Alzheimer’s Association Denies Conflict in Aducanumab Support | Nutrition Fit

The Alzheimer’s Association is denying accusations by two researchers in the field and a watchdog group that its repeated endorsement of aducanumab, a drug under US Food and Drug Administration (FDA) review for the treatment of Alzheimer’s disease (AD), has been unduly influenced by financial support from the two companies seeking approval, Biogen and Eisai.

In response to a request from Medscape Medical News, the Alzheimer’s Association disclosed that it has received at least $1.4 million from Biogen and Eisai since fiscal year 2018 (FY18).

Mike Greicius, MD, MPH, associate professor of neurology at Stanford University’s Wu Tsai Neurosciences Institute, Stanford, California, who has received research support from the Alzheimer’s Association and is at the center of a dispute with the organization’s affiliated journal, Alzheimer’s and Dementia, says the association did not disclose financial backing from the two companies in an October letter to the FDA supporting the drug’s approval or in a January 29 note to supporters and staff when the FDA delayed the approval decision.

Greicius is one of three authors of an opinion piece on aducanumab in Alzheimer’s and Dementia. That article concluded that the drug is not effective and should not receive FDA approval.

Leslie Norins, MD, PhD, CEO of Alzheimer’s Germ Quest, a Naples, Florida–based company that funds research into a potentially infectious cause for AD, has also said that the association has failed to properly and fully disclose these potential conflicts.

Accusations about the Alzheimer’s Association’s lack of disclosure are the latest development in a string of controversies and setbacks surrounding aducanumab — including the Alzheimer’s and Dementia journal dustup.

“Baseless, Entirely False” Speculation

Greicius was one of three authors recently disciplined for what editor-in-chief Ara Khachaturian, MD, said was a failure to disclose a potentially relevant conflict. However, Griecius believes the journal retaliated because the Alzheimer’s Association did not like the article’s conclusion.

Maria Carillo, PhD, the Alzheimer’s Association’s chief science officer, told Medscape Medical News that the journal is editorially independent and that she would not comment on Khachaturian’s action. Carillo also said she has not had any communication with Khachaturian about the article.

Alzheimer’s Association spokesperson Kate Meyer told Medscape Medical News that “speculation that the association had any role in actions by the journal is just that, speculation, baseless and entirely false.”

Meyer noted that one of Greicius’ coauthors, David Knopman, MD, told Stat that he did “not believe the Alzheimer’s Association has engaged in retaliation in this matter.”

When asked by Medscape Medical News to weigh in, Knopman and coauthor David T. Jones, MD, said in a joint statement, “The comments attributed to us as reported in Stat are accurate.”

Greicius said he, Knopman, and Jones decided to write the opinion piece about aducanumab because they were concerned that Biogen was promoting it primarily through press releases and investors, not in scientific venues, where it would be vetted on the basis of evidence.

They approached Khachaturian about writing an opinion piece, and he agreed, said Greicius. The article was accepted in early October. On October 27, Jones allegedly tweeted a screen shot of an uncorrected galley proof.

Carillo, who saw the tweet, said she tweeted at Jones (whom she knows) to remove the tweet because the article was embargoed. Jones quickly deleted his tweet. A day later, he tweeted to someone who was asking to see more of the article, “Apparently it is embargoed. This was news to me as I thought it was not.”

As it turns out, the article was not embargoed, as Carillo acknowledged, saying her terminology was incorrect. She said she had merely wanted to alert Jones that a galley proof should not be made public.

The article was published November 2, but not before Khachaturian determined that Knopman had a “relevant conflict of interest” that he had not disclosed in the manuscript ― namely, his membership on the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee. Knopman agreed to add the language, which now appears in the article.

Knopman also did not disclose that he is a member of the Alzheimer’s Association’s Medical and Scientific Advisory Committee (MSAC). When asked by Medscape Medical News whether he should have mentioned the MSAC membership, he declined to comment.

“Incredibly Costly, Resource-Devouring”

Khachaturian said the lack of disclosure about the MSAC position was not important. He noted that the journal publishes “the names of all MSAC members on the journal’s masthead, every month.”

Sometime after the article’s publication on December 28, Khachaturian wrote to the three authors, informing them that tweeting the galley proof was a copyright breach and an “ethical violation.”

In addition, he wrote that Knopman’s failure to disclose his FDA advisory committee membership, which he had been forced to recuse for the aducanumab meeting, was another ethical breach.

Khachaturian wrote that such breaches “cannot be ignored” and told the authors that any new submission during the next 2 years must be accompanied by a certification from their institutions that they made proper disclosures. The email was also sent to Carillo, the authors’ department chairs, and other academic superiors.

Greicius was infuriated. He emailed Khachaturian, saying that Jones’ tweet “strikes me more as a simple misunderstanding rather than an ethical breach ‘that cannot be ignored.’ ” He called the editor’s action a “heavy-handed sanction.”

The journal must have been pressured by the Alzheimer’s Association “to punish us for the opinion piece that ran directly counter to the Alzheimer’s Association’s letter of support to the FDA,” wrote Greicius.

Knopman and Jones, however, told Medscape that the association had “acted within their obligations.”

Khachaturian defended his action, telling Medscape, “the editors have a responsibility to protect the integrity of the journal as a reputable forum.” The journal sought advice from “colleagues in academic publishing, our publisher (Wiley), and the Council on Publication Ethics (COPE)” before taking action.

Ten journal editors found that the authors erred in distributing an uncorrected galley proof, he said.

“We ultimately took a path that we believed addressed this serious matter while enabling the authors to continue to publish important future articles in the journal,” Khachaturian said.

Knopman and Jones said they “look forward to furthering Mayo Clinic’s strong working relationship with the Alzheimer’s Association.”

However, Greicius said he is not likely to submit to the journal again and that he knows he may have damaged his ability to receive future funding. He said he’s not against the organization. “I’m very grateful for their public advocacy efforts,” he said.

However, he believes the association is “kind of shooting themselves in the foot and hampering the progress they set the stage for by pushing so aggressively to get this, in my view, useless medication ― incredibly costly, resource-devouring medication — approved.”

Call for Candor

Neither Knopman or Jones addressed the issue of whether the Alzheimer’s Association might have a conflict regarding its support of aducanumab.

Carillo says the association has been forthcoming about the financial support it has received from Biogen, Eisai, and other drug and device makers. “Anybody can find it at any time” on the association’s website, Carillo said.

That’s not an acceptable answer, said Greicius, who noted that when he submits a paper, he discloses his ownership of shares in SBGneuro.

“It’s with the paper. You don’t have to go to my personal website and try and figure out where my conflicts are listed,” said Greicius. “It has to be with the text that people are reading so that they can understand it in that context.”

Michael Carome, MD, director of Public Citizen’s Health Research Group, told Medscape Medical News he believes the Alzheimer’s Association is “biased because they get funding from industry.

“Too often there are patient advocacy groups that take significant funding from industry groups, and that money either consciously or subconsciously influences the positions they take,” Carome added.

Through multiple press releases, Norins has called on the association to be more candid.

“The standard is not whether it’s mentioned somewhere else in the world but whether you reveal right at that moment that there is a potential conflict of interest,” said Norins. “I totally reject this tap dance the association is doing,” he said, referring to the claim that the Alzheimer’s Association is transparent because sponsored support is listed on its website.

Alzheimer’s Germ Quest accepts no outside support. It is entirely funded by Norins, who was previously a medical publisher. He is also the publisher of MCI911.org, a website that aggregates news about mild cognitive impairment and offers tips for prevention through exercise, nutrition, and supplements.

Although it’s true the Alzheimer’s Association does not hide its industry backing, it is not easy to clearly delineate and aggregate the support. Many companies have given money to the association, although it appears that Biogen and Eisai have been among the largest, if not the largest, donors over the past few years.

The association discloses on its website the total support that it has received over the past 5 years from drug, biotech, and device makers. The information is on a landing page about its corporate partners.

Industry Support

Since fiscal 2016, about 1% of the association’s $300 or so million in annual revenue has been supplied by industry. The organization also lists corporate donors in broad categories of dollar amounts in its annual report.

Individual drug company contributions for fiscal year 2020 are featured on a separate web page, but contributions for other years are no longer publicly available.

Data provided by the Alzheimer’s Association show that in FY19, Biogen and Eisai were the number one and three contributors among drug company donors, pledging $380,380 and $361,250, respectively.

Data available on the association website show that in FY20, Eisai pledged $250,000 and Biogen pledged $200,000. In comparison, Eli Lilly and Genentech gave slightly higher amounts — just over $300,000 — and Merck pledged $855,000. Merck discontinued trials of its verubecestat for Alzheimer’s in 2018 and does not currently have any Alzheimer’s therapies in its pipeline.

Both Biogen and Eisai are “platinum sponsors” of the upcoming 2021 Alzheimer’s Association International Conference, which requires a $200,000 donation. Biogen was also a platinum sponsor in 2018, 2019, and 2020. Eisai was a platinum sponsor in 2019 and 2020.

Acadia Pharmaceuticals, Eli Lilly, and Grifols are gold sponsors, contributing $100,000, and AbbVie, Boehringer Ingelheim, and Janssen/Johnson & Johnson paid $50,000 each and are silver sponsors.

Meyer provided the sponsorship amounts to Medscape Medical News upon request. The sponsorship dollar amounts are not listed on the Alzheimer’s Association’s website but are included in the overall annual report, which gives figures the organization makes public, Meyer said.

In 2020, the association launched a new conference ― Neuroscience Next ― which was held virtually in November. Biogen was a gold sponsor, donating $25,000, according to Meyer. No other companies were listed as sponsors.

Biogen is also a “sustainer” of the association’s political action committee (PAC), Alzheimer’s Impact Movement. For that role, companies contribute $25,000 annually.

A Rocky Road

The Alzheimer’s Association also reports that just two other drugmakers, Amgen and Lundbeck, were sustainers in FY20. The PAC contributions are not included in the overall donation tally to the Alzheimer’s Association, because that PAC is separate, and the disclosure rules are different for PACs, said Meyer.

Aducanumab has had a rocky road to get to where it is now — it is in a holding pattern awaiting final word from the FDA. As reported by Medscape Medical News, the agency postponed the approval date by 3 months — from March to June – on January 29.

The FDA granted aducanumab priority review in August, in part because it would be the first-ever disease-modifying treatment for AD.

The agency worked closely with Biogen to ensure a smoother course — a collaboration that has drawn criticism, in particular from Public Citizen. In December, the group asked the Department of Health and Human Services’ Office of the Inspector General (IG) to investigate. The IG acknowledged the letter but did not say whether it would proceed.

On November 6, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee recommended against approval, citing a lack of effectiveness. Only 1 of 11 members voted in favor; eight voted no, and two were uncertain.

Carillo, the Alzheimer’s Association chief science officer, said that despite the panel’s doubts, the organization was encouraged by the FDA staff’s positive review of the data. The association supports approval as long as Biogen is also required to conduct a phase 4 postmarketing study, she said.

“We as an organization have to weigh the crushing realities that individuals and their families face when living with Alzheimer’s,” said Carillo. She noted that the association believes the publicly released data tilt in favor of the drug’s effectiveness. Given the lack of a therapy that would even slow progression, “for us, approval is justified,” she added.

Carrillo would not say whether the Alzheimer’s Association had sought the counsel of its medical and scientific advisory group.

Flimsy Evidence?

Another advocacy group, US Against Alzheimer’s, has also endorsed aducanumab. It also receives funding from Biogen and Eisai, although the companies are only listed as “donors” in the organization’s most recent annual report.

US Against Alzheimer’s had revenue of $8.4 million in 2019; $8.1 million came from contributions and grants from foundations, individuals, corporations, and drugmakers.

The FDA should be commended for its work with Biogen, said US Against Alzheimer’s CEO George Vradenburg and neurologist Jeffrey Cummings, MD — a Biogen consultant — in a February 8 opinion piece in Stat.

“This partnership was not only appropriate but is expected by the FDA as defined in its recommended best practices for communication,” they write.

Aducanumab may not be a breakthrough, but it could represent incremental improvement, which in itself is important, they note.

Carome disagreed. Noting that his mother died after 10 years of living with Alzheimer’s, he said, “I understand the desperation and the desire to find treatments that really work.” But, he added, if aducanumab is approved with what he characterized as “flimsy evidence,” it could potentially bankrupt Medicare, given that the drug is projected to cost $50,000 a year.

Barron’s reports that Wall Street analysts estimate that aducanumab could generate $10 billion a year in sales.

Giving aducanumab a green light “could ultimately delay finding treatments that actually do work and give false hope to millions of patients and their families,” said Carome.

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