Matt Hoffman

This article was originally published in NeurologyLive

The US Food and Drug Administration (FDA) has approved investigational anti-amyloid, disease-modifying agent aducanumab (Aduhelm) for treatment of 

The approval was granted to Biogen, Inc. It is the first novel approach for the neurogenerative condition since 2003.

The therapy approval met the Accelerated Approval pathway, which will require post-approval phase 4 studies to confirm the benefit of the treatment.

FDA noted that in the case the clinical benefit is not confirmed, it has procedures in place that could ultimately lead to the drug removed from market.

The decision noted the late-stage development program consisted of 2 trials, with 1 which met the primary end point and 1 that did not.

In all studies, data show aducanumab had a consistent reduction in amyloid plaques in both a dose- and time-dependent fashion. The FDA noted it anticipated the reduction will result in reduction in clinical decline.

The decision followed debate in the medical community in the path of development and evaluation of aducanumab.

In March 2019, Biogen announced they would discontinue the 2 phase 3 clinical trials evaluating the agent, EMERGE and ENGAGE and a phase 2 safety study EVOLVE. Then, in October 2019, the company announced they reversed course on the decision.

Data in EMERGE and a post hoc analysis of patients who received high-dose treatment in Engage were presented at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) annual meeting. It suggested statistically significant changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, with 

Data show both trials included low-dose (EMERGE: n = 544; ENGAGE: n = 548) and high-dose (EMERGE: n = 547; ENGAGE: n = 558) treatment arms compared with placebo (EMERGE: n = 548; ENAGE: n = 541).

The analyses of EMERGE led to consistent reduction in clinical decline measured by secondary end points, including the Mini-Mental State Exam (MMSE; 15% versus placebo; 

 = .05), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo; 

 = .01), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo; 

Further, imaging of amyloid plaque deposits showed that both low- and high-dose aducanumab were associated with reduced burden in comparison with placebo at 26 and 78 weeks (

Then, the company submitted the original biologics license application (BLA) to the FDA in July 2020 when it was accepted for review with a Prescription Drug User Fee Act date of March 2021.

Data was reviewed by the FDA Peripheral and Central Nervous System Drugs Advisory Committee in November 2020, which voted to not recommend regulatory approval.

The final vote of the Advisory Committee saw the committee vote 10 – 0 (10 no; 0 yes; 1 uncertain) that the EMERGE trial did not provide primary evidence for the effectiveness of aducanumab in Alzheimer disease.

The committee also voted 8 – 1 (8 no; 1 yes; 2 uncertain) that the phase 3 EMERGE study in patients with mild Alzheimer disease was enough to demonstrate efficacy and voted 7 – 0 (7 no; 0 yes; 4 uncertain) that the PRIME study demonstrated supporting evidence of efficacy.

For the presence of strong evidence of the pharmacodynamic effect on Alzheimer disease, the committee voted 5–0 (0 no; 5 yes; 6 uncertain).

In January 2021, the agency extended its review period by 3 months to June 2021, after Biogen submitted additional clinical data and analyses after an FDA information request.

Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, noted that the approval was significant in the agency statement.

“Perhaps more significantly, Aduhelm is the first treatment directed at the underlying pathophysiology of Alzheimer disease, the presence of amyloid-beta plaques in the brain,” Cavazzoni said. “The clinical trials for Aduhelm were the first to show that a reduction in these plaques—a hallmark finding in the brain of patients with Alzheimer—is expected to lead to a reduction in the clinical decline of this devastating form of dementia."

nvestigator Marwan Sabbagh, MD, director, Cleveland Clinic Lou Ruvo Center for Brain Health, noted the similar thought of seminal moment in the field in an interview with NeurologyLive.

"I was surprised at how polarizing it was—we really had strong opinions for and against—but if you take the pro-patient aspect and look at this in the context of the fact that many drugs are starting to show similar signals, I think this is a great step forward,” Sabbagh said. “People have to understand that contextually, medically speaking, we need the first drug in the class to get the class going forward. Otherwise, there's going to be no progress."

Sabbagh also noted that while they are unsure if aducanumab will be the final drug in this amyloid class, the team is sure of the consistency of clinical signals and it can remove amyloid robustly.

“I cannot tell you how excited I am to actually have a new treatment option for my patients—I've been waiting 2 decades to get it,” Sabbagh said.

A new phase 3b trial EMBARK is currently enrolling by invitation patients who were participating in the clinical trial program when the PRIME, EVOLVE, EMERGE, and ENGAGE studies were terminated in March 2019.

EMBARK will be an open-label, single-arm clinical safety study with a 24-month treatment period.

The study will evaluate long-term safety and efficacy of aducanumab in participants with Alzheimer Disease, who will be titrated to receive 10-mg/kg aducanumab by intravenous infusion every 4 weeks.

Primary endpoints include number of participants with adverse events (AEs), serious AEs, AEs leading to treatment discontinuation or study withdrawal, as well as amyloid-related imaging abnormality-edema (ARIA) or amyloid-related imaging abnormality-hemorrhage or superficial siderosis; and the number of participants with anti-aducanumab antibodies.

Articles

The approval for Biogen’s disease-modifying, anti-amyloid agent aducanumab follows a long regulatory journey.



FDA Approves Aducanumab for Alzheimer Disease Treatment

This article was originally published in NeurologyLive.

Donanemab could yield better composite scores for cognition and ability to perform activities of daily living after 76 weeks compared to placebo in patients with early Alzheimer disease, according to new data from the phase 2 TRAILBLAZER-ALZ study, published in the 

The primary outcome was the change from baseline in the score on the Integrated Alzheimer’s Disease Rating Scale (iADRS), which ranged from 0-144, with lower scores indicating greater cognitive and functional impairment. At baseline, iADRS score was 106 in both the donanemab (n = 131) and placebo (n = 126; 1 participant was excluded from the modified intent-to-treat population) groups.

After 76 weeks, the treatment group’s scores changed by –6.86 points while the placebo group’s changed by −10.06 (difference, 3.20; 95% CI, 0.12-6.27; 

 = .04). This change was equivalent to a 32% difference in slowing decline for the donanemab group, a significant difference that was identifiable by month 9.

"We are confident in the results of the TRAILBLAZER-ALZ study," said Daniel Skovronsky, MD, PhD, chief scientific officer, and president, Lilly Research Laboratories, Eli Lilly and co., donanemab’s developer, in a statement."This is the first late-stage study in Alzheimer's disease to meet its primary endpoint at the primary analysis. Donanemab has the potential to become a very important treatment for Alzheimer's disease.

“We were pleased to see not only slowing of cognitive and functional decline, but also very substantial clearance of amyloid plaques and slowing of spread of tau pathology," Skovronsky added. “The constellation of clinical and biomarker results indicates the potential for long-term disease modification. We are grateful to the patients, caregivers, and investigators who participated in this landmark study.”

At the 76-week mark, reductions in the amyloid plaque level were 85.06 centiloids (−84.13 vs. 0.93) greater with donanemab than with placebo.

Amyloid-related cerebral edema or effusion (ARIA-E), which were mostly asymptomatic, occurred with donanemab treatment. As early as 6 months, 40% of those treated with donanemab achieved amyloid negativity (defined as an amyloid plaque level of <24.10 centiloids), with 68% achieving this at 18 months. The percentage of participants in the donanemab group who had amyloid-negative status at 24, 52, and 76 weeks was 40.0%, 59.8%, and 67.8%, respectively.

"The combination of changes in Alzheimer's biomarkers and the slowing of clinical symptoms of the disease seen in this study is promising," said Howard Fillit, MD, founding executive director and chief science officer, Alzheimer's Drug Discovery Foundation (ADDF), in a statement on the data. "We are encouraged by today's news, and if these results are confirmed in the larger study now in progress, donanemab could offer the potential for a disease-modifying therapy that can help patients maintain cognitive abilities and their independence longer. We eagerly await results from future trials.”

In the safety population, 90.8% (n = 119) of the donanemab group and 90.4% (113 of 125) of the placebo group had at least 1 adverse event (AE) during the double-blind intervention period. The incidence of ARIA-E was significantly higher in the donanemab group (26.7%) than in the placebo group (0.8%; 

 <.001). Symptomatic ARIA-E was reported by 6.1% of all participants in the donanemab group (22% of those with ARIA-E), as compared with 0.8% of all participants in the placebo group.

Most cases of ARIA-E occurred at or by week 12 of the intervention period, with the serious symptomatic cases (n = 2; 1.5%) occurring in the donanemab group. The symptoms resolved in both of those patients, in a mean time of 18 weeks.

The results for the secondary outcomes of the trial were mixed. Those measures included the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13), the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on positron emission tomography (PET).

The difference between the donanemab group and the placebo group in the change from baseline at 76 weeks was −0.36 (95% CI, −0.83 to 0.12) for CDR-SB score, −1.86 (95% CI, −3.63 to −0.09) for ADAS-Cog13 score, 1.21 (95% CI, −0.77 to 3.20) for ADCS-iADL score, and 0.64 (95% CI, −0.40 to 1.67) for MMSE score.

Lead author Mark A. Mintun, MD, vice president, Pain and Neurodegeneration Research and Clinical Development, Eli Lilly and Company; president, Avid Radiopharmaceuticals, and colleagues noted that several features of the trial design are worth consideration, including the selection of the dosing regimen (700 mg for first 3 doses, 1400 mg thereafter) which was done to facilitate aggressive removal of amyloid plaques.

Additionally, all participants were required to meet flortaucipir PET screening criteria, which “may have narrowed the range of underlying pathologic features and in turn decreased variation in clinical decline” as well as led to the exclusion of those with the highest levels of tau.

As the trial followed the Baysien disease progression model proposed by the European Prevention of Alzheimer’s Dementia project, Mintun et al noted that it produced estimates of disease slowing that were similar to the single point estimate of the MMRM.

"As a clinician and researcher, I'm particularly encouraged by the significant plaque lowering and the slowing of clinical decline with donanemab," said Stephen P. Salloway, MD, MS, director, Memory and Aging Program, and Martin M. Zucker professor of Psychiatry and Human Behavior, Department of Neurology, Warren Alpert Medical School, Brown University, in a statement.2 "The donanemab results are a significant and encouraging milestone for people impacted by Alzheimer's disease and we are eager to continue on in this fight."

At the 76-week mark, reductions in the amyloid plaque level were 85.06 centiloids with donanemab than with placebo.

Donanemab Shows Promise as a Alzheimer Disease Treatment

was published online by sister publication NeurologyLive.

A new investigational, oral small molecule treatment could aid in improving the cognitive behavior of patients with 

Cassava Sciences, the manufacturer of simufilam, announced the findings from a recent open-label study and noted that in combination with prior clinical trial results, they support the advancement of simufilam into a phase 3 clinical program in AD. That trial is currently expected to begin in the second half of 2021.

Additionally, the US Food and Drug Administration (FDA) concluded a successful end-of-phase 2 meeting for the drug’s development program, the details of which Cassava anticipates announcing after official meeting minutes are finalized. The enrollment target for this current open-label study is planned to be increased by up to 50 additional patients, for a total target of approximately 150 patients, Cassava announced.

“We could not be more pleased with these interim results,” Remi Barbier, chief executive officer and president, Cassava, said in a statement. “We would have been satisfied to show simufilam stabilizes cognition in patients over 6 months. An improvement in cognition and behavior tells us this drug candidate has [the] potential to provide lasting treatment effects for people living with Alzheimer’s disease. It’s an exciting development.”

The study, funded by the National Institutes of Health (NIH), showed that after 6 months of treatment with the altered filamin A (FLNA) restoration agent that cognition scores measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) improved by 1/6 points from baseline scores of 15.5, equivalent to a 10% mean improvement.

Additionally, dementia-related behavior—including anxiety, delusions, and agitation—improved by 1.3 points from baseline scores of 4.5 on the Neuropsychiatric Inventory (NPI). This improvement equaled a 29% mean improvement at 6 months.

The 1-year, open-label, multi-center study is still ongoing, and seeks to evaluate the long-term safety and tolerability of 100-mg simufilam, administered twice daily to 100 patients with mild-to-moderate AD. It began in March 2020 and is now approximately 80% enrolled, according to Cassava Sciences.

“Today’s pre-planned interim analysis summarizes clinical data at the midway point of enrollment, i.e., the first 50 patients who have completed at least 6 months of drug treatment,” the company stated.

Cassava noted that by its nature, the open-label data are limited to an extent, a fact that must be taken into account by comparison to fully completed, large, randomized controlled trials.

The company noted that prior clinical research in AD can provide context as a reference for the rates of expected decline in placebo patients, citing Biogen/Eisai’s trial EMERGE (which notably was cut short due to futility, causing 

 being assessed), as well as Eisai’s phase 3 evaluation of donepezil (Aricept).

In EMERGE, those on placebo showed a mean decline in cognition of approximately 1.4 points on the ADAS-Cog13 (–6.3% from baseline to month 6), with a mean baseline ADAS-Cog13 score of 22.2 and a mean baseline Mini-Mental State Exam (MMSE) score of 26.4.

In the donepezil trial, patients on placebo showed a mean decline in cognition of approximately 1.9 points on ADAS-Cog, a 7.3% decline, from baseline to week 24. The mean baseline ADAS-Cog score was 26 and the MMSE score range was 10-26.

The Cassava Sciences agent showed 6-month improvements in both ADAS-Cog and NPI scores, and a phase 3 trial is expected to begin in late 2021.

Simufilam Shows Promise Improving Cognition, Behavior in Alzheimer Disease Patients

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 

 in the publication of his eighth edition of the 

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 

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.

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 

 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 

 and post hoc analysis of a subset of high-dose treatment in 

 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 

 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 

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 

, in possibly the most anticipated advisory committee decision of the year. 

 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.

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 

, 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 

“[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; 

 = .01) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo; 

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 (

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 

“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 

. “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 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 

 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 

 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 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 

. “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 

 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.

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.