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Aducanumab - Biogen/Neurimmune Therapeutics

Drug Profile

Aducanumab - Biogen/Neurimmune Therapeutics

Alternative Names: Aducanumab - Biogen; Anti-beta amyloid monoclonal antibody - Biogen Idec; BART; BIIB 037; NI-10

Latest Information Update: 03 Feb 2020

At a glance

  • Originator Neurimmune Therapeutics; University of Zurich
  • Developer Biogen
  • 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

  • Phase III Alzheimer's disease

Most Recent Events

  • 30 Jan 2020 Biogen intends to submit a regulatory application in USA
  • 27 Jan 2020 Biogen plans a phase III trial for Alzheimer's disease (IV) in March 2020 (NCT04241068)
  • 30 Oct 2019 Biogen plans to submit marketing authorisation submissions in Europe and Japan for Alzheimer's disease (Biogen website, October 2019)

Development Overview

Introduction

Aducanumab is a fully human immunoglobulin gamma 1 (IgG1) recombinant monoclonal antibody, being developed by Biogen 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 Alzheimer patients and reduce soluble and insoluble Aβ in a dose-dependent manner. The antibody was discovered from a de-identified library of B cells collected from healthy elderly subjects without cognitive impairment, with unusually slow cognitive decline. Clinical development of the intravenous and subcutaneous formulations is underway in the US, Canada, Europe, Australia and Asia.

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.

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

Company Agreements

In December 2019, Eisai and BioArctic entered into a research collaboration to characterise the unique binding profile of BAN 2401. Payments to BioArctic under this research collaboration total up to a potential of $US3.61 million (EUR 3.25 million). Previously, the companies had expanded their agreement in October 2017, 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

In January 2020, Biogen intends Biogen intends to submit a regulatory application in the US for Alzheimer's disease [12] .

In October 2019, Biogen reported that after consulting with the U.S. Food and Drug Administration (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 as determined by dose dependent effects in reducing brain amyloid and in reducing clinical decline as assessed by the pre-specified primary endpoint Clinical Dementia Rating-Sum of Boxes (CDR-SB). 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 [13] .

In October 2019, the Alzheimer's Association reported that Biogen will pursue regulatory approval from the 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 [14] .

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 seems that the drug development was discontinued (Neurimmune Therapeutics pipeline and Biogen pipeline, April 2019).

In April 2017, the Japanese MHLW granted SAKIGAKE designation system to aducanumab for the treatment of Alzheimer’s disease in Japan [15] .

In August 2016, Biogen reported that aducanumab was granted fast track designation by the US FDA, for treatment of early Alzheimer's disease [16] .

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] [17] .

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) [13] . Earlier, in March 2019, Biogen and Eisai discontinued 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. The double-blind, randomised trial was initiated in July 2015 and intended to enrol approximately 1605 patients aged between 50 to 85 years. The global trial completed enrolment of 1 605 patients in the second quarter of 2018 in the US, Japan, Belgium, Finland, France, Germany, Switzerland, Canada, Italy, Netherlands, Sweden, Poland and Spain. The enrolment was also expected to begin in Austria, Australia, Denmark, Taiwan, UK, South Korea [18] [19] [20] [21] [22] .

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 intended to enrol approximately 1605 patients aged between 50 to 85 years. The global trial completed enrolment of 1 605 patients in the second quarter of 2018 in the US, Canada, Australia, Austria, France, Germany, Denmark, Spain, Italy, Portugal, UK, Taiwan and South Korea. The enrolment was also expected to begin in Czech Republic, Hungary, Japan, Netherlands, Poland, Scotland, Sweden, Switzerland. The first patient in the phase III programme was enrolled in September 2015, thereby triggering a $US60 million milestone payment to Neurimmune [13] [18] [19] [23] [24] [20] [25] .

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 [18] .

In March 2019, Biogen and Eisai discontinued the phase II EVOLVE trial 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 (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, the Australia, Canada, Italy and Spain [18] [26] .

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 [27] .

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 [28] .

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 [29] . Interim results were presented at the 2013 Alzheimer's Association International Conference in July 2013 [30] [31] . Biogen Idec submitted the IND for the trial in April 2011 [32] .

In October 2012, Biogen initiated the randomised, double-blind, placebo-controlled phase Ib PRIME trial to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of aducanumab in patients with prodromal or mild Alzheimer's disease (NCT01677572; EudraCT2012-000349-10). 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, Australia and Belgium in August 2015 [33] . 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 [34] [35] [22] . 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) [36] . 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 [37] . 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 [15] . 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 [38] [34] [39] . In March 2019, the long-term extension phase of the trial was discontinued. The decision was taken following discontinuation of phase III trials EMERGE and ENGAGE [see above] [18] . In May 2019, data from the long term extension trial were released at the American Academy of Neurology (AAN- 2019) [40] .

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 [41] .

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

    N06D (Anti-Dementia Drugs)

  • EPhMRA code

    N7D9 (All other anti-Alzheimer products)

  • Chemical name Immunoglobulin G1-kappa, anti-[Homo sapiens amyloid beta (Abeta, Aβ) peptide], Homo sapiens monoclonal antibody
  • Molecular formula C6472 H10028 N1740 O2014 S46
  • CAS Registry Number 1384260-65-4

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Alzheimer's disease - Early-stage disease, In adults, In the elderly Phase III Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Italy, Japan, Netherlands, Poland, Portugal, South Korea, Spain, Sweden, Switzerland, Taiwan, USA (fast track), United Kingdom IV / Infusion Biogen 18 Jan 2016
Alzheimer's disease - In volunteers Phase I USA SC / Injection Biogen 01 May 2016

Priority Development Status

Type Region Indication
Fast Track US Alzheimer's disease
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 Collaborator Japan

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Alzheimer's Wrld (50% US) Biogen, Eisai III 2021 40 2035 01 Jan 2035 22 Oct 2018

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Alzheimer's Wrld (50% US) 0 0 0 0 0 460 926 1390 4865 7298 22 Oct 2018
Total 0 0 0 0 0 460 926 1390 4865 7298

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 [22] .

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% [31] .

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 [13] .

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 [40] [15] [37] [35] [22] [33] .

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 [30] .

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 [38] [34] [33] .

Pharmacodynamics

Summary

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 [34] . 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 [22] [33] .

Therapeutic Trials

Phase III:

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 (23% 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; 15% versus placebo, P = 0.06), 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). 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 [13] .

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 [42] [39] . 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 [15] [37] [36] [35] [22] [33] .

Future Events

Expected Date Event Type Description Updated
31 Mar 2020 Regulatory Status Biogen announces intention to submit BLA to the US FDA for Alzheimer's disease, in early 2020 [13] 30 Oct 2019
31 Mar 2020 Trial Update Biogen plans a phase III trial for Alzheimer's disease (IV) in March 2020 (NCT04241068) (700317777) 03 Feb 2020
17 Dec 2018 Trial Update Biogen plans a phase II trial for Alzheimer's Disease (Early-stage disease) (IV), in December 2018 (700299044), (NCT03639987) 26 Mar 2019

Development History

Event Date Update Type Comment
30 Jan 2020 Regulatory Status Biogen intends to submit a regulatory application in USA [12] 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 03 Feb 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 [13] Updated 30 Oct 2019
22 Oct 2019 Scientific Update Adverse events data from the phase III EMERGE and ENGAGE trial in Alzheimer's disease released by Biogen [13] Updated 30 Oct 2019
22 Oct 2019 Scientific Update Efficacy data from the phase III EMERGE trial in Alzheimer's disease released by Biogen [13] 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) [13] Updated 25 Oct 2019
22 Oct 2019 Active Status Review Aducanumab is still in phase-III for Alzheimer's disease (Early-stage disease, In the elderly, In adults) in Finland, Japan, Australia, United Kingdom, Taiwan, Denmark, Switzerland, Belgium, Sweden, Netherlands, Germany, France, Poland, Spain, South Korea, Italy, Portugal, Austria, Canada, USA (IV) [13] 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) [40] 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 (Early-stage disease, In the elderly, In adults) 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 discontinue the long-term extension trial of the phase I PRIME trial in Alzheimer’s disease in Australia, Belgium and USA (NCT01677572) [18] Updated 26 Mar 2019
21 Mar 2019 Trial Update Biogen and Eisai discontinue the phase II EVOLVE trial in Alzheimer’s disease in Spain and USA (NCT03639987, EudraCT2018-002102-31) [18] Updated 26 Mar 2019
21 Mar 2019 Trial Update Biogen and Eisai discontinue the phase III ENGAGE trial in Alzheimer's disease (Early-stage disease, In adults, In the elderly) in USA, Canada, Australia, Austria, France, Germany, Denmark, Spain, Italy, Portugal, UK, Taiwan and South Korea as the independent data monitoring committee advised aducanumab unlikely to meet primary endpoint of the trial (NCT02477800; EudraCT2015-000966-72) [18] Updated 26 Mar 2019
21 Mar 2019 Trial Update Biogen and Eisai discontinue the phase III EMERGE trial in Alzheimer's disease (Early-stage disease, In adults, In the elderly) 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 (NCT02484547; EudraCT2015-000967-15) [18] Updated 26 Mar 2019
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
22 Oct 2018 Financial Update Credit Suisse financial data update Updated 04 Nov 2018
28 Aug 2018 Scientific Update Additional adverse events data from the phase Ib PRIME trial for Alzheimer's disease (Early-stage disease) released by Biogen [38] Updated 31 Aug 2018
21 Aug 2018 Trial Update Biogen plans a phase II trial for Alzheimer's Disease (Early-stage disease) (IV), in December 2018 , (NCT03639987) Updated 26 Mar 2019
24 Jul 2018 Trial Update Biogen completes enrolment in its phase III ENGAGE and EMERGE trials for Alzheimer's disease (Early stage disease, In adults, In the elderly) [19] 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 [34] 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 [34] 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(Early-stage 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 [39] 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 designates SAKIGAKE designation dystem aducanumab for Alzheimer's disease in Japan [15] 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 [15] 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 [37] Updated 06 Jan 2017
01 Dec 2016 Trial Update Biogen completes a phase I trial in Alzheimer's disease (Early-stage disease, Mid-stage disease) in Japan (IV) (NCT02434718) Updated 27 Jan 2017
01 Nov 2016 Trial Update Biogen completes a phase I bioavailability trial in Healthy 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-stage disease) in USA [16] Updated 08 Sep 2016
01 Jun 2016 Regulatory Status Aducanumab receives Priority Medicine (PRIME) status for Alzheimer's disease in European Union [17] 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 Healthy volunteers in USA (IV) (NCT02782975) Updated 16 Jun 2016
18 Jan 2016 Phase Change - III Phase-III clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) 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 (Early-stage disease, In adults, In the elderly) 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 (Early-stage disease, In adults, In the elderly) in USA, Canada and Japan (NCT02484547) Updated 06 Aug 2015
24 Sep 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) in Spain and Poland (IV) (NCT02484547) Updated 21 Oct 2015
31 Aug 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) 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 (Early-stage disease, In adults, In the elderly) in Portugal and Italy (IV) (NCT02477800) Updated 21 Oct 2015
31 Aug 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) in South Korea (IV) (NCT02477800) Updated 21 Oct 2015
31 Aug 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) 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 (Early-stage disease) in USA, Australia and Belgium (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) [36] Updated 24 Jul 2015
01 Jun 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease in Canada (Early-stage disease) (IV) after June 2015 (NCT02477800) Updated 06 Aug 2015
01 Jun 2015 Phase Change - III Phase-III clinical trials in Alzheimer's disease (Early-stage disease, In adults, In the elderly) in USA (IV) (NCT02477800) Updated 20 Jul 2015
01 May 2015 Phase Change - I Phase-I clinical trials in Alzheimer's disease (Early-stage disease, Mid-stage 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 [22] Updated 03 Apr 2015
20 Mar 2015 Trial Update Biogen Idec plans a phase III trial in Alzheimer's disease (Early-stage disease, In adults, In the elderly) 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 [22] , 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 [35] 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 [30] , [31] Updated 07 Mar 2014
31 Oct 2012 Phase Change - I Phase-I clinical trials in Alzheimer's disease (Early-stage disease) in Belgium and Australia (IV) Updated 21 Oct 2015
30 Jun 2011 Phase Change - I Phase-I clinical trials in Alzheimer's disease in USA (IV) 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

References

  1. Biogen Idec Becomes Biogen.

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  2. Eisai and Biogen Idec Enter Collaboration to Develop and Commercialize Alzheimers Disease Treatments.

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  3. EISAI EXPANDS COLLABORATION WITH BIOGEN IDEC TO DEVELOP AND COMMERCIALIZE NEXT GENERATION ALZHEIMER'S DISEASE TREATMENTS TO INCLUDE JAPAN.

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  4. NOTICE REGARDING EISAI'S OPTIONS RELATING TO BIOGEN IDEC'S INVESTIGATIONAL ANTI-ALZHEIMER'S DISEASE TREATMENTS .

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  5. Biogen and Eisai Expand Existing Collaboration Agreement to Develop and Commercialize Investigational Alzheimers Disease Treatments Including Phase 3 Aducanumab.

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  6. ADAPTIVE PHASE II STUDY OF BAN2401 IN EARLY ALZHEIMER'S DISEASE CONTINUES TOWARD 18-MONTH ENDPOINT.

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  7. BioArctic Announces Research Collaboration with Eisai Regarding BAN2401.

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  8. Biogen Idec and Neurimmune Therapeutics Announce Alliance to Develop Treatments for Alzheimer's Disease.

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  9. Biogen Idec and Neurimmune Announce Agreement on Three Neurodegenerative Disease Programs.

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  10. Biogen Increases Profit Potential on Investigational Alzheimers Disease Treatment Aducanumab Through Amended Agreement with Neurimmune Holding AG.

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  11. Biogen and Neurimmune Announce Option Exercise for Alzheimers Disease Investigational Treatment Aducanumab.

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  12. BIOGEN REPORTS FULL YEAR 2019 REVENUES OF $14.4 BILLION.

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  13. Biogen Plans Regulatory Filing for Aducanumab in Alzheimer's Disease Based on New Analysis of Larger Dataset from Phase 3 Studies.

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  14. Alzheimer's Association Statement Biogen to Submit Aducanumab Results in Early Alzheimer's to U.S. FDA.

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  15. Biogen Reports New Data from Phase 1b Study of Investigational Alzheimers Disease Treatment Aducanumab.

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  16. Biogens Investigational Alzheimers Disease Treatment Aducanumab Granted FDA Fast Track Designation.

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  17. Biogens Investigational Alzheimers Disease Treatment Aducanumab Accepted into European Medicines Agencys PRIME Program.

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

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  19. 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
  20. Biogen Second Quarter 2015 Revenues Increase 7% to $2.6 Billion.

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

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

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

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  26. 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

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  27. 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

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  28. 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

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  29. 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.

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  32. Biogen Idec Reports First Quarter 2011 Results.

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  33. 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

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

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  35. Biogen Idec 2014 Revenues Increase 40% to $9.7 Billion.

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

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

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

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

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  40. 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.

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  41. ProMIS Neurosciences Reports Highlights from the 2016 Alzheimer's Association International Conference.

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  42. 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
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