In this article, we revisit the many twists and turns of the aducanumab clinical trials and explore the scientific community's response to the latest analysis of the data.
On October 22, Biogen surprised the scientific community by announcing their plans to apply for US Food and Drug Administration (FDA) marketing approval for aducanumab, an investigational treatment for Alzheimer's disease (AD). Why was this surprising? Just a few months earlier on March 21, the biotechnology company declared that they were discontinuing the drug’s development on the basis that two Phase III AD trials, ENGAGE (NCT 02477800) and EMERGE (NCT 02484547), were "unlikely to meet their primary endpoint upon completion."
What is adunacumab?
The brains of AD patients are often found to be riddled by amyloid plaques that disrupt healthy neuronal function and cause toxicity, ultimately leading to cognitive decline. Aducanumab is a monoclonal antibody (mAb) designed to bind to aggregated forms of β-amyloid to clear it. The drug was originally developed by Neurimmune via a reverse translational medicine approach, in which the antibody was extracted from older individuals who have not developed AD.
Where has the extra data come from? Understanding ENGAGE and EMERGE
For both ENGAGE and EMERGE, patients were assigned (randomly) to placebo, a low dose of aducanumab or a high dose of aducanumab, depending on whether they were APOE ε4 carriers. The primary outcome of the trial was the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) cognitive test, with secondary outcomes including the Mini Mental State Examination, the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale, and the Alzheimer's Disease Cooperative Study-Activities of Daily Living-MCI scale.
The original sample size for each of trials was 1350, but this was increased in November 2017 to 1650 to maintain the statistical power of the results.
Here's the key part. In December 2018, a futility analysis, in which the ability of a clinical trial to achieve its objectives is assessed, was conducted on 945 and 803 patients in ENGAGE and EMERGE respectively. The criteria assessed was the probability of participants in both the higher and lower dose arms of both studies achieving statistically significant improvements in CDR-SB. Unfortunately, the analysis did not suggest this would be the case, and so, the trial was stopped in March 2019.
However, during the three-month period between the futility analysis starting and the trial being stopped, an additional 139 and 179 participants completed the trials. It is the additional data including these participants that Biogen say warrants their FDA application for aducanumab.
This is an incredibly unique situation that almost never happens; once a drug is discontinued mid-development, it rarely makes a comeback. It's also unusual for post-hoc analysis to be conducted and result in a company retracting their original statements regarding a drug's efficacy. Naturally, you’d think that the new-found results must be impressive to merit such a bold move.
At an investor's conference on Oct 22, Biogen released the additional data.
Lon Schneider, Professor of Psychiatry, Neurology, and Gerontology at the Keck School of Medicine of the University of Southern California, eloquently assessed the data sets in his article for the Lancet. The major key finding was an apparent dose-responsive effect in the CDR-SB scale for the larger EMERGE data set. However, parallels could not be found in the ENGAGE data, where participants actually showed a decline in performance on the CDR-SB scale when compared to placebo, but a dose-responsive improvement in the ADAS-Cog13 and the ADAS-ADL-MCI scales.
Safe to say, the results left the scientific community feeling somewhat perplexed. In his article, Derek Lowe commented, "I have no idea why four different dementia rating systems should give such different results, and to a first approximation, no one else seems to have a good idea, either."
Schneider said, "Biogen's slide presentation at the investors conference contained sparse information on clinical outcomes, mainly percentage differences and lone p values." He continued, "Although Biogen claims that the positive results of the EMERGE trial were driven by greater exposure to a higher dose in the larger dataset, the effect could just as likely been due to greater worsening in the placebo group."
The hope, therefore, was that Biogen would provide some clarity on the disparity in the results at the 12th Clinical Trials on Alzheimer's Disease (CTAD) conference that took place on December 5.
Did Biogen deliver?
The full presentation of the results is available over on the Biogen website. To (briefly) summarize, the biotechnology company attributed the discrepancy in the number of patients that received the higher dosage of aducanumab as the explanation for why the outcomes from EMERGE and ENGAGE were different. The high-risk APOE4 patients were originally started on a precautionary lose dose, but in 2017, this was ramped up to the higher dosage. As ENGAGE started approximately one month before EMERGE, it had more participants included in the trial when this change was made. Subsequently, ENGAGE had a smaller number of participants receiving the higher dose, which Biogen have used to explain why this group did not demonstrate benefit from aducanumab.
They also commented that the high dose of the drug in the EMERGE trial did lead to slight improvements on cognitive tests; however, some subjects did experience side effects from said higher dosage.
Biogen’s decryption of this data as "a major advance" and a "milestone achievement" has left much of the scientific community, who are still trying to get to grips with the data themselves, feeling confounded. There is real polarity in the response to aducanumab.
Kathy Liu, Clinical Training Fellow in Old Age Psychiatry at University College London told Technology Networks: “Personally, I don't think the situation has changed very much. The data that Biogen has released yesterday I don't think really moves my position forwards at all, because I think that we still know what we knew before, which is that EMERGE had a significant effect in the high dose group with a 0.4-0.5 difference versus placebo in the primary endpoint. ENGAGE was still negative."
She adds, "The results are still, to me personally, that if there is an effect, it's very small and it’s associated with side effects in the high-dose subgroups, so I think that that all needs to be balanced.”
Biogen – "rule breakers"?
In an interview, Robert Howard, a psychiatrist at University College London commented, “I surely don’t think that it should be given market approval on the basis of these data,” before saying that Biogen has "broken all the rules, really, about how you analyze data and report it."
In a more cautious reaction, James Pickett, Head of Research at the Alzheimer’s Society said: "Following the results presented today, it’s not possible to be sure whether people in the early stages of Alzheimer’s disease would meaningfully benefit from aducanumab," he continues: "The drug company is collecting more data which may help further answer this question over the coming months. It’s now also the role of the drug regulators to scrutinise the data to find out if on balance, there is a benefit to people with Alzheimer’s disease."
Carol Routledge, Director of Research at Alzheimer’s Research UK stated, “Since Biogen announced unexpected positive results from two Phase III clinical trials of aducanumab, the field has been waiting to see more detailed data. The positive news is that, given the long wait for a disease-modifying drug for Alzheimer’s, aducanumab shows a clear effect on key hallmarks of the disease. The additional data provides an explanation for why the two Phase III trials may have showed such different top-line results, suggesting people benefitted more when on a higher dose for a longer period of time."
Providing a sense of false hope?
The lack of efficacious treatments for AD is an emotive issue. Patients and loved ones are desperate for a cure for a disease that robs them of memories built over a lifetime. There is a worry that approval of aducanumab by the FDA based on current data could ultimately lead to false hope.
Liu, when asked about the impact these data may have on AD patients, says “I don't think that they should be downstream of what effectively is a large drug company with a great deal of investors to answer to. They are the ones who have suffered the effects of incomplete data reporting, and an objective analysis is really what's needed for everyone.”
Routledge adds, “Regulators now have a critical decision to make - are the benefits seen in these two 18-month-long trials large enough to make a meaningful difference to the lives of people with dementia? That decision will ultimately determine who may get access to aducanumab, and other drugs like it, in future and under what restrictions."
Video credit: The Alzheimer's Association
Routledge says "We are now in unchartered territory for an Alzheimer’s drug, and there will be huge anticipation around how the FDA decides to proceed. “Studies like these add hugely to our understanding of diseases like Alzheimer’s and the best approach to treat them. Dementia research is making strides and gaining momentum. It’s testament to the commitment of scientists, funders and those who take part in trials like this that we’re moving closer to the first life-changing treatment for Alzheimer’s.”
Time to take a fresh look at an older theory?
Across social media, some critics of the data are hailing Biogen's data as further evidence that the amyloid hypothesis for AD pathogenesis should be scrapped once and for all. Back in March, Lowe wrote “Amyloid definitely has something to do with Alzheimer’s—there’s far too much evidence to dismiss,” he wrote in a recent blog post. “But the situation is clearly more complicated than people have hoped, because otherwise, all the attempts to address amyloid (via antibodies and otherwise) would have yielded some tiny bit of clinical benefit. They have not.”
Lowe is referring to the numerous clinical trials of amyloid-targeting therapies over recent years that have failed to demonstrate clinical benefit – of which there have been at least 140. Several key questions arise here. Are the conflicting results from the Phase III aducanumab clinical trials an unfortunate outcome of questionable clinical trial design, a drug that simply doesn't deliver as hoped when it comes to efficacy and safety, or cold hard proof that a heavily-relied on disease theory needs urgent reassessment?
Let us know your thoughts in the comments.