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An Experimental Drug for Alzheimer's Disease Heads to the FDA
Experts Ask: Where Are the Data?

Article In Brief

Seven months after scientists at Biogen stopped its investigation of aducanumab, the company announced that a new and more thorough analysis of the amyloid-clearing monoclonal antibody from the company's two pivotal phase 3 clinical trials showed a strong signal, after all. Alzheimer's disease researchers were pleasantly surprised but want to see more data.

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The headline in Alzforum, the listserv for and by Alzheimer's disease (AD) researchers, may have said it best: “Reports of My Death Are Greatly Exaggerated. Signed, Aducanumab.”

The end of the line for aducanumab seemed largely in the cards earlier this year in March when Biogen, Inc. announced that it was stopping clinical trials of the experimental drug for AD after an interim futility analysis suggested that the drug did not have a clear benefit.

But seven months later, on October 22, scientists at the company opened a quarterly performance review call for the investment community with a stunning announcement—complete with more than a dozen data slides. It suggested that a new and more thorough analysis of the amyloid-clearing monoclonal antibody from the company's two pivotal phase 3 clinical trials showed a strong signal, after all.

It was enough to reverse the company's earlier decision. Biogen has been in discussions with the US Food and Drug Administration (FDA) since the re-analysis and announced it will file a Biologics License Application (BLA) in 2020 to bring the drug to market.

Company scientists also reached out to all centers worldwide involved in the two studies and said that they want to offer the highest dose of the experimental medication to everyone in the study, even those on placebo. The study was designed to test the benefits and safety of the intravenous medication in patients with mild cognitive impairment (MCI) or early AD.

If the FDA agrees that the data filed are strong enough to warrant approval, it would be the first disease-modifying drug for dementia. The drug is designed to reduce levels of toxic amyloid-beta (Abeta), the protein that clumps between neurons. It does not directly target the other common disease protein, phosphorylated tau.

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“Having watched this unfold in real time makes it harder for me to suspend disbelief here during this apparent dramatic reversal of misfortune. What I would really like to see at this point would be for Biogen to send the data for an independent analysis to the Alzheimers Disease Cooperative Study or the Alzheimers Therapeutic Research Institute.”—DR. SAMUEL E. GANDY

It is still not clear whether reducing Abeta earlier in the disease process (in MCI patients and those in the early AD stages) will have a clinical impact and change the trajectory of the disease, but many AD experts are hopeful that the sudden reversal will move the field forward.

All of the clinical trials targeting the toxic amyloid protein have failed and many pharmaceutical companies have shut down their research and development pipelines for AD and other dementias. This new development could bring companies back in the fold, experts in the field told Neurology Today.

It is still a gamble whether the FDA will approve this disease-modifying therapy for AD. The re-analysis of only one of Biogen's studies was positive across the board while the other was not.

Neurologists and neuroscientists said that there are still so many unanswered questions. Much of the data remains with the company and will probably be saved for its FDA filing, and the gaps in information leave many in the field surprised, stunned, excited, and wanting more detail.

“We had a lot of high expectations for this drug,” said one of the study site principal investigators, Anton P. Porsteinsson, MD, the William B. and Sheila Konar professor of psychiatry, neurology and neuroscience at the University of Rochester School of Medicine and Dentistry and director of the Alzheimer's disease care, research and education program.

“The results from the phase 1b PRIME study showed a strong signal that the drug was reaching its target and clearing out toxic amyloid-beta. There were also positive changes in biomarkers and on clinical measures.”

What Happened?

After encouraging results from the phase 1b PRIME study, Biogen began its two phase 3 efficacy trials in the summer of 2015 to compare monthly infusions of one of two undisclosed doses of aducanumab or placebo over an 18-month treatment course. Together, the trials enrolled 3,285 patients at a few hundred medical centers in the US and Europe.

The ENGAGE study was conducted in 150 centers in North America, Europe, Australia, and Asia. They enrolled 1,350 people with MCI or early-stage AD. The EMERGE study was conducted in 1,350 additional patients at 131 other sites in North America and Europe.

They looked at cognitive, functional, and biomarker assessments: Clinical Dementia Rating-Sum of Boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale, and Alzheimer's Cooperative Study-Activities of Daily Living Inventory.

In addition, Biogen did a futility analysis. Pharmaceutical companies often add in such an analysis mid-study to determine whether it is worth continuing the research. When the company had enough study subjects who had completed 18 months of the treatment or placebo arms of the two studies, they sent the data out for an independent analysis. The futility analysis was done on data available as of December 26, 2018. By March 2019, the results of the futility analysis were in, and it was not what anyone had expected. The numbers didn't add up, and the company made a decision to shelve the drug in March.

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Findings from the early phase 1 trial of aducanumab: Amyloid PET imaging at baseline (left) and one year (right) showed that a placebo had no effect (top), but 10 mg/kg aducanumab reduced amyloid burden (bottom).

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“The EMERGE data look very good but the negative findings in the ENGAGE trial clouds the issue somewhat. Nevertheless, this is the closest the field has come in slowing down the disease. It removes amyloid-beta and lowers phospho-tau [p-tau] and helps cognition and improves activities of daily living. We have been waiting for these kinds of results for a long time.”—DR. DENNIS J. SELKOE

Patients in the trials no longer had access to the drug but the company continued to collect the additional data and try to figure out what could have happened. The phase 1b study results were quite strong, which is why they launched these two phase 3 studies. Company scientists had as many as 50 study site investigators also weighing in on the puzzle.

They redid the analysis with the data from December to March. By then, they had more people who had completed 18 months on the drug plus there were many more study subjects switched to the higher 10 mg per kilogram dose. This time, the analysis was very different—and more positive—than the results from the futility analysis. The EMERGE study was positive on every parameter they looked at, but ENGAGE, which started a few months earlier, didn't come in with the same positive signal. It turned out that study had changed its parameters during the first half of the trials, and many more study subjects, including all of the patients who had at least one APOE4 variant, were changed to the highest dose of aducanumab: 10 mg per kilogram compared to 6 mg per kilogram.

At the end of the analysis, the suspicion was that there were probably not enough people on the highest dose for a long enough time period in the ENGAGE study, which was further ahead with recruitment at the time of the dose escalation, said Dr. Porsteinsson.

“There was an assumption that the first 50 percent of the patients recruited will be identical to the second 50 percent of the patients,” he explained. “But how could that be? The dosing was made more aggressive shortly before they completed recruitment for the futility analysis cohort. If you change the dosing criteria you are not going to have the same cohort.”

The FDA Agrees to Reconsider

With the new findings in hand, the company met several times with the FDA, and there was agreement that the signal was stronger at the highest dose, and the design changes could have led to the differences. The FDA officials agreed that the company may want to rethink its decision and submit a BLA application, using the complete data set.

“Right now, all they have is permission to file an application,” said Ronald C. Petersen, MD, PhD, FAAN, director of the Mayo Clinic Alzheimer's Disease Research Center and the Mayo Clinic Study of Aging. Biogen has brought him in to consult on this drug, but he is not one of the study investigators. “Will this drug have a clinically meaningful impact on patients? We need to see all the data,” he added.

“Whatever happens,” he said, “this latest turnaround rejuvenates the whole field.” All of the negative clinical studies, including the trials that target Abeta, have many pharmaceutical companies questioning their AD portfolios.

What About the Data?

The limited data shared by the company concerns many of the scientists interviewed. Dr. Petersen and others want to see the raw data and effect sizes. “Biogen presented data as a percent change but it is challenging to interpret the meaningfulness without the actual numbers and the effect size. Maybe the data are clinically relevant but right now we don't know.”

“I would really like to believe that there is serious hope (for this drug) but I am so far unpersuaded,” added Samuel E. Gandy, MD, PhD, professor of neurology and psychiatry and the Mount Sinai chair in Alzheimer's disease research at the Icahn School of Medicine at Mount Sinai. “At the very best, while maybe a 40 percent change in activities of daily living has a good p value, that might still not be clinically meaningful. Showing that the needle has moved does not mean that the needle has moved far enough.

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“It would provide compelling support for the amyloid hypothesis, and opens the door for aducanumab, other certain amyloid treatments, and future combination therapies to help affected patients and families. Moreover, it would also accelerate our efforts to find and support the approval of effective prevention therapies in cognitively unimpaired persons who, based on their genetic background and/or amyloid test results, are at increased risk for developing this terrible disease.”—DR. ERIC REIMAN

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“A broader presentation (by the company) might make it clearer why there was significance in one phase 3 study and not the other. It would be nice to have a home run for the field and then see what happens at the end of the season. But we need a lot more information about the trials to assess the effect size of high dose treatment.”—DR. DOUGLAS GALASKO

“Having watched this unfold in real time makes it harder for me to suspend disbelief here during this apparent dramatic reversal of misfortune,” Dr. Gandy added. “What I would really like to see at this point would be for Biogen to send the data for an independent analysis to the Alzheimer's Disease Cooperative Study [ADCS] or the Alzheimer's Therapeutic Research Institute. The solanezumab trials set the gold standard for data analysis. The solanezumab raw data were routinely shared between, and independently analyzed by, the drug company sponsor and by the ADCS.”

Dennis J. Selkoe, MD, FAAN, the Vincent and Stella Coates professor of neurologic diseases at Harvard Medical School and co-director of the Center for Neurologic Diseases at Brigham and Women's Hospital, agreed.

“The EMERGE data look very good but the negative findings in the ENGAGE trial clouds the issue somewhat. Nevertheless, this is the closest the field has come in slowing down the disease. It removes amyloid-beta and lowers phospho-tau [p-tau] and helps cognition and improves activities of daily living. We have been waiting for these kinds of results for a long time.”

(The study team looked at p-tau and total tau and found that lowering Abeta appeared to lower both p-tau and total tau.)

“There was an assumption that the first 50 percent of the patients recruited will be identical to the second 50 percent of the patients. But how could that be? The dosing was made more aggressive shortly before they completed recruitment for the futility analysis cohort. If you change the dosing criteria you are not going to have the same cohort.”

—DR. ANTON P. PORSTEINSSON

Eric Reiman, MD, executive director of Banner Alzheimer's Institute and a leader of the Alzheimer's Prevention Initiative (API), added: “We look forward to reviewing the encouraging findings when they are described in more detail. If aducanumab's amyloid plaque-reducing effects are associated with a clinical benefit, it would have a profound impact on the fight against Alzheimer's.

“It would provide compelling support for the amyloid hypothesis,” he said, “and opens the door for aducanumab, other certain amyloid treatments, and future combination therapies to help affected patients and families. Moreover, it would also accelerate our efforts to find and support the approval of effective prevention therapies in cognitively unimpaired persons who, based on their genetic background and/or amyloid test results, are at increased risk for developing this terrible disease.”

“At the end of the day, there is a divide between statistical significance and clinically meaningful results. I think there is a lot more we need to know. If it does work, when do you begin treatment? How long do you continue it? What are the clinical measures that will tell us that it is working enough? I am not convinced that this is groundbreaking. I think it is cutting the ribbon but we have not broken ground yet.”

—DR. MARCIA RATNER

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“Will this drug have a clinically meaningful impact on patients? We need to see all the data. Whatever happens, this latest turnaround rejuvenates the whole field.”—DR. RONALD C. PETERSEN

Dr. Reiman also noted several reasons to exercise caution in conducting futility analyses and making treatment discontinuation decisions on the basis of futility analyses in AD trials, and this is why, he said.

“A broader presentation (by the company) might make it clearer why there was significance in one phase 3 study and not the other,” added Douglas Galasko, MD, professor of neuroscience at the University of California, San Diego.

“It would be nice to have a home run for the field and then see what happens at the end of the season. But we need a lot more information about the trials to assess the effect size of high dose treatment.”

He added that “there is discussion about re-dosing patients. However, many have been off treatment for six months or longer, and I am not sure how many are available for redosing, which may limit the value of additional follow-up data.”

“Biogen has a long way to go,” added Marcia Ratner, PhD, a toxicologist and behavioral neuroscientist in the department of pharmacology and experimental therapeutics at Boston University School of Medicine. Dr. Ratner studies toxins and their impact on neurological diseases. “At the end of the day, there is a divide between statistical significance and clinically meaningful results. I think there is a lot more we need to know. If it does work, when do you begin treatment? How long do you continue it? What are the clinical measures that will tell us that it is working enough? I am not convinced that this is groundbreaking. I think it is cutting the ribbon but we have not broken ground yet.”

Given the mixed data results, AD scientists said that the FDA will probably put together an advisory panel of outside experts to help review the data. The federal agency could also recommend that Biogen conduct another phase 3 study.

“It is important for the field and it is important for the patients and their families to get this right,” added Dr. Porsteinsson, who called the dozen patients enrolled in the study in Rochester. “Everyone wanted back in.”

There will be many questions raised if the drug is approved, said Rudolph Tanzi, PhD, the Joseph P. and Rose F. Kennedy professor of neurology at Harvard University, and director of the genetics and aging research unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital.

The therapy will be expensive and could cost people up to $5,000 a month. If the drug is aimed at people with MCI and those in the earliest stages, how long will they have to take the drug to be protected? Who will pay for this? What if a promised blood test for amyloid-beta becomes available and the pool of people opens up to asymptomatic individuals who are at risk? That could be tens of millions of people. Will it be safe to be taking the drug for decades?

“If this drug is approved, it will mean that we may also need small molecules that can do the same thing as aducanumab but are exponentially cheaper for use as serial combination partners or alternatives,” he added, saying that “there are several undergoing clinical trials that look promising in clearing amyloid and reducing clinical signs for a fraction of the cost of monoclonal antibodies.”

Disclosures

Dr. Ratner had no competing interests. Dr. Porsteinsson disclosed receiving research support to his institution from AstraZeneca, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, Janssen Alzheimer Initiative, Merck, Novartis, the National Institutes of Healthm the National Institute of Mental Health, The National Institute on Aging, and the Department of Defense. He has received fees for serving on data safety and monitoring boards for Acadia, Neurim, Tetra Discovery Partners and the New York State Psychiatric Institute; the scientific advisory board member for Alzheon; and for development of educational presentations for MCM Education, and consulting for BioXcel, Eisai, Grifols, Merck, and Pfizer. Dr. Petersen consults for Roche, Merck, Biogen, Eisai, abd serves on a data safety monitoring board for Genentech and has given educations talks for GE Healthcare. Dr. Gandy has received funding for a grant from Polyphenolics Inc and Constellation Pharmaceuticals Inc for study of sirtuin-related molecules.

What Is Known Now About Aducanumab

Aducanumab, a monoclonal antibody, was derived from studying the blood from so-called “super normal” older people with no cognitive impairment. Scientists at Neuroimmune screened their blood for b-cell antibodies against amyloid oligomers. A monoclonal antibody was developed that binds to a small piece of the protein recognized by the antibody and it reduced toxic amyloid-beta plaques in the brain.

Delivering high doses of monoclonal antibodies can cause problems in the brain, including local swelling and microbleeds in the vasculature. As a result, many trials have been underdosed, and this may have explained the poor study results of previous trials, experts told Neurology Today.

Biogen tested a number of doses during the phase 1b study and then selected two of the highest doses for the phase 3 studies. The most commonly reported adverse events were amyloid-related imaging abnormalities—edema and headache. The local edema did not lead to symptoms in most that developed it and resolved within one to four months, according to Biogen scientists. The company felt comfortable with the highest dose, and that is why there was a design change midway through the study.

With the new analysis, EMERGE met its primary endpoints: A reduction of brain amyloid and a slowing of clinical decline assessed by the Clinical Dementia Rating–Sum of Boxes (CDR-SB). The company released slides during their investment briefing suggesting that the highest 10 milligram per kilogram dose showed significant reduction (23 percent) of clinical decline from baseline in CDR-SB scores at 78 weeks, but they did not publish any data on the effects in the placebo group.

They also reported positive changes on a number of secondary measures, including the Mini-Mental State Examination, the AD Assessment Scale-Cognitive Subscale 13 Items, and the AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version, but again they showed the changes in percentages and did not provide any data on the placebo group.

Biogen plans to present more detailed data at the Clinical Trials on Alzheimer's Disease meeting in Southern California in December.

Link Up for More Information

• Haeberlein SB, Gheuens S, Chen T, et al. Aducanumab 36-month data from PRIME: A randomized, double-blind, placebo-controlled phase 1b study in patients with prodromal or mild Alzheimer's disease https://n.neurology.org/content/90/15_Supplement/S2.004. Neurology 2018;90 (15 Supplement): S2.004.