AduhelmEarly Alzheimer's disease (MCI and mild)
New molecular entity
Development and Regulatory status
Phase III Clinical Trials
Apr 22Biogen withdraws its MA application in the EU after talks with regulators made it clear the data provided so far are unlikely to support marketing approval .
Feb 22Biogen request a re-examination of EMA’s December 2021 opinion .
Jan 22In the US, the Centers for Medicare & Medicaid Services (CMS) has released a proposed National Coverage Determination (NCD) decision memorandum stating that FDA-approved drugs in the class of amyloid-targeting monoclonal antibodies would be covered for people with Medicare only if they are enrolled in qualifying clinical trials. This is following analysis of the evidence which found that, while there is potential for promise with these treatments, there is also potential for harm (e.g. headaches, dizziness, fall, intracranial haemorrhage). After reviewing all comments received on the proposal, CMS will announce its final decision by Apr 2022 .
Dec 21In the US, Biogen has announced a reduced price for aducanumab to improve patient access. The wholesale acquisition cost will be reduced by almost 50% so that for a patient of average weight (74kg), the yearly cost at a maintenance dose (10mg/kg) will be $28,200. A company statement said the reduced price "takes into consideration the questions raised about this first class of therapies, the potential eligible population and revised pharmaco-economic assumptions" .
Dec 21Biogen announces it will seek a re-examination of the opinion by the CHMP, and will seek to address the grounds for refusal. The European Commission regulations allow an applicant to request a re-examination of a CHMP opinion, followed by submission of documentation with detailed grounds for the request. The Committee has 60 days after receipt of this documentation to re-examine their opinion 
Dec 21The EMA has issued a negative opinion for aducanumab for Alzheimers disease on the 16th Dec. The EMA noted that although aducanumab reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established. Results from main studies were conflicting and did not show overall that aducanumab was effective at treating adults with early stage Alzheimer’s disease, issues were also raised about safety. Biogen has 15 days to request re-examination of the opinion .
Nov 21The CHMP of the EMA issued a negative trend vote on the MAA for aducanumab. CHMP will have a meeting on December 13-16, 2021, and is expected to give a formal opinion. 
Jul 21In the US Medicare is planning a 9-month process to determine standardised national procedures for Aduhelm coverage. At the moment, the Centers for Medicare & Medicaid Services (CMS) are processing claims on a case-by-case basis. 
Jul 21FDA updates the label for Aduhelm says it should only be used in patients with mild cognitive impairment due to AD or mild AD. The change, submitted by Biogen and Eisai, also now reads that there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. Biogen said that based on ongoing conversations with prescribing physicians, FDA and patient advocates, it submitted the label update with the goal to further clarify the patient population that was studied across the three Aduhelm clinical trials that supported approval .
Jun 21Following a revised cost-effectiveness analysis the Institute for Clinical and Economic Review (ICER) in the US has concluded that Aduhelm´s controversial price tag "is not in reasonable alignment with its clinical benefits". An 85% to 95% discount from its current list price to a price of between $3,000 to $8,400/year would be fair. If Aduhelm halted the progression of disease, the fair price could increase to up to $70,000. But with conflicting trial results, and a slight improvement shown only in one of the PIII trials (EMERGE), the institute said the evidence is "insufficient to be able to demonstrate that patients get benefits that would outweigh the risks" .
Jun 21In the US, the House Committee on Oversight and Reform has announced it will launch an investigation into the FDA approval process and Biogen´s pricing strategies for Aduhelm stating they have "serious concerns" 
Jun 21Launched in the US amidst calls from Public Citizen for resignation of FDA staff and criticism over basing the approval on an unvalidated surrogate marker .
Jun 21Biogen intends to start shipping Aduhelm within two weeks to around 1,000 infusion centres across the US, and has said it will prioritise access to people with early-stage AD .
Jun 21Biogen has priced Aduhelm at at $56,000 per year in the US, far above the expectations of some analysts who were expecting it to be set at around $10,000, while ICER has said a fair price would be in the $2,500 to $8,300 range. ICER are critical of the decision to approve the drug for all AD patients, rather than just the patients with MCI and mild dementia .
Jun 21Approved in the US using the Accelerated Approval pathway, under which the FDA approves a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about clinical benefit. The FDA is requiring Biogen to conduct a post-approval clinical trial .
Apr 21Biogen announces that if approved in the US they would expect to launch aducanumab immediately .
Feb 21Aducanumab is considered by analysts to be the most anticipated drug launch of 2021 in the US .
Jan 21FDA extended the review period for aducanumab until June 7, 2021. This delay is related to the FDA requesting additional analyses and clinical data which Biogen have supplied. The FDA consider it a Major Amendment to the application, thus requiring additional review time. 
Nov 20FDA decision expected 21 Mar 2021 .
Nov 20The advisory committee for the FDA voted 1-8, with two members voting “uncertain” that EMERGE provides “strong evidence that supports the effectiveness” of the drug in Alzheimers. In a second vote asking whether a small phase 1b study, called PRIME provides “supportive evidence” for the efficacy of aducanumab; the tally came down 0-7, with four members voting “uncertain”.
Nov 20Aducanumab is due to be reviewed by FDA advisory committee this month. Data underpinning filing comes from two PIII studies EMERGE and ENGAGE. Whilst the PIII program failed a futility analysis in March 2019, Biogen argued the analysis was based on a smaller data set that featured fewer patient who received high-dose aducanumab. If successful approval from the FDA is anticipated in March 2021 .
Oct 20EU PRIME designation was withdrawn in 2019 following discontinuation of clinical studies .
Oct 20Filed in EU .
Aug 20Eisai are preparing for an EU submission .
Aug 20FDA has awarded Priority Review status to aducanumab. A decision is expected by March 2021 at the latest .
Jul 20Filed for approval in USA. 
Apr 20Company announce plans to file for approval Q3 2020. Analysts predict approval in 2021/2022. 
Oct 19Based on new analysis of the PIII trial data, Biogen has announced plans for regulatory filing in the US in early 2020 .
Mar 19Biogen and Eisai discontinued continuing development of aducanumab for Alzheimers .
Sep 16Granted fast-track designation by the FDA .
Jun 16Accepted into the EU PRIME program, which offers the possibility of accelerated assessment and allows companies more regulatory assistance .
Apr 15Biogen plan to launch two 18-month PIII studies in 2H 2015, each in 1,350 patients with early-stage disease. In the next few months, Biogen expects to get final signoff from the FDA on its trial design, clearing the way for recruitment .
A fully human immunoglobulin gamma 1 (IgG1) monoclonal antibody that is selective for the fibrillar form of beta amyloid. Given by monthly infusion over 1 hour.
The prevalence of dementia is below 1% in individuals aged 60-64 years, but shows an almost exponential increase with age, so that in people aged 85 years or older the prevalence is between 24% and 33% in the Western world .
Early Alzheimer's disease (MCI and mild)
Trial or other data
Jun 22Biogen terminates the observational ICARE AD trial, which was meant to collect real-world data on Aduhelm use in the US. The termination comes as a result of the national coverage policy, as it is expected there will be limited [Aduhelm] prescription and usage in routine clinical practice, making the study not feasible for enrolment .
Mar 22New topline data reported by Biogen from a long-term extension phase of the PIII clinical studies of aducanumab. Studies evaluated pts after ~2.5 yrs treatment and significant decreases in amyloid beta plaques and plasma p-tau181 were reported. At 78 weeks, pts with decreased plasma p-tau181 levels had less clinical decline than in pts whose plasma p-tau181 levels did not decrease. 
Jan 22PIV study ENVISION will review the use of this medicine in pts with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s disease, with confirmation of amyloid beta pathology (n= 1500 planned). The company plans to enrol 18% of US pts from African American and Latin population. Primary endpoint will be measured via the Clinical Dementia Rating-Sum of Boxes at 18 months after the beginning of treatment. Pt screening expected to start May 2022 and completion of study will be 4 years. No NCT number found. 
Dec 21NICE appraisal suspended after EMA negative opinion
Dec 21Biogen announce that they intend to deliver results from Phase 4 confirmatory trial for the FDA by 2026, well ahead of the nine year schedule set by the FDA .
Nov 21Results of secondary analysis of safety data from the EMERGE and ENGAGE trials (n=3285) reporting on the characteristics of amyloid-related imaging abnormalities (ARIA) during aducanumab treatment in individuals with early Alzheimer disease have been published in JAMA Neurology. The results reported 425 patients (41.3%) in the combined 10 mg/kg aducanumab group (n = 1029) experienced ARIA; ARIA-oedema occurred in 362 patients (35.2%), and 94 of these patients (26.0%) experienced associated symptoms (eg, headache, confusion, dizziness, and nausea). ARIA-microhaemorrhage and ARIA–superficial siderosis occurred in 197 patients (19.1%) and 151 patients (14.7%), respectively. These adverse effects were already known and the US prescribing label specifically recommends having an MRI scan done within 1 year of starting Aduhelm treatment and ahead of a patient´s 7th and 12th infusions. Published efficacy data in a peer-reviewed journal are still awaited 
Nov 21Analysis of data from PIII trials EMERGE and ENGAGE published in JAMA .
Nov 21Death of a 75 year old pt taking Aduhelm reported to the FDA’s Adverse Event Reporting System (FAERS). FAERS has recorded 3 other new ARIA cases from July to September 2021, all requiring hospitalisation. 
Jul 21Biogen and Ionis report positive topline clinical data on aducanumab at the Alzheimer’s Association International Conference. One of the posters presented item-level data from the EMERGE PIII trial, looking at data on individual domains that made up the trial’s pre-specified endpoints of cognition, function, and behavior. The data presented demonstrated consistency of high-dose aducanumab treatment effects across all six domains, three cognitive and three functions, as measured by Clinical Dementia Rating-Sum of Boxes, the primary endpoint of the study. Aducanumab was also reported to be associated with a decrease in the behavioral and psychiatric symptoms of Alzheimer’s as measured by the Neuropsychiatric Inventory-10 (NPI-10), a tertiary efficacy endpoint of the EMERGE study. [38,39]
Oct 19Decision to proceed with a filing application in the US was reached following new analysis by Biogen in consultation with the FDA, of a larger dataset (n=3,285) from the PIII clinical studies discontinued in Mar 2019. This analysis shows that, in the EMERGE trial, the drug actually met the primary endpoint of significant reduction of clinical decline from baseline in CDR-SB scores at 78 weeks (23% versus placebo, p=0.01). Patients treated with high dose aducanumab also showed a consistent reduction of clinical decline as measured by the pre-specified secondary endpoints: 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). In the ENGAGE trial, the cohort of patients who achieved sufficient exposure to high dose aducanumab support the findings from EMERGE .
Mar 19Biogen and Eisai discontinue PIII ENGAGE and EMERGE Trials. This was based on results of a futility analysis conducted by an independent data monitoring committee, which indicated the trials were unlikely to meet their primary endpoint upon completion. Detailed data from the ENGAGE and EMERGE studies will be presented at future medical meetings to inform ongoing research. As part of this decision, the EVOLVE Phase 2 safety study and the long-term extension of the PRIME Phase1b study of aducanumab will also be discontinued .
Aug 18PIII trials ENGAGE and EMERGE have finished recruiting. Collection of primary outcome data in both trials should now complete Jan 20 .
Nov 17PIII ENGAGE (NCT02477800) study is still recruiting. Collection of primary outcome data should now complete Nov 19; PIII EMERGE (NCT02484547) remains on course to complete collection of its primary outcome data in Feb 20 .
Sep 16Biogen announce early-stage data from a preclinical animal model and a Phase Ib, placebo-controlled study in 165 prodromal and mild AD patients; both showed that aducanumab reduced amyloid-beta in the brain, and that the reduction was dose-dependent .
Sep 15PIII EMERGE (NCT02484547) study is recruiting from sites in the US, Canada & EU (but not UK). primary outcome (change from baseline in CDR-SB score) data collection should complete in Feb 20 .
Sep 15Biogen announces that the first patient has been enrolled in the Phase 3 studies, ENGAGE and EMERGE .
Aug 15PIII ENGAGE (NCT02477800) is recruiting from sites worldwide, including the UK, and is expected to compete collecting primary outcome (change from baseline in CDR-SB score) data in Feb 20 .
Jul 15Biogen announces new results from a prespecified interim analysis of PRIME, which includes patients treated up to 54 weeks with the 6 mg/kg dose. Aducanumab demonstrated acceptable safety and tolerability, and the findings reinforce the previously reported results from PRIME. Consistent with previously reported results, the 54-week data from the 6mg/kg arm demonstrated a statistically significant reduction of beta amyloid in the brain. In exploratory analyses, the 6mg/kg dose showed an improvement in the slowing of clinical decline, as measured by the Mini Mental State Examination (MMSE) and Clinical Dementia Rating sum of boxes (CDR-SB) scales, which was not statistically significant. In a pre-specified analysis across placebo and all doses of aducanumab, the slowing of clinical decline was shown to be dose-dependent, and this dose-dependence achieved statistical significance for both scales .
Jul 15Biogen revealed positive results with aducanumab in Alzheimers, which led to reductions in brain amyloid plaque by as much as 71%. The plaque reduction was more pronounced as the dose was increased over time. Biogen also announced that aducanumab was able to reduce cognitive decline. More data will be announced soon. Biogen plans to begin a PIII trial, which if successful, would then to seeking approval to market the drug .
Apr 15The PI study previously reported is the PRIME trial, designed to investigate the tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of aducanumab in patients with prodromal or mild Alzheimer´s disease (NCT01677572) .
Mar 15Biogen announce results of a PI trial in which three out of four dosage levels of BIIB037 led to statistically significant reductions in beta amyloid compared to placebo after 26 weeks, and, for the two doses with enough data to measure, that effect was even greater at week 54. More importantly, that reduction in beta amyloid correlated with statistically significant improvements over placebo on two common measures of cognition, a result many say affirms the hypothesis that the protein is to blame for Alzheimer´s memory-destroying effects .