A Stunning Surprise: Aducanumab Works in Trials, Heads to FDA

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In March, Biogen discontinued advanced Alzheimer’s trials for aducanumab, predicting it was not likely to produce meaningful benefits. Now, new data did demonstrate real benefits, the FDA will review a fresh analysis, and former trial patients are getting back on the drug. See what happened.

Biogen plans to seek regulatory approval for their drug “aducanumab” as a potential new treatment for Alzheimer’s, particularly for people living with the early stages of Alzheimer’s.

Trials for the drug had been discontinued in March 2019. Now, Biogen has decided to revive trials, and in addition, to apply to the FDA to market the drug. If the FDA approves, this would be the first drug in history to alter the course of Alzheimer’s.

So What Happened?

According to a 17-page update released by Biogen, the company says it is now confident in the drug’s effectiveness based on a new analysis of an even larger data set. Here are the key points from the update’s summary:

1. “Following discussions with the FDA, Biogen plans to submit a regulatory filing in early 2020.”
2. “The futility analysis in March 2019 was based on a smaller, earlier dataset with less exposure to high dose aducanumab. The result of the futility analysis was incorrect.”
3. “New analysis of larger dataset showed that aducanumab reduced clinical decline in patients with early Alzheimer’s disease as measured by the pre-specified primary and secondary endpoints.”
4. “The positive results of this new analysis were driven primarily by greater exposure to high dose aducanumab in the larger dataset.”
5. “If approved, aducanumab would become the first therapy to reduce clinical decline in Alzheimer’s disease.”

For now, you can read Biogen’s full update (complete with flowcharts and extensive data analyses) by clicking here.

Snapshot, In Plain English

In March, Biogen announced it would discontinue its Phase 3 clinical trials for aducanumab after an interim analysis showed the drug was not likely to produce a meaningful benefit. Now, based on new data, benefit can be demonstrated. Therefore, an analysis including an additional three months of data will be submitted to the FDA. While under review by the FDA for possible approval, the company says it plans to offer access to aducanumab to eligible participants previously enrolled in the Phase 3 studies, the long-term extension of the Phase 1b study, and a safety study.

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FDA Agrees to Review Aducanumab for Possible Approval

According to Biogen, thye new data showed a subset of patients who received a higher dose of aducanumab experienced significant slowing of decline on measures of cognition and activities of daily living, such as household chores. The new data also showed positive changes in biomarkers.

This news comes after Biogen’s announcement last March that it was discontinuing Phase 3 clinical trials of aducanumab due to “futility analysis” of data. The trial for aducanumab – which was designed to slow the progression of Alzheimer’s by removing beta-amyloid plaques from the brain – evaluated the efficacy and safety of aducanumab in patients with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease dementia.

“In the earlier phases of clinical development, I had hope for this study,” said Howard Fillit, MD, Founding Executive Director and Chief Science Officer at the ADDF (Alzheimer’s Drug Discovery Foundation). “It was one of the first clinical trials to use amyloid PET imaging to ensure the study participants had Alzheimer’s disease showing the importance of developing better biomarkers to improve the rigor of trial design. We need to see more data to evaluate the real strengths and weaknesses of the study. We look forward to receiving further analyses in the coming months. It is certainly too early to tell if aducanumab will be approved, but it is encouraging the FDA has agreed to review the drug application for possible approval.”

100 Open Alzheimer’s Trials

This news must be taken in context of the overall goal of finding better ways to detect and treat Alzheimer’s disease. There are over 100 drugs in clinical trials for Alzheimer’s disease with the majority focused on novel targets, according to a recent ADDF clinical trial report. The ADDF has long supported a broader approach that champions the biology of aging, which targets multiple aging pathways, such as inflammation, vascular problems, metabolic and mitochondrial changes, and epigenetics.”

“While we await review of further data, we need to keep in mind that we are dealing with a complicated disease that can be caused by many factors,” said Dr. Fillit. Like other diseases of aging including cancer, diabetes and heart disease, it is likely a combination of drugs addressing multiple target pathways will be needed to effectively treat Alzheimer’s. Combination therapy through precision medicine is ultimately the goal.”

What is Biogen Saying About Aducanumab?

Biogen plans to pursue regulatory approval for aducanumab, an investigational treatment for early Alzheimer’s disease (AD). The Phase 3 EMERGE Study met its primary endpoint showing a significant reduction in clinical decline, and Biogen believes that results from a subset of patients in the Phase 3 ENGAGE Study who received sufficient exposure to high dose aducanumab support the findings from EMERGE. Patients who received aducanumab experienced significant benefits on measures of cognition and function such as memory, orientation, and language. Patients also experienced benefits on activities of daily living including conducting personal finances, performing household chores such as cleaning, shopping, and doing laundry, and independently traveling out of the home. If approved, aducanumab would become the first therapy to reduce the clinical decline of Alzheimer’s disease and would also be the first therapy to demonstrate that removing amyloid beta resulted in better clinical outcomes.

The decision to file is based on a new analysis, conducted by Biogen in consultation with the FDA, of a larger dataset from the Phase 3 clinical studies that were discontinued in March 2019 following a futility analysis. This new analysis of a larger dataset that includes additional data that became available after the pre-specified futility analysis shows 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). In both studies, the safety and tolerability profile of aducanumab was consistent with prior studies of aducanumab.

“With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s. This is the result of groundbreaking research and is a testament to Biogen’s steadfast determination to follow the science and do the right thing for patients,” said Michel Vounatsos, Chief Executive Officer at Biogen. “We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.”

The FDA, The Patients

Based on discussions with the FDA, the Company plans to file a Biologics License Application (BLA) in early 2020 and will continue dialogue with regulatory authorities in international markets including Europe and Japan. The BLA submission will include data from the Phase 1/1b studies as well as the complete set of data from the Phase 3 studies.

The Company aims to offer access to aducanumab to eligible patients previously enrolled in the Phase 3 studies, the long-term extension study for the Phase 1b PRIME study, and the EVOLVE safety study. Biogen will work towards this goal with regulatory authorities and principal investigators with a sense of urgency.

Study Results

EMERGE (1,638 patients) and ENGAGE (1,647 patients) were Phase 3 trials. The trials were multicenter, randomized, double-blind, placebo-controlled, parallel-group studies designed to evaluate the efficacy and safety of two dosing regimens of aducanumab. These studies were discontinued on March 21, 2019, following the results of a pre-specified futility analysis which relied on an earlier and smaller dataset. The futility analysis was based on data available as of December 26, 2018, from 1,748 patients who had the opportunity to complete the 18-month study period and predicted that both studies were unlikely to meet their primary endpoint upon completion. Futility analyses are common in large clinical studies and use statistical modeling to attempt to predict the outcome of the studies based on a number of pre-specified assumptions and criteria.

Following the discontinuation of EMERGE and ENGAGE, additional data from these studies became available resulting in a larger dataset, which included a total of 3,285 patients, 2,066 of whom had the opportunity to complete the full 18 months of treatment. A new extensive analysis of this larger dataset showed a different outcome than the outcome predicted by the futility analysis. Specifically, the new analysis of this larger dataset showed EMERGE to be statistically significant on the pre-specified primary endpoint (P=0.01). Biogen believes that data from a subset of ENGAGE support the findings from EMERGE, though ENGAGE did not meet its primary endpoint. Biogen consulted with external advisors and the FDA on these different results and their implications.

First Time Phase 3 Reduces Decline

“This large dataset represents the first time a Phase 3 study has demonstrated that clearance of aggregated amyloid beta can reduce the clinical decline of Alzheimer’s disease, providing new hope for the medical community, the patients, and their families,” said Dr. Anton Porsteinsson, William B. and Sheila Konar Professor of Psychiatry, Neurology and Neuroscience, director of the University of Rochester Alzheimer’s Disease Care, Research and Education Program (AD-CARE), and principal investigator. “There is tremendous unmet medical need, and the Alzheimer’s disease community has been waiting for this moment. I commend Biogen, the FDA, the medical community, and the patients and their study partners for their persistence in working to make today’s announcement a reality.”

In EMERGE, which met its pre-specified primary endpoint in the new analysis, patients treated with high dose aducanumab showed a significant reduction of clinical decline from baseline in CDR-SB scores at 78 weeks (23% versus placebo, P=0.01). In EMERGE, 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). Imaging of amyloid plaque deposition in EMERGE demonstrated that amyloid plaque burden was reduced with low and high dose aducanumab compared to placebo at 26 and 78 weeks (P<0.001). Additional biomarker data of tau levels in the cerebrospinal fluid supported these clinical findings. Biogen believes that data from patients in ENGAGE who achieved sufficient exposure to high dose aducanumab supported the findings of EMERGE.

Adverse Events

In both studies, the most commonly reported adverse events were amyloid-related imaging abnormalities-edema (ARIA-E) and headache. 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 sequelae. Biogen plans to present further detail on the new analysis of the larger dataset from EMERGE and ENGAGE at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in December 2019.

Higher Dose

After reviewing the data in consultation with the FDA, Biogen believes that the difference between the results of the new analysis of the larger dataset and the outcome predicted by the futility analysis was largely due to patients’ greater exposure to high dose aducanumab. Multiple factors contributed to the greater exposure to aducanumab in the new analysis of the larger dataset, including data on a greater number of patients, a longer average duration of exposure to high dose, the timing of protocol amendments that allowed a greater proportion of patients to receive high dose, and the timing and pre-specified criteria of the futility analysis.