Support, Skepticism, and Statistics: The Aducanumab Saga

After a sudden reversal and complex analyses, aducanumab’s future rests in the hands of the FDA while the community stands split on if the available data are enough to justify an approval.

A little more than a century ago, a German psychiatrist and neuropathologist by the name of Aloysius Alzheimer, MD, first described the pathology and symptoms of a disease known as presenile dementia at a 1906 meeting of the Southwest German Psychiatrists.

Nearly 4 years later, his colleague and fellow psychiatrist Emil Kraepelin, MBBS, coined the name Alzheimer disease in the publication of his eighth edition of the Handbook of Psychiatry.

Since then, the disease has captivated those who treat the elderly and cognitively impaired, though serious and modern attempts to develop treatments for the disease did not begin until much later in the twenty-first century. Despite that delay, the understanding of Alzheimer disease pathology has become clearer over these last hundred years, though its etiology remains clouded.

Similarly, even with the advances of modern medicine and rigorous trials, the attempts to develop disease-modifying therapies have resulted in what Gregory Day, MD, MSc, once described to HCPLive® as a “graveyard of past studies” filled to the brim with the headstones of agents that have failed to produce a viable candidate drug.

While COVID-19 has maintained its grips on the attention of the public in 2020, in the circles of physicians treating Alzheimer disease, another topic has ensnared the conversation: the investigational agent aducanumab.

An Abrupt About-Face

The challenge of solving this disease has proven in all this time to be as complex and frustrating as the disease itself.

For this reason, it came as no surprise in March 2019 when Biogen and Eisai announced that they were discontinuing a pair of phase 3 clinical trials, EMERGE and ENGAGE as well as a phase 2 safety study, EVOLVE, after the independent data monitoring committee determined that the candidate therapy would not achieve the primary end point.

At the time, it appeared as though aducanumab would be just another addition on the growing list of failures. The amyloid-clearing agent seemed to be positioned to fall into the obscurity that accompanies that futility, and some viewed this as the proverbial nail in the coffin for theamyloid-beta (Aβ) hypothesis.

But, in October, the pair of pharmaceutical giants announced they were changing course to seek FDA approval for aducanumab, and by December, new data from EMERGE and post hoc analysis of a subset of high-dose treatment in ENGAGE were presented at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) meeting, December 4–7, 2019 in San Diego, California.

The data suggest that there were statistically significant changes on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, with P values of .010 or .031 based on cutoff dates.

Suddenly, it seemed that aducanumab had legs to stand on, and in January 2020, the FDA gave the go-ahead for Biogen to re-administer aducanumab to patients who were previously enrolled in the trials in a phase 3b redosing study as it prepared to submit for approval.

Almost as immediately, a fissure of opinions split the medical community. On one side stands those who believe the therapy is poised to become the first-in-class treatment that patients with Alzheimer disease and their families have been waiting on for decades. On the other side stood those skeptical of such an unanticipated reversal.

This division has bubbled over the course of 2020, coming to somewhat of a head in early November, when the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted not to recommend regulatory approval of Biogen's aducanumab, in possibly the most anticipated advisory committee decision of the year.

The results of a small NeurologyLive Twitter poll suggested this division was clear and present, with 40.5% (n = 53) noting their disagreement with the committee, 37.4% (n = 48) stating their agreement, and another 22.1% (n = 30) declaring their uncertainty overall.

The Believers

It’s no secret that the 2 sides of this aducanumab-engraved coin emerged as a result of the October 2019 data announcement.

The analyses, even by admission of those involved in the process, as investigator Marwan Sabbagh, MD, director, Cleveland Clinic Lou Ruvo Center for Brain Health, told NeurologyLive, are extremely complex and can be equally challenging to understand. Ultimately, those who stand with aducanumab have clung to these additional data as the anchor of their favorable view of the drug.

Sabbagh, along with co-investigator Jeffrey L. Cummings, MD, ScD, director emeritus, Cleveland Clinic Lou Ruvo Center for Brain Health and vice-chair, department of brain health, University of Nevada–Las Vegas, also noted in an editorial published days before the Advisory Committee meeting that “the results of the aducanumab studies have not been published in peer‐reviewed form” suggesting that until those data are available to the public, these “discussions must be seen as tentative.”

Though the point made by Sabbagh and Cummings is a salient one, the lack of access to these data outside of what was presented a full year prior at CTAD has in part helped drive this discord.

“[The data are] contextually driven, in that it's not like the EMERGE data is by itself. It comes built on the on the shoulders of PRIME, [the phase 1b trial,] and there is clearly a dose-related effect and it is clearly driven at the highest dose,” Sabbagh said. “Every time you see the FDA come out with a position statement, it keeps lowering the bar. At the last iteration, a year ago, EMERGE data hit the target of what the FDA has said is the threshold it will consider [for approval]. I think it hits that, so I disagree with the negative voices.”

Additionally, the data shows a consistent reduction of clinical decline as measured by the pre-specified secondary end points: The Mini Mental State Exam (MMSE; 18% versus placebo; = .05), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo; P = .01) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo; P = .001).

As well, imaging of amyloid plaque deposits showed that both low- and high-dose aducanumab were associated with reduced burden compared with placebo at 26 and 78 weeks (P <.001).

Alongside that belief in the data stands an undeniable desire to bring a long-lost hope back to the forefront of the Alzheimer community—one shared by both sides. After Biogen’s biologics license application was filed in July 2020, FDA set a decision date for aducanumab for March 7, 2021.10 Although an approval would not bring a cure for the disease or the end of a decades-long fight, it would potentially usher in a new and modern era of treatment for Alzheimer disease.

“It would just be the beginning; a steppingstone. Rather than the final breakthrough, it would be the first,” principal investigator Stephen Salloway, MD, MS, director, Neurology and the Memory and Aging Program, Butler Hospital, told NeurologyLive. “To quote a colleague of mine, ‘in order to get the best-in-class drug, we must have the first-in-class drug.’ That's how I see this.”

The context of this present moment, as Sabbagh put it, is rooted in the last 17 years of failure. In that time, at least 40 phase 3 studies have failed, equating to more than $8 billion in investments with nothing to show for the efforts.

As a result, several companies have left the space altogether, deeming the effort not worth the cost. It would not be out of the question to assume this has led to a bit of cynicism piling on top of healthy skepticism. But many still believe in the therapy’s chances at approval.

The Skeptics

The need for an approval in Alzheimer has never been greater, and in part, this prerequisite has motivated the scientific community to ensure the upkeep of rigorous and well-executed clinical trials. As such, the other side of the aducanumab coin has pointed to the need for further analysis when it comes to the investigational treatment.

The pushback on the excitement about aducanumab is perhaps best summarized by a commentary from a trio of authors: David S. Knopman, MD, professor of neurology, Mayo Clinic; David T. Jones, MD, assistant professor of neurology and radiology, Mayo Clinic; and Michael D. Greicius, MD, MPH, associate professor of neurology and neurological sciences, Stanford Hospital and Clinics. Published in Alzheimer’s & Dementia in early November, it pointed to the lack of evidence presented to correlate the observed biomarker changes in treated patients to actual cognitive benefits.

Acknowledging that cognitive benefits are a possible offering of the therapy, Knopman, who was a site investigator in the aducanumab trials, and colleagues proposed that the existing data are “clearly insufficient to support a claim of efficacy,” even when looking past the distortions brought on by the premature termination of the trials. Most notably, they surmised that the finding of 1 positive (EMERGE) and 1 negative (ENGAGE) result from the 2 trials “is a statement of inconclusiveness.”

As well, they pointed to the differing performances of placebo groups in the 2 trials. “The larger decline in the placebo group in EMERGE is an alternative explanation for statistically significant benefits for high‐dose aducanumab in that trial,” they wrote.

For many, the issue is rooted in the point raised by Knopman and colleagues about pairing a positive and negative trial together and calling the result definitive.

Lon Schneider, MD, MS, professor of Psychiatry and the Behavioral Sciences, and Della Martin Chair in Psychiatry and Neuroscience, University of Southern California Keck School of Medicine, told NeurologyLive that for him, the challenge for aducanumab all started with Biogen’s reversal, and because of the trial results, the controversy shouldn’t exist to begin with.

“The studies weren't completed. The studies were stopped. They were stopped for futility, and now you have incomplete studies,” Schneider said. “That's the beginning of it. If these studies had actually been completed and showed something like they're showing now, we would have controversy, but we would not have controversy over whether the positive study was a positive study. We would have some controversy over whether it was adequate and well-controlled, certainly.”

He explained that the majority of the discussions surrounding aducanumab are based on the notion that the studies, particularly EMERGE, were completed. One particular conversation that did not operate on this perception, he noted, is the Advisory Committee meeting—the results of which speak for themselves.

“What should have happened is that they should have done 2 studies and completed those 2 studies. Both could have been positive, adequate, and well controlled, and the drug would have been approved,” Schneider said. “Or 1 would have been positive and the other would have had data that could be interpreted as confirming. Here, they don’t have the data that could be interpreted as confirming.”

Those in the camp with Schneider and Knopman ultimately do not oppose the approval of a first-in-class therapy. In fact, they have not even given up hope that aducanumab could be that therapy—really, they just want to see more data. There is debate, though, about when those data should be collected. Sabbagh and Cummings, for example, called for a phase 4 study after the potential approval, whereas Knopman and Schneider, want another phase 3 trial.

“If there's a future here, they need to do an adequate and well-controlled trial. At least 1, that's all that's needed. Now, you don't have to do a trial of 1600 patients over a year and a half necessarily. It could be a shorter, more focused trial,” Schneider explained. Either way, it seems, the doubt around the available data has been sowed.

The Decision

The controversy surrounding aducanumab has seemingly brought about more questions than it has answered. Expectedly, many have brought forward opinions about the challenges of simply conducting a trial in Alzheimer disease—which is no walk in the park—and pointed to how an approval may impact future trials and which scales of measurement they use. Perhaps, though, it might push the field in the right direction. At the very least, this discussion has helped highlight the remaining obstacles in therapy assessment.

“I hope if we have an approval of the of the first disease modifying therapy, in a population of pre-dementia care, I hope that future trials continue to focus on the earliest stages, the pre-dementia phases,” Richard S. Isaacson, MD, director, Alzheimer’s Prevention Clinic, Weill Cornell Medicine, told NeurologyLive. “I also hope that it pushes people to think about even earlier than that, meaning the preclinical or pre-symptomatic phases. I also hope that when trials are planned, they're planned in a way that stratifies outcomes based on genetics, not just clinical outcomes, but safety outcomes. It's really important to plan ahead. In terms of sex differences, we need to be very mindful that Alzheimer, in a lot of ways, is somewhat different in men versus women. We need to have diversity in our recruitment. The APOE4 belief for variants is different in terms of its impact in women versus men, and, for example, African Americans versus Caucasians. We're lumping all these folks together, who we may need to split up, in order to truly understand our outcomes. If we're mismatching everyone together, the data is going to be garbage in, garbage out.”

Ultimately, these challenges are not going to be addressed in the next 3 months, but the FDA will come to a decision on aducanumab by then. Whether an approval will in fact usher in a new era or set a precedent for trials in Alzheimer remains to be seen. The agency can still approve the therapy in spite of its Advisory Committee not recommending that path, and if it does, the impact that will have is at best an educated guess.

Probing the 2 sides for certainty leaves one without much certainty at all, and the last year of debate and data analysis has seemingly only muddied the water. Fortunately, though, through all of this, there has been an indisputable constant weighing on the minds and influencing the positions of both sides: the patients.