analysis of three trials (phase Ib PRIME trial, phase III EMERGE and ENGAGE trials), in patients with Alzheimer's disease demonstrated a positive association between aducanumab treatment effect on brain amyloid beta (Aß) plaques and clinical measures across dose groups and studies, with the exception of the high-dose group from ENGAGE trial. In second set of analyses of EMERGE and PRIME trials, a greater reduction in brain Aß plaque levels was associated with less decline across clinical endpoints in each study. In EMERGE trials, greater reduction in brain Aß plaque levels was also associated with greater reduction in cerebrospinal fluid (CSF) markers of tau and neurodegeneration as well as less decline on clinical endpoints. Several of these relationships were not apparent in ENGAGE, in which a clinical treatment effect of aducanumab was not observed. The third analysis showed that a smaller magnitude of clinical decline was observed in patients in PRIME, EMERGE and ENGAGE trials, whose brain Aß plaque levels were lowered to a threshold considered to be amyloid negative relative to patients who did not reach this threshold. These results were consistent with the hypothesised mechanism of action of aducanumab and supported relationship between aducanumab-induced changes in biomarkers of Alzheimer's disease pathophysiology and slowing of clinical decline [33] [57] [46] [39] .

Treatment with aducanumab indicated a dose- and time-dependent reduction of amyloid plaque over 54 weeks of treatment, during the phase I PRIME trial. At 54 weeks, patients receiving aducanumab (10 mg/kg) experienced a 69% reduction from baseline in amyloid plaque as observed on the Centiloid Conversion scale (p<0.001 versus placebo). There was no change from baseline in the placebo arm [58] . Aducanumab treatment reduced amyloid plaque by - 0.087 (p < 0.01) in the 3 mg/kg cohort, by - 0.143 (p < 0.001) in the 6 mg/kg cohort and by - 0.205 (p < 0.001) in the 10 mg/kg cohort, compared with placebo, at 26 weeks. At week 54, the reduction of amyloid plaque in the 3 mg/kg cohort was - 0.139 (p < 0.001) and in the 10 mg/kg cohort was - 0.266 (p < 0.001). The reduction of amyloid plaque in the 1 mg/kg arm was - 0.056 at week 54 and - 0.030 at week 26, which were not significant. The composite standardized uptake value ratio for the placebo treatment arm was unchanged at 26 and 54 weeks. The interim results were reported from the randomised, double-blind trial that enrolled 165 patients in the placebo, 1 mg/kg, 3 mg/kg and 10 mg/kg and 6 mg/kg cohorts [44] [57] .

Therapeutic Trials

Phase III:

Updated results of the double-blind, randomised, phase III EMERGE trial in patients with early Alzheimer's disease, demonstrated reduced clinical decline with high-dose aducanumab treatment, evidenced by a statistically significant treatment effect on pre-specified primary and secondary clinical efficacy endpoints, when compared with placebo. Treatment effects were observed across all six domains (three cognitive and three functional) measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB), the primary endpoint of the trial. Aducanumab treatment effects were observed across ADAS-Cog13 items sensitive to cognitive change in early symptomatic Alzheimer’s disease and across a broad range of items measuring ability to conduct activities of daily living, as measured by ADCS-ADL-MCI, the secondary endpoint of the trial. Aducanumab treatment was also associated with a reduction in the behavioral and psychiatric symptoms of Alzheimer’s disease, as measured by the Neuropsychiatric Inventory-10 (NPI-10), the tertiary efficacy endpoint of the trial [33] . Interim results from this trial, patients on placebo showed from baseline to week 50 a mean decline in cognition of approximately -2.2 points on MMSE, an 8.3% decline, and from baseline to week 78 approximately -3.3 points on MMSE, a 12.5% decline, respectively. Mean baseline MMSE score was 26.4 [40] . The results from the phase III EMERGE trial showed that the patients treated with high dose aducanumab exhibited significant reduction of clinical decline from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores at 78 weeks (22% versus placebo, P = 0.01). The patients also demonstarted a consistent reduction of clinical decline as measured by the pre-specified secondary endpoints like the Mini-Mental State Examination (MMSE; 18% versus placebo, P = 0.05), the AD Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo, P = 0.01), and the AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo, P = 0.001), thus, indicating significant slowing of decline on measures of cognition and function, as well as activities of daily living. The amyloid plaque burden was reduced with low and high dose aducanumab compared to placebo at 26 and 78 weeks (P < 0.001), as depicted by imaging of amyloid plaque deposition [20] [31] .

Phase I:

New data from the long-term extension of phase Ib study, at 24, 36 and 48 months demonstrated a continued decrease of amyloid plaque in a dose and time dependent manner in the fixed-dose cohorts in patients with Alzheimer's disease. The average decline on the Clinical Dementia Rating sum of boxes (CDR-SB) at 24 weeks was 2.32, 2.98 and 1.69 points in the 3 mg/kg, 6 mg/kg and 10 mg/kg groups, respectively, versus 2.65 in the placebo group. A 3.25 points average decline was reported in patients who switched from placebo to aducanumab and a 3.52 points in those who switched from 1 to 3 mg/kg at 12 months. The average decline on the MMSE at 24 weeks was 2.81, 5.20 and 1.97 points in the 3 mg/kg, 6 mg/kg and 10 mg/kg groups, respectively versus 1.95 in the placebo group. A 4.28 points average decline was reported in those who switched from placebo to aducanumab and 3.65 points in those who switched from 1 to 3 mg/kg at 12 months. The average decline on the Clinical Dementia Rating sum of boxes (CDR-SB) at 36 weeks, was 3.86, 4.49 and 2.84 points in the 3 mg/kg, 6 mg/kg and 10 mg/kg groups, respectively. A 5.28 points average decline was reported in patients who switched from placebo to 3 mg/kg or 3-6 mg/kg and a 6.11 points in those who switched from 1 to 3 mg/kg at 12 months. The average decline on the MMSE at 36 weeks was 4.83, 8.97 and 4.10 points in the 3 mg/kg, 6 mg/kg and 10 mg/kg, respectively. A 7.98 points average decline was reported in those who switched from placebo to 3 mg/kg or 3-6 mg/kg and 6.35 points in those who switched from 1 to 3 mg/kg at 12 months. At 48 months, the average decline on the CDR-SB was 5.57, 7.75 and 3.87 in the 3 mg/kg, 6 mg/kg and 10 mg/kg groups, respectively [67] [63] . Earlier results included that, aducanumab demonstrated statistically significant reduction in beta amyloid in the brain and dose-dependent slowing of clinical decline in patients with Alzheimer's disease, in the phase I PRIME study. A statistically significant reduction of amyloid plaque was observed in patients treated with 1mg/kg [-0.050 (p < 0.05)], 3mg/kg [-0.130 (p < 0.001)], 6mg/kg [-0.206 (p < 0.001)] and 10mg/kg [-0.263 (p < 0.001)] of the drug and in the titration arm [-0.171 (p < 0.001)]. Alzheimer's disease related impairment measured using MMSE, indicated worsening of 2.21 points in the 1 mg/kg arm, 0.75 points in the 3 mg/kg arm, 1.99 points in 6 mg/kg arm and 0.55 points in the 10 mg/kg arm, compared with 2.45 points in the placebo group, at one year. The 3 mg/kg and 10 mg/kg doses indicated a statistically significant slowing of cognitive decline on the MMSE (p < 0.05), relative to placebo. The Clinical Dementia Rating sum of boxes (CDR-SB) showed a worsening of 1.69, 1.33, 1.09 and 0.63 in the 1 mg/kg, 3 mg/kg, 6 mg/kg and 10 mg/kg groups, respectively, versus 1.89 in the placebo group, at 54 weeks. Statistical significance was observed in the 10 mg/kg group (p < 0.05). The interim results were from 165 patients who were randomised to placebo, 1 mg/kg, 3 mg/kg and 10 mg/kg and 6 mg/kg cohorts of aducanuab. Analyses of exploratory clinical endpoints, CDR-SB and the MMSE, were consistent with the results from the fixed-dose cohorts and suggested a continued benefit on the rate of clinical decline. At 36 months, the results suggested a continued benefit on the rate of clinical decline during the third year of treatment [28] [61] [60] [59] [44] [57] .

Pooled analysis

Updated pooled analysis from two phase III EMERGE and EMERGE trials demonstrated that treatment with aducanumab significantly lowered plasma p-tau181 in a dose- and time-dependent manner vs. placebo. The change in plasma p-tau181 was significantly correlated with change in amyloid beta plaque and reduced cognitive and functional decline on all primary and secondary outcome measures. . The effect was greater with higher doses and longer duration of treatment. Greater reduction in plasma p-tau181 also had a statistically significant correlation with less decline in cognition and function in aducanumab treated patients. Furthermore, the analysis also demonstrated a statistically significant correlation between change in plasma p-tau181 and lowering of amyloid beta plaque, showing the effect of aducanumab on the two core pathological features of Alzheimer’s disease. In the EMERGE high-dose group, p-tau decreased 13% from baseline (p<0.001), while placebo rose 8%; in the ENGAGE high-dose group, p-tau decreased 16% from baseline (p<0.001), while placebo rose 9%. Greater reduction in plasma p-tau181 was correlated with less clinical decline in all four clinical outcome measures in both the trials. Correlation values across the endpoints for EMERGE and ENGAGE were Clinical Dementia Rating Sum of Boxes Score (CDR-SB) R = 0.11 (p = 0.0166) and R = 0.14 (p = 0.0005); Mini-Mental State Examination (MMSE) R = -0.21 (p < 0.0001) and R = -0.15 (p = 0.0002); Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog 13) R = 0.17 (p = 0.0001) and R = 0.15 (p = 0.0002); and Alzheimer’s Disease Cooperative Study/Activities of Daily Living scale adapted for MCI (ADCS-ADL-MCI) R = -0.12 (p = 0.0086) and R = -0.14 (p = 0.0010). Changes in plasma p-tau181 was also significantly correlated with change in amyloid beta positron emission tomography (PET) standardized uptake value ratio (SUVR): EMERGE R = 0.38, p < 0.0001; ENGAGE R = 0.42, p < 0.0001 [36] [38] [39] . Earlier results showed that patients receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque [14] .

Future Events

Expected Date Event Type Description Updated
31 Dec 2021 Regulatory Status Biogen announces intention to launch aducanumab in Alzheimer's disease in 2021 [22] 25 Aug 2021
16 Dec 2021 Trial Update Biogen and Eisai expects a formal opinion form Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on Marketing Authorization Application in Alzheimer's disease [27] 19 Nov 2021
09 Jul 2021 Trial Update Biogen and Eisai plans a phase I bioavailability trial in Healthy volunteers in July 2021 (SC, Injection) (IV, Infusion) (NCT04924140) (700338335) 22 Jul 2021
07 Jun 2021 Regulatory Status PDUFA action date extended by US FDA to 07/06/2021 for BLA for Alzheimer's disease [16] 09 Jun 2021
06 Nov 2020 Regulatory Status The USFDA plans virtual advisory committee meeting of the Peripheral and Central Nervous System Drugs Advisory Committee for review of BLA in November 2020 [66] 10 Jun 2021
31 Mar 2020 Regulatory Status Biogen announces intention to submit BLA to the US FDA for Alzheimer's disease, in early 2020 [31] 24 Apr 2020
31 Mar 2020 Trial Update Biogen plans a phase III trial for Alzheimer's disease (IV) in March 2020 (NCT04241068) (700317777) 26 Mar 2020
17 Dec 2018 Trial Update Biogen plans a phase II trial for Alzheimer's Disease (IV), in December 2018 (700299044) (NCT03639987) 11 Jun 2021

Development History

Event Date Update Type Comment
17 Nov 2021 Trial Update Biogen and Eisai expects a formal opinion form Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on Marketing Authorization Application in Alzheimer's disease [27] Updated 19 Nov 2021
11 Nov 2021 Scientific Update Pooled efficacy data from the phase III EMERGE and ENGAGE trials in Alzheimer's disease released by Biogen [36] Updated 22 Nov 2021
05 Nov 2021 Biomarker Update Biomarkers information updated Updated 21 Nov 2021
28 Oct 2021 Phase Change - No development reported No recent reports of development identified for phase-I development in Alzheimer's-disease(In volunteers) in USA (SC, Injection) Updated 28 Oct 2021
01 Oct 2021 Trial Update Biogen and Eisai Co. Ltd. complete a phase I trial in Alzheimer's disease (In volunteers) in USA (SC, IV) in October 2021 (NCT04924140) Updated 01 Nov 2021
23 Aug 2021 Phase Change - Marketed Launched for Alzheimer's disease in USA (IV) - First global launch [12] Updated 25 Aug 2021
26 Jul 2021 Scientific Update Pharmacodynamics data from the phase III EMERGE and ENGAGE trials in Alzheimer's disease presented at the Alzheimer's Association International Conference 2021(AAIC-2021) [35] Updated 16 Sep 2021
26 Jul 2021 Scientific Update Adverse events data from the phase III EMERGE and ENGAGE trial in Alzheimer's disease presented at the Alzheimer's Association International Conference 2021(AAIC-2021) [34] Updated 15 Sep 2021
26 Jul 2021 Scientific Update Interim efficacy data from a phase III EMERGE trial in Alzheimer’s disease released by Biogen and Eisai [33] Updated 28 Jul 2021
26 Jul 2021 Scientific Update Pooled pharmacodynamics data from three clinical PRIME, EMERGE and ENGAGE trials in Alzheimer’s disease released by Biogen and Eisai [33] Updated 28 Jul 2021
30 Jun 2021 Phase Change - I Phase-I clinical trials in Alzheimer's disease (In volunteers) in USA (IV) (NCT04924140) Updated 22 Jul 2021
30 Jun 2021 Trial Update Biogen and Eisai Co. Ltd. initiate a phase I trial in Alzheimer's disease (In volunteers) in USA (SC) (NCT04924140) Updated 22 Jul 2021
11 Jun 2021 Regulatory Status Biogen announces intention to launch aducanumab in Alzheimer's disease in 2021 [22] Updated 25 Aug 2021
11 Jun 2021 Trial Update Biogen and Eisai plans a phase I bioavailability trial in Healthy volunteers in July 2021 (SC, Injection) (IV, Infusion) (NCT04924140) Updated 22 Jul 2021
07 Jun 2021 Scientific Update Pooled efficacy data from three clinical trials in Alzheimer's disease trials released by Biogen [14] Updated 10 Jun 2021
07 Jun 2021 Phase Change - Registered Registered for Alzheimer's disease in USA (IV) (accelerated approval) - First global approval [14] Updated 09 Jun 2021
07 Jun 2021 Trial Update Biogen plans an additional randomised clinical trial for Alzheimer's disease [14] Updated 09 Jun 2021
31 Mar 2021 Phase Change - Preregistration Preregistration for Alzheimer's disease in Australia (IV) [22] Updated 11 Jun 2021
31 Mar 2021 Phase Change - Preregistration Preregistration for Alzheimer's disease in Brazil (IV) [22] Updated 11 Jun 2021
31 Mar 2021 Phase Change - Preregistration Preregistration for Alzheimer's disease in Canada (IV) [22] Updated 11 Jun 2021
31 Mar 2021 Phase Change - Preregistration Preregistration for Alzheimer's disease in Switzerland (IV) [22] Updated 11 Jun 2021
16 Mar 2021 Scientific Update Efficacy data from the phase III EMERGE trial in Alzheimer's disease released by Biogen [40] Updated 18 Mar 2021
02 Feb 2021 Regulatory Status US FDA extends the review period for the BLA for Alzheimer’s disease [16] Updated 02 Feb 2021
01 Feb 2021 Financial Update Credit Suisse financial data update Updated 14 Mar 2021
29 Jan 2021 Regulatory Status PDUFA action date extended by US FDA to 07/06/2021 for BLA for Alzheimer's disease [16] Updated 09 Jun 2021
11 Dec 2020 Phase Change - Preregistration Preregistration for Alzheimer's disease in Japan (IV) [24] Updated 11 Dec 2020
09 Dec 2020 Regulatory Status Biogen submits Japanese New Drug Application (J-NDA) to the Ministry of Health, Labor and Welfare (MHLW) for Alzheimer’s disease [24] Updated 11 Dec 2020
30 Oct 2020 Regulatory Status European Medicines Agency accepts the Marketing Authorization Application of Aducanumab for review for Alzheimer's Disease [25] Updated 03 Nov 2020
21 Oct 2020 Phase Change - Preregistration Preregistration for Alzheimer's disease in European Union (IV) [26] Updated 23 Oct 2020
29 Sep 2020 Regulatory Status The USFDA plans virtual advisory committee meeting of the Peripheral and Central Nervous System Drugs Advisory Committee for review of BLA in November 2020 [66] Updated 10 Jun 2021
07 Aug 2020 Regulatory Status Aducanumab receives priority review status for Alzheimer's disease in USA [18] Updated 11 Aug 2020
07 Aug 2020 Regulatory Status The US FDA accepts BLA for aducanumab for Alzheimer's disease for review [18] Updated 11 Aug 2020
08 Jul 2020 Regulatory Status Biogen completes BLA submission with the US FDA for Alzheimer's disease [20] Updated 10 Jul 2020
08 Jul 2020 Scientific Update Updated efficacy data from the phase III EMERGE trial in Alzheimer's disease released by Biogen [20] Updated 10 Jul 2020
22 Apr 2020 Regulatory Status Biogen plans a pre-BLA meeting with the US FDA for Alzheimer's disease in summer of 2020 Updated 27 Apr 2020
22 Apr 2020 Phase Change - Preregistration Preregistration for Alzheimer's disease in USA (IV) [21] Updated 24 Apr 2020
13 Mar 2020 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Australia, Austria, Belgium, Denmark, Canada, Finland, France, Germany, Italy, Japan, South Korea, Netherlands, Poland, Portugal, Spain, Sweden, Switzerland, Taiwan, United Kingdom (IV), after March 2020 (NCT04241068) (EudraCT2019-004368-22) Updated 14 Apr 2021
13 Mar 2020 Phase Change - III Phase-III clinical trials in Alzheimer's disease in USA (IV) (NCT04241068) Updated 26 Mar 2020
30 Jan 2020 Regulatory Status Biogen intends to submit a regulatory application in USA Updated 03 Feb 2020
27 Jan 2020 Trial Update Biogen plans a phase III trial for Alzheimer's disease (IV) in March 2020 (NCT04241068) Updated 26 Mar 2020
30 Oct 2019 Regulatory Status Biogen plans to submit marketing authorisation submissions in Europe and Japan for Alzheimer's disease (Biogen website, October 2019) Updated 30 Oct 2019
22 Oct 2019 Regulatory Status Biogen announces intention to submit BLA to the US FDA for Alzheimer's disease, in early 2020 [31] Updated 24 Apr 2020
22 Oct 2019 Scientific Update Adverse events data from the phase III EMERGE and ENGAGE trial in Alzheimer's disease released by Biogen [31] Updated 30 Oct 2019
22 Oct 2019 Scientific Update Efficacy data from the phase III EMERGE trial in Alzheimer's disease released by Biogen [31] Updated 30 Oct 2019
22 Oct 2019 Active Status Review Aducanumab is still in phase I for Alzheimer's disease (In volunteers) in USA (SC) [31] Updated 25 Oct 2019
22 Oct 2019 Active Status Review Aducanumab is still in phase-III for Alzheimer's disease in Finland, Japan, Australia, United Kingdom, Taiwan, Denmark, Switzerland, Belgium, Sweden, Netherlands, Germany, France, Poland, Spain, South Korea, Italy, Portugal, Austria, Canada, USA (IV) [31] Updated 25 Oct 2019
04 May 2019 Scientific Update Adverse events data from a phase Ib trial in Alzheimer's Disease presented at the American Academy of Neurology (AAN-2019) [64] Updated 30 Oct 2019
22 Apr 2019 Phase Change - Discontinued(I) Discontinued - Phase-I for Alzheimer's disease (In volunteers) in USA (SC) (Neurimmune Therapeutics pipeline and Biogen pipeline, April 2019) Updated 22 Apr 2019
22 Apr 2019 Phase Change - Discontinued(III) Discontinued - Phase-III for Alzheimer's disease in Finland, Japan, Australia, United Kingdom, Taiwan, Denmark, Switzerland, Belgium, Sweden, Netherlands, Germany, France, Poland, Spain, South Korea, Italy, Portugal, Austria, Canada, USA (IV) (Neurimmune Therapeutics pipeline and Biogen pipeline, April 2019) Updated 22 Apr 2019
21 Mar 2019 Trial Update Biogen and Eisai terminate the long-term extension of the phase I PRIME trial in Alzheimer’s disease in USA based on futility analysis (NCT01677572) [41] Updated 26 Mar 2019
21 Mar 2019 Trial Update Biogen and Eisai terminate the phase II EVOLVE trial in Alzheimer’s disease in USA, UK, France, Italy and Spain (IV, Infusion) based on futility analysis (NCT03639987, EudraCT2018-002102-31) [41] Updated 26 Mar 2019
21 Mar 2019 Trial Update Biogen and Eisai terminate the phase III ENGAGE trial in Alzheimer's disease in USA, Canada, Australia, Austria, France, Germany, Denmark, Spain, Italy, Japan, Portugal, UK, Taiwan and South Korea as the independent data monitoring committee advised aducanumab unlikely to meet primary endpoint of the trial (IV) (NCT02477800; EudraCT2015-000966-72) [41] Updated 26 Mar 2019
21 Mar 2019 Trial Update Biogen and Eisai terminate the phase III EMERGE trial in Alzheimer's disease in USA, Japan, Belgium, Finland, France, Germany, Switzerland, Canada, Italy, Netherlands, Sweden, Poland and Spain as the independent data monitoring committee advised aducanumab unlikely to meet primary endpoint of the trial (IV) (NCT02484547; EudraCT2015-000967-15) [41] Updated 26 Mar 2019
20 Mar 2019 Trial Update Biogen initiates enrolment in a phase II trial for Alzheimer's Disease in UK, France, Italy after March 2019 (EudraCT 2018-002102-31) (NCT03639987) Updated 11 Jun 2021
20 Mar 2019 Trial Update Biogen initiates Phase-III clinical trials in Alzheimer's disease in Canada, Italy (IV) before March 2019(NCT02484547; EudraCT2015-000967-15) Updated 11 Jun 2021
20 Mar 2019 Trial Update Biogen initiates Phase-III clinical trials in Alzheimer's disease in France, Germany, Spain (IV) (NCT02477800) Updated 11 Jun 2021
20 Dec 2018 Trial Update Biogen initiates enrolment in a phase II trial for Alzheimer's Disease in the US (NCT03639987) Updated 15 Jan 2019
27 Nov 2018 Trial Update Biogen initiates enrolment in a phase II trial for Alzheimer's Disease in Spain (EudraCT 2018-002102-31) Updated 15 Jan 2019
28 Aug 2018 Scientific Update Additional adverse events data from the phase Ib PRIME trial for Alzheimer's disease released by Biogen [62] Updated 31 Aug 2018
21 Aug 2018 Trial Update Biogen plans a phase II trial for Alzheimer's Disease (IV), in December 2018 (NCT03639987) Updated 11 Jun 2021
24 Jul 2018 Trial Update Biogen completes enrolment in its phase III ENGAGE and EMERGE trials for Alzheimer's disease [42] Updated 30 Jul 2018
01 May 2018 Licensing Status Biogen exercises its option to reduce the negotiated royalty rates payable on potential future sales of aducanumab [11] Updated 04 May 2018
15 Mar 2018 Scientific Update Safety data from the long-term extension phase Ib PRIME study in Alzheimer's disease released by Biogen Idec [58] Updated 22 Mar 2018
15 Mar 2018 Scientific Update Updated pharmacodynamic data from the phase Ib PRIME study in Alzheimer's disease released by Biogen Idec [58] Updated 22 Mar 2018
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Alzheimer's-disease in Australia (IV, Infusion) Updated 04 Nov 2017
02 Nov 2017 Scientific Update New efficacy data from the long-term extension phase Ib PRIME trial in Alzheimer’s disease released by Biogen [63] Updated 09 Nov 2017
23 Oct 2017 Licensing Status Eisai exercises its option to co-develop and co-promote aducanumab [5] Updated 27 Oct 2017
28 Aug 2017 Regulatory Status The Ministry of Health, Labour and Welfare grants SAKIGAKE designation to aducanumab for Alzheimer's disease in Japan [28] Updated 30 Aug 2017
28 Aug 2017 Scientific Update Updated efficacy and adverse events data from the Long-term extension part of the phase Ib PRIME trial in Alzheimer's disease released by Biogen [28] Updated 30 Aug 2017
08 Dec 2016 Scientific Update Interim efficacy and adverse events data from a phase Ib trial in Alzheimer's disease released by Biogen [61] Updated 06 Jan 2017
01 Dec 2016 Trial Update Biogen completes a phase I trial in Alzheimer's disease in Japan (IV) (NCT02434718) Updated 27 Jan 2017
01 Nov 2016 Trial Update Biogen completes a phase I bioavailability trial (In volunteers) in USA (SC, IV) (NCT02782975) Updated 25 Jan 2017
01 Sep 2016 Regulatory Status Aducanumab receives Fast Track designation for Alzheimer's disease [IV,Infusion] (Early Alzheimer's disease) in USA [29] Updated 08 Sep 2016
01 Jun 2016 Regulatory Status Aducanumab receives Priority Medicine (PRIME) status for Alzheimer's disease in European Union [30] Updated 27 Apr 2017
01 May 2016 Phase Change - I Phase-I clinical trials in Alzheimer's disease (In volunteers) in USA (SC) (NCT02782975) Updated 07 Aug 2017
01 May 2016 Trial Update Biogen initiates a phase I bioavailability trial (In volunteers) in USA (IV) (NCT02782975) Updated 16 Jun 2016
18 Jan 2016 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Belgium, France, Germany, Netherlands, Sweden and Switzerland (IV) (NCT02484547) Updated 18 Jan 2016
30 Sep 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Finland (IV) (NCT02484547) Updated 23 May 2018
30 Sep 2015 Trial Update Biogen initiates enrolment in the phase III EMERGE trial for Alzheimer's disease in USA, Canada and Japan (NCT02484547) Updated 06 Aug 2015
24 Sep 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Spain and Poland (IV) (NCT02484547) Updated 21 Oct 2015
31 Aug 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Japan, United Kingdom, Australia, Taiwan, Denmark (IV) (NCT02477800) Updated 23 May 2018
31 Aug 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Portugal and Italy (IV) (NCT02477800) Updated 21 Oct 2015
31 Aug 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in South Korea (IV) (NCT02477800) Updated 21 Oct 2015
31 Aug 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Austria (IV) (NCT02477800) Updated 10 Sep 2015
06 Aug 2015 Trial Update Biogen completes enrolment in the phase Ib PRIME trial for Alzheimer's disease in USA (NCT01677572) Updated 21 Oct 2015
22 Jul 2015 Scientific Update Interim efficacy data from the phase Ib, PRIME trial for Alzheimer's disease, presented at the Alzheimer's Association International Conference (AAIC-2015) [60] Updated 24 Jul 2015
01 Jun 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Canada (IV) after June 2015 (NCT02477800) Updated 06 Aug 2015
01 Jun 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in USA (IV) (NCT02477800) Updated 20 Jul 2015
01 May 2015 Phase Change - I Phase-I clinical trials in Alzheimer's disease in Japan (IV) (NCT02434718) Updated 21 Jul 2015
30 Apr 2015 Trial Update Biogen plans a phase I trial for Alzheimer's disease in Japan (NCT02434718) Updated 08 May 2015
23 Mar 2015 Company Involvement Biogen Idec is now called Biogen Updated 08 Apr 2015
20 Mar 2015 Scientific Update Efficacy, safety, pharmacokinetics and pharmacodynamic data from the phase Ib PRIME study released by Biogen Idec [44] Updated 03 Apr 2015
20 Mar 2015 Trial Update Biogen Idec plans a phase III trial in Alzheimer's disease in USA, Austria, Australia, Belgium, Canada, Czech Republic, Denmark, Germany, the Netherlands, Hungary, Spain, Switzerland, South Korea, Italy, Japan, France, Sweden, Poland, Portugal, Taiwan and United Kingdom [44] , NCT02484547) Updated 03 Apr 2015
05 Feb 2015 Licensing Status Eisai and Biogen Idec enter into a collaboration to develop and commercialise aducanumab for the treatment of Alzheimer's disease [4] Updated 09 Feb 2015
29 Jan 2015 Scientific Update Interim efficacy and safety data from a phase Ib trial in Alzheimer's disease released by Biogen Idec [59] Updated 04 Feb 2015
07 Mar 2014 Active Status Review Phase I development is ongoing for Alzheimer's disease in USA Updated 07 Mar 2014
01 Aug 2013 Trial Update Biogen Idec completes a phase I trial in Alzheimer's disease in USA (NCT01397539) Updated 07 Oct 2014
14 Jul 2013 Scientific Update Interim safety and pharmacokinetics data from a phase I trial in Alzheimer's disease presented at the 2013 Alzheimer's Association International Conference [54] , [55] Updated 07 Mar 2014
05 Oct 2012 Trial Update Biogen Idec initiates Phase-I clinical trials in Alzheimer's disease in USA (IV) (NCT01677572) Updated 11 Jun 2021
30 Jun 2011 Phase Change - I Phase-I clinical trials in Alzheimer's disease in USA (IV) (NCT01397539) Updated 18 Jul 2011
06 Apr 2011 Regulatory Status Biogen Idec files an IND application for BIIB 037 with the US FDA for Alzheimer's disease Updated 18 Jul 2011
20 Nov 2007 Licensing Status Aducanumab licensed to Biogen Idec worldwide [8] Updated 27 Apr 2017
20 Nov 2007 Phase Change Early research in Alzheimer's disease in Switzerland (IV) Updated 18 Jul 2011
20 Nov 2007 Phase Change Early research in Alzheimer's disease in USA (IV) Updated 18 Jul 2011

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  38. Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 (Aducanumab) in Subjects With Alzheimer's Disease Who Had Previously Participated in the Aducanumab Studies 221AD103, 221AD301, 221AD302 and 221AD205

    ctiprofile
  39. A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease

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  40. Anavex Life Sciences Reports ANAVEX(Rm)2-73 (blarcamesine) featured as a Disease-Modifying Small Molecule in Phase 3 Clinical Trials in a New Publication in Medical Journal titled Future Avenues for Alzheimers Disease Detection and Therapy.

    Media Release
  41. Biogen and Eisai to Discontinue Phase 3 ENGAGE and EMERGE Trials of aducanumab in Alzheimers Disease.

    Media Release
  42. Biogen: Second Quarter 2018 Financial Results and Business Update. Internet-Doc 2018;.

    Available from: URL: http://investors.biogen.com/static-files/2355f7cb-f7b2-4ce9-b421-0901fb89ddba
  43. Biogen Second Quarter 2015 Revenues Increase 7% to $2.6 Billion.

    Media Release
  44. Biogen Idec Presents Positive Interim Results from Phase 1B Study of Investigational Alzheimers Disease Treatment Aducanumab (BIIB037) at 2015 AD/PD(Tm) Conference.

    Media Release
  45. Cohen S, He P, Benea ML, Miller R, Forrestal F, Pang M, et al. Item-level analysis of clinical measures in patients with early symptomatic Alzheimer?s disease following treatment with high-dose aducanumab in the Phase 3 study EMERGE. AAIC-2021 2021; abstr. N/A.

    Available from: URL: https://alz.confex.com/alz/2021/meetingapp.cgi/Paper/57619
  46. Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease

    ctiprofile
  47. Neurimmune Receives Major Development Milestone Upon Initiation of Global Phase 3 Studies With Aducanumab for Early Alzheimer's Disease.

    Media Release
  48. Biogen Enrolls First Patient in Global Phase 3 Study of Investigational Treatment Aducanumab (BIIB037) for Early Alzheimers Disease.

    Media Release
  49. A Phase 2, Multicenter, Randomized, Parallel-Group, Double-Blind, Controlled Study of Aducanumab (BIIB037) in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease or With Mild Alzheimer's Disease Dementia to Evaluate the Safety of Continued Dosing in Subjects With Asymptomatic Amyloid-Related Imaging Abnormalities

    ctiprofile
  50. A Randomized, Open-Label, Parallel-Arm Study to Assess the Absolute Bioavailability of a Single, Fixed Subcutaneous Dose of Aducanumab (BIIB037) Compared to a Single, Weight-Based Intravenous Dose in Healthy Volunteers

    ctiprofile
  51. A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of BIIB037 in Japanese Subjects With Mild to Moderate Alzheimer's Disease

    ctiprofile
  52. A Randomized, Open-Label, Parallel-Arm Study to Assess the Absolute Bioavailability of a Single, Fixed Subcutaneous Dose of Aducanumab (BIIB037) in Healthy Subjects Compared to a Single, Weight-Based Intravenous Dose

    ctiprofile
  53. A Randomized, Blinded, Placebo-Controlled Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of BIIB037 in Subjects With Mild to Moderate Alzheimer's Disease.

    ctiprofile
  54. Sevigny J, Leitermann K, Song T, Stella H, Ferrero J, Williams L, et al. A Single Ascending-Dose Study of BIIB037 in People With Mild-to-Moderate Alzheimer's Disease. AAIC-2013 2013; abstr. P1-359.

    Available from: URL: https://event.crowdcompass.com/aaic2013/activity/4524w86n53
  55. Ferrero J, Song T, Mikulskis A, Leitermann K, Stella H, Sevigny J. Pharmacokinetics of BIIB037 in People With Mild-to-Moderate Alzheimer's Disease (AD) Participating in a Phase 1 Dose-Escalation Trial. AAIC-2013 2013; abstr. P1-348.

    Available from: URL: https://event.crowdcompass.com/aaic2013/activity/NlxqTtTEJy
  56. Biogen Idec Reports First Quarter 2011 Results.

    Media Release
  57. A Randomized, Double-Blinded, Placebo-Controlled Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB037 in Subjects With Prodromal or Mild Alzheimer's Disease

    ctiprofile
  58. Biogen to Present at the 2018 Advances in Alzheimers and Parkinsons Therapies (AAT-AD/PD) Focus Meeting.

    Media Release
  59. Biogen Idec 2014 Revenues Increase 40% to $9.7 Billion.

    Media Release
  60. Biogen Presents New Data from Phase 1B Study of Investigational Alzheimers Disease Treatment Aducanumab (BIIB037) at Alzheimers Association International Conference(Rm) 2015.

    Media Release
  61. Biogen Presents Data from Phase 1b Study of Investigational Alzheimers Disease Treatment Aducanumab at 2016 Clinical Trials on Alzheimers Disease Meeting.

    Media Release
  62. Biogen and Eisai Report Data from Long-Term Extension Phase 1b Study of Investigational Alzheimers Disease Treatment Aducanumab.

    Media Release
  63. Biogen Presents New Data from Long-Term Extension of Phase 1b Study of Investigational Alzheimers Disease Treatment Aducanumab.

    Media Release
  64. Castrillo-Viguera C, Haeberlein SB, Von Rosenstiel P, Chen T, O?Gorman J, Rajagovindan R, et al. Interim Analyses of Fixed-Dose and Titration Cohorts from PRIME: A Randomized, Double-Blind, Placebo-Controlled Phase 1b Study of Aducanumab. AAN-2019 2019; abstr. S9.006.

    Available from: URL: https://n.neurology.org/content/92/15_Supplement/S9.006
  65. ProMIS Neurosciences Reports Highlights from the 2016 Alzheimer's Association International Conference.

    Media Release
  66. STATEMENT ABOUT THE FDA ADVISORY COMMITTEE ON ADUCANUMAB.

    Media Release
  67. Biogen and Eisai Announce Presentation of Detailed Analyses from the Phase 1b Long-Term Extension Study of Aducanumab at Clinical Trials on Alzheimers Disease (CTAD).

    Media Release
  68. ProMIS Neurosciences Offers its Perspective on the Likelihood of Regulatory Approval of Aducanumab.

    Media Release
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