On Tuesday, October 22nd, 2019, the drug company Biogen released an update stating that it will move forward with submitting a regulatory filing with the Food and Drug Administration (FDA) for approval of aducanumab in 2020. This decision surprised investors, patients, and the research community as it comes on the heels of Biogen’s disappointing press release in March 2019 revealing that it would discontinue two large Phase 3 clinical trials for aducanumab, EMERGE and ENGAGE. Analysis of a larger dataset breathed new life into the possibility for high dose aducanumab to reduce clinical decline in some Alzheimer’s patients in early stages of the disease.
This is an ongoing breaking news story that will require further evaluation. We will continue to update this story as more details are made available. Biogen has released preliminary data to investors. This information is available at the following link: https://investors.biogen.com/static-files/40565136-b61f-4473-9e58-9be769bbac6c
At this time, Biogen is stating that its experimental drug, aducanumab, may slow cognitive impairment in patients with the earliest clinical signs of Alzheimer’s disease who received the highest dose of aducanumab for the longest duration. More extensive data from the clinical trial is expected to be presented at the Clinical Trials on Alzheimer’s Disease meeting in December of 2019.
What is aducanumab and how does it work?
Aducanumab, a monoclonal antibody, attaches to amyloid beta – a protein that abnormally aggregates to form plaques in the brains of Alzheimer’s patients – and facilitates the clearing of plaques from the brain. The decision to move forward with requesting FDA approval has been headline news; if approved, aducanumab would become the first therapy shown to reduce clinical symptoms in Alzheimer’s disease. As a monoclonal antibody, aducanumab is expensive to manufacture and must be delivered intravenously. The current protocol requires monthly intravenous administration and is estimated to cost up to $10k per month per patient.
What were the objectives of the EMERGE and ENGAGE Phase 3 Clinical Trials for Aducanumab in the first place?
Biogen began two parallel Phase 3 clinical trials, EMERGE and ENGAGE, in August of 2015. The studies both enrolled ~1600 patients with mild cognitive impairment due to Alzheimer’s disease. The trial was designed to compare monthly infusions of either aducanumab or placebo over an 18-month treatment period. Different treatment arms received different doses of the drug. Biogen changed the design of the trials midway in order to give one group of patients a higher dose. The ENGAGE trial was intended to run through 2020 in 150 centers in North America, Europe, Australia, and Asia. The EMERGE study was identical to ENGAGE but differed by a month in terms of patient enrollment start date. In addition, EMERGE enrolled patients in 150 sites across North America and Europe1.
Why is aducanumab being revived after news that it failed in the Phase 3 clinical trial in March 2019?
To answer this question requires taking a step back and examining the reason Biogen decided to terminate the Phase 3 ENGAGE and EMERGE clinical trials of aducanumab for early Alzheimer’s disease back in March of 2019. Biogen collaborated with an independent data-monitoring committee to run a “futility analysis.”
In the case of Biogen’s decision, the results of the trial were analyzed before all of the patient data had been collected. This analysis is done with the intention of stopping a clinical trial that seems unlikely, according to statistics, to demonstrate a beneficial effect of treatment. The primary endpoint for the Phase 3 aducanumab trial was the slowing of cognitive decline as measured by a test called the Clinical Dementia Rating-Sum of Boxes.
What results from the new analysis has Biogen released to the public?
What information has come to light to influence the reversal of the aducanumab decision?
The interim analysis conducted by Biogen included data from 803 participants in the EMERGE trial and 945 participants in the ENGAGE trial who completed the full 18-months of treatment as of December 2018. This represented only half of the enrollment of each trial. By March 2019, when the trials were stopped, an additional 179 EMERGE participants and 139 ENGAGE participants completed the treatment protocol. Biogen’s analysis of the larger dataset included these additional participants as well as other participants who had not originally completed the treatment due to side-effects.
It is also important to point out that there were changes to the original clinical trial protocol that changed the number of participants receiving the highest dose of aducanumab. One amendment to the protocol was the decision to add APOE4 carriers to the group receiving the highest dose of aducanumab.
Being an APOE4 carrier increases the risk of developing late-onset Alzheimer’s disease. APOE4 carriers are more susceptible to a side-effect called ARIA, including monoclonal antibodies such as aducanumab. (There are two types of ARIA: ARIA-E, cerebral edema that may include headaches, swelling, and confusion, and ARIA-H, cerebral micro haemorrhages on the brain.) 18 months into the clinical trials, Biogen’s protocol was amended to include more APOE4 patients into the group receiving the highest dose of aducanumab (10 mg/kg). This decision was based on several studies suggesting that ARIA could be a manageable side-effect that usually resolves without harm to the patient.
In the original protocol, participants who developed ARIA stopped taking aducanumab until the side-effects resolved. Once the side-effects subsided, the patient would resume the treatment at a lower dose. A year into the study, participants with ARIA were allowed to resume dosing at the highest level. This protocol adjustment increased the number of patients at the highest dose of aducanumab and likely contributed to the new data showing more of an improvement for cognitive decline. These protocol adjustments affected more EMERGE than ENGAGE participants because the ENGAGE trial started enrolling a month earlier. This is Biogen’s leading explanation at the moment for why the results of the ENGAGE and EMERGE trials differed.
For a more extensive discussion of ARIA, please see the following reference: “Amyloid related imaging abnormalities (ARIA) in amyloid-modifying therapeutic trials” from Reisa Sperling and colleagues: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063417/
Brief Timeline of Aducanumab
Aducanumab, which is also referred to as BIIB037, is a high-affinity antibody against aggregated, abnormally folded forms of amyloid-beta and targets plaques in brain tissue rather than vascular amyloid.
Biogen moved aducanumab into Phase 3 clinical trials after initial results established safety, target engagement, and reduction in the rate of decline on two cognitive tests, the Mini-Mental State Examination and the Clinical Dementia Rating Scale Sum of Boxes, in a dose-dependent fashion (patients with the highest dose received the greatest benefit).
Biogen began two parallel Phase 3 clinical trials, EMERGE and ENGAGE. The studies both enrolled ~1600 patients with mild cognitive impairment due to Alzheimer’s disease. The trial was designed to compare monthly infusions of either aducanumab or placebo over an 18-month treatment period. Biogen changed the design of the trials midway in order to give one group of patients a higher dose.
Biogen introduces a protocol amendment to the phase 3 clinical trial for aducanumab. Patients who had their doses suspended due to ARIA (amyloid-related imaging abnormality) resume aducanumab treatment at their originally assigned, higher dose.
Biogen introduces a protocol amendment to the phase 3 clinical trial for aducanumab. ApoE4+ carriers. At this point, more ApoE4 carriers are added to the group receiving the highest dose of aducanumab. This amendment is possibly the reason the trial data emerged as positive following further analysis that included these patients.
March 21st, 2019
Biogen announced that it would terminate all currently ongoing aducanumab trials following a pre-planned interim futility analysis from an outside consulting agency that predicted that the EMERGE and ENGAGE trials would miss their desired primary endpoint readout. On April 24, 2019, Biogen announced that it would not initiate an anticipated Phase 3 prevention program with aducanumab and removed it from its pipeline.
October 22nd, 2019
Biogen released an update on aducanumab to investors announcing a plan to submit a regulatory filing to the FDA in early 2020. Biogen claimed that a new analysis of the entire available dataset showed that aducanumab reduced clinical decline in patients with early Alzheimer’s disease in the EMERGE trial. The company asserted that the newly positive results were largely driven by the inclusion of the data from patients who received a higher dose for a longer time period, patients whose data was not available for the earlier futility analysis.
Patient Group Clarification
Rudy Tanzi, Chair of the Cure Alzheimer’s Fund Research Leadership Group, Co-Director of the Henry and Allison McCance Center for Brain Health, Director of the Genetics and Aging Research Unit at Mass General Hospital, in an update to Cure Alzheimer’ Fund has provided the following insights: “Importantly, whether we see approval of aducanumab or not, the EMERGE trial single-handedly provides the first clinical proof of concept for the amyloid hypothesis: the first evidence in humans that removing amyloid in the brain improves cognition. As you know, genetics and pathology data have always supported amyloid as a key target for AD therapy. Regarding the previous clinical trial failures, we have always maintained that the key is to hit amyloid very early – preferably pre-symptomatically. In other words, following the earlier failed trials, the question was not “whether” to still target beta-amyloid, but “when” to hit amyloid. The new Biogen EMERGE trial results in the earliest stage, mildest AD patients now nicely drive home this point. It is also worth noting that despite the overwhelming recent negative hyperbole in the press regarding the earlier futility analysis and projected failure of aducanumab, the Cure Alzheimer’s Fund never abandoned amyloid as a target.”
Rudy Tanzi has also commented on Cure Alzheimer’s Fund’s approach to supporting research that targets the disease from a diversity of angles: “Of course, we will also vigorously continue on work on reducing neuroinflammation and on targeting microbes that seed amyloid deposition and subsequent AD pathology. And, as we develop the Gamma Secretase Modulators (GSMs) and other early-intervention pathways to treatment, we will closely keep in mind that Abeta is needed in the brain to protect against microbial infection. So, we do not want to wipe out Abeta, we will only want to dial it down to safe levels, just as we do with cholesterol lowering drugs.”
In an interview with The New York Times, Dr. Ronald Peterson, an Alzheimer’s researcher at the Mayo Clinic who is a member of the Cure Alzheimer’s Fund Research Leadership Group stated: “the company has not yet convinced the F.D.A. of the drug’s efficacy. Biogen is allowed to file – no guarantees on approval, but it gives the drug a chance.”
Michael Weiner, an Alzheimer’s researcher at the University of California, San Francisco added: “this is not a cure, it is a slowing of decline. The practical impact on patients remains to be seen.”
In response to the original press release from Biogen stating that aducanumab failed in phase 3 clinical trial, Cure Alzheimer’s Fund Research Leadership Group member, Dr. David Holtzman of Washington University in St. Louis stated: “Even though this trial was in the early symptomatic phase of AD, it is still in the phase when Aβ is no longer likely to be the driving process but where tau and inflammation probably are. I think Aβ is still a good target for the primary and maybe secondary prevention trials of AD before tau and inflammation have started driving the disease.”
In an editorial in STAT news, Dr. Dennis Selkoe, Co-Director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and professor of neurologic diseases at Harvard Medical school wrote, “Even if the FDA decides to not approve the drug at this point, it can’t take away the evidence of anti-amyloid approaches, even in people who already have symptoms, can benefit both clinical features, and pathological changes in the brain.”
In an interview with both The New York Times and The Wall Street Journal, Dr. Murali Doraiswamy cautioned that with so little data released to the public that the announcement: “Looks very encouraging, but I would need to see more details.”
Biogen’s stock price jumped considerably following the announcement. However, analysts and institutional investors provided very guarded responses. If the FDA approves aducanumab and Medicare covers it for a wide spectrum of patients, Biogen will have a uniquely lucrative new product. However, many analysts are wary of the odds of success in each of these two necessary steps.
Resources for learning more about Aducanumab