A third member of a prestigious FDA panel has resigned over the approval of a controversial new Alzheimer’s drug

A doctor observes medical scans of a patient's brain.
  • A third member of an FDA expert panel has resigned over the agency’s accelerated approval of a new Alzheimer’s drug.
  • The committee voted against approving the treatment. The FDA isn’t required to follow the panel’s recommendation but usually does.
  • Aduhelm failed one of its late-stage clinical trials and didn’t produce conclusive results in another trial.
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A third member of a Food and Drug Administration expert panel has resigned over the approval of a controversial new Alzheimer’s drug.

In a resignation letter obtained by CNBC, Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School, said the agency’s decision to approve Biogen’s new Alzheimer’s drug, Aduhelm, “was probably the worst drug approval decision in recent US history.”

Kesselheim joins two other former members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, who resigned from their positions earlier this week, as the backlash against the agency’s accelerated approval process continues to mount.

Aduhelm, formerly known as aducanumab, was approved by the FDA on Monday, despite the prestigious advisory committee voting against the approval of the treatment in November. Though the FDA isn’t required to follow the panel’s recommendation, it typically does so.

The drug has been a point of debate in the scientific community for years, because it failed one of its late-stage clinical trials, and another trial failed to produce conclusive evidence that Aduhelm helped patients with memory and cognition issues.

But facing ongoing pressure from Alzheimer’s patients’ friends and family, the FDA decided to approve the drug under accelerated approval, a special mechanism that allows authorization on the condition that Biogen runs a follow-up trial to confirm the drug works. The method is usually used for cancer medications, according to CNBC.

In his resignation letter, Kesselheim said the FDA switched its review to the accelerated pathway “at the last minute” based on a “debatable premise” about the drug’s effectiveness, CNBC reported. He also said it was clear to him that the agency is not “presently capable of adequately integrating the committee’s scientific recommendations into its approval decisions.”

“This will undermine the care of these patients, public trust in the FDA, the pursuit of useful therapeutic innovation, and the affordability of the health care system,” Kesselheim wrote.

The FDA did not immediately respond to Insider’s request for comment.

Dr. David Knopman, a neurologist at the Mayo Clinic whose resignation from the central nervous system panel was first reported by Insider’s Allison DeAngelis, said he was baffled by the FDA’s decision and felt the advisory committee had been “mistreated.”

“The FDA, in using the accelerated approval mechanism, they could not endorse any evidence of demonstrable clinical benefit. That’s what their press release said in so many words,” he told Insider. “That seems illogical to me.”

“I don’t want to be a part of that in the future,” Knopman added.

Neurologist Dr. Joel Perlmutter of Washington University in St. Louis also resigned from the panel on Monday.

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The FDA approved a drug to treat the underlying cause of Alzheimer’s and potentially slow its progression. But not all doctors are willing to prescribe it.

Scientist working in lab
The FDA approved the first drug to treat the underlying cause of Alzheimer’s.

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Yesterday, the FDA approved Biogen’s aducanumab, the first drug to treat the underlying cause of Alzheimer’s (sticky brain plaques) and potentially slow the disease’s progression in early stage patients. Although far from a cure, aducanumab could mark a new era in treating the leading cause of dementia and the sixth leading cause of death in the US.

Not all doctors are ready to prescribe

Biogen had shelved the drug in early 2019, then surprised the medical community by breaking it back out that October. Last November, an expert panel advised the FDA not to approve aducanumab after a pair of studies showed conflicting results about its effectiveness.

But the agency fast-tracked it, arguing that the benefits of slowing Alzheimer’s outweigh the risks. Since aducanumab’s clinical effectiveness isn’t certain, Biogen still has to conduct post-approval trials, but some health experts worry the FDA made the wrong decision.

Big picture: It’s easier to crack the TikTok algorithm than it is to treat Alzheimer’s. A string of failures led many pharma companies to give up, though some analysts think Biogen’s breakthrough could renew interest, Reuters reports. There’s certainly money to be made: Biogen says the treatment, which will be sold under the name “Aduhelm,” will cost $56,000 a year.

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Eli Lilly falls 9% after its Alzheimer’s drug data underwhelms Wall Street

FILE PHOTO: The logo of Lilly is seen on a wall of the Lilly France company unit, part of the Eli Lilly and Co drugmaker group, in Fegersheim near Strasbourg, France, February 1, 2018. Picture taken February 1, 2018. REUTERS/Vincent Kessler
The logo of Lilly is seen on a wall of the Lilly France company unit, part of the Eli Lilly and Co drugmaker group, in Fegersheim near Strasbourg

  • Eli Lilly fell 9% on Monday after additional data for its Alzheimer’s drug, donanemab, was released in The New England Journal of Medicine over the weekend.
  • The drug showed “no substantial difference” than a placebo in secondary outcomes like an improvement in scores on the Clinical Dementia Rating Scale Sum of Boxes.
  • An effective Alzheimer’s drug has been viewed as the holy grail in the biotech industry as it represents a significant unmet need.
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Eli Lilly fell as much as 9% on Tuesday after additional data for its Alzheimer’s drug candidate, donanemab, was released in The New England Journal of Medicine and presented at the 2021 International Conference on Alzheimer’s and Parkinson’s Diseases over the weekend.

The data reinforced previously released top-line data that showed donanemab slowed the cognitive decline in patients with early symptoms of dementia.

But donanemab showed “no substantial difference” than a placebo for secondary outcomes, like improvement in scores on the clinical dementia rating scale-sum of boxes and the 13-item Alzheimer’s disease assessment scale-cognitive subscale, according to the data.

“The use of donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed,” researchers said in The New England Journal of Medicine.

A successful Alzheimer’s drug has been viewed as the holy grail in the biotech industry, as it would help combat a devastating disease that represents a large unmet need. Biogen is another biotech company that is working on a highly anticipated Alzheimer’s drug candidate, aducanumab.

JPMorgan analyst Cory Kasimov said in a note on Monday based on the data so far, Eli Lilly’s donanemab “isn’t yet a clearly superior drug to [Biogen’s] aducanumab,” and that “it’s less likely donanemab is approved early on the basis of these results.”

Another phase 2 trial for donanemab is underway to gauge the safety, tolerability, and efficacy of the drug.

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New data on Eli Lilly’s experimental Alzheimer’s drug backs a hotly debated scientific theory, but shows mixed benefits for patients

FILE PHOTO:  Patients with Alzheimer's and dementia are sit inside the Alzheimer foundation in Mexico City April 19, 2012. REUTERS/Edgard Garrido
Patients sit inside the Alzheimer’s Foundation in Mexico City

  • Eli Lilly’s experimental treatment slowed down cognitive decline by 32% in a midstage trial.
  • But the drug missed most of the secondary trial goals, including one watched by experts.
  • An Eli Lilly executive told Insider the data was mixed, but very exciting.
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The latest test of Eli Lilly’s Alzheimer’s disease drug ended with a mixed bag of results, but experts say there are signs the experimental treatment may curb the disease’s decimation of cognition and memory.

Lilly gave an in-depth look at the performance of its drug, called donanemab, on Saturday at the International Conference on Alzheimer’s and Parkinson’s Diseases. The drug met the trial’s primary goals, reducing a harmful substance that builds up in the brains of patients with Alzheimer’s disease. It also slowed down the rate of cognitive decline by 32%, according to data scheduled to be published Saturday in a medical journal. But it missed the mark on several secondary tests.

The Alzheimer’s drug-development field has been marked by failure after failure, so the news that Lilly may have a working drug sent a surge of energy through the field when the drugmaker first disclosed some information about the results in January.

Those earlier failures – even within Lilly’s own drug-development pipeline – may have tempered expectations for donanemab. Dr. Mark Mintun, the vice president of the Alzheimer’s disease unit at Lilly, said he couldn’t think of a similar Alzheimer’s disease trial that hit its primary goal.

At this point, any news is good news, Dr. Howard Fillit, executive director of the Alzheimer’s Drug Discovery Foundation, told Insider.

“We’ve basically had a 100% failure rate on drug approvals since 2003. The thing that we’re going for is incremental benefits,” he said.

The donanemab data may give hope to the scientific community and other drug companies, but Fillit said the jury is still out on how effective the drug will be for patients themselves.

Donanemab missed the mark on a memory assessment experts were watching

Donanemab was designed to target a plaque that builds up in the brains of Alzheimer’s patients called amyloid beta. The hope is that getting rid of the plaque will reduce the rate of decline of a person’s memory and cognition.

Scans of trial participants’ brains showed that people taking donanemab did see their plaques fade away. That’s not only a boon to Eli Lilly, but other drugmakers that are working on treatments targeting amyloid beta, such as Biogen and Roche.

FILE - In this May 19, 2015, file photo, a doctor points to PET scan results that are part of a study on Alzheimer's disease at a hospital in Washington. Scientists know that long before the memory problems of Alzheimer's become obvious, people experience more subtle changes in their thinking and judgment. (AP Photo/Evan Vucci, File)
FILE – In this May 19, 2015, file photo, a doctor points to PET scan results that are part of a study on Alzheimer’s disease at a hospital in Washington. Scientists know that long before the memory problems of Alzheimer’s become obvious, people experience more subtle changes in their thinking and judgment. (AP Photo/Evan Vucci, File)

It wasn’t as clear how much benefit donanemab had on subjects’ ability to recall words, follow instructions and other abilities lost to dementia.

The drug passed the main test of memory and cognition.

But Alzheimer’s experts had their eyes on one datapoint in particular: the scores from a widely accepted dementia assessment known as CDR-SB. The tool is used to measure things like memory and judgement, as well as a person’s ability to do household chores and maintain their personal hygiene. The higher the score, the more skills have been lost to dementia like Alzheimer’s.

Eli Lilly’s drug didn’t meet expectations there.

The company reported that trial participants taking donanemab had a 0.36 point score difference compared to the participants that received a placebo treatment.

For comparison, Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at University of Southern California, had hoped to see at least a one-point difference, according to the Wall Street research firm Mizuho.

Mintun, the Eli Lilly executive, said he hadn’t expected that donanemab would pass all five dementia tests, calling it statistically impossible. But giving patients more time to hold onto memories is meaningful for them, he said.

The clinical trial took a ‘Goldilocks approach,’ and more testing is needed

The donanemab trial assessed a small and very specific group of patients. The trial was limited to participants with amyloid plaques, as well as another protein linked to Alzheimer’s called tau. Fillit called it a Goldilocks approach – in the end, Lilly ended up with participants whose Alzheimer’s disease wasn’t too early or too advanced.

Fillit and Alzheimer’s disease researcher Rudy Tanzi said that Lilly will need to run another clinical trial, preferably a much larger late-stage test with participants from multiple countries, if it wants to bring the treatment to the US Food and Drug Administration for approval. In particular, the company would need to show the drug works, as measured by the CDR-SB score, Tanzi said.

Eli Lilly’s current plan is to run at least one more mid-stage trial. The format of that trial had already been set, but Mintun said the drug giant is discussing possible changes with the FDA, including potentially removing a significant CDR-SB change as the main goal.

Changing that CDR-SB requirement, particularly given that the original Phase 2 trial failed on that regard, would make investors skeptical of the drug, according to a note from Morgan Stanley analysts before the full results were announced.

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Cassava Sciences jumps 16% on meeting with FDA paving the way for phase 3 study of Alzheimer’s treatment

brain scan alzheimer's dementia
  • Shares of Cassava Sciences jumped as much as 16% on Monday on news that it successfully completed an end-of-phase two meeting with the FDA for its Alzheimer’s treatment Simufilam.
  • The biotech company will be moving forward with a pivotal phase-three study in the second half of this year. 
  • Simufilam is a novel drug that targets “both neuroinflammation and neurodegeneration.
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Shares of Cassava Sciences jumped as much as 16% on Monday on news that the biotech company successfully completed an end-of-phase 2 meeting with the US Food and Drug Administration for Simufilam, its leading drug candidate for the treatment of Alzheimer’s disease. The meeting paved the way for a pivotal phase-three study in the second half of this year. 

The Austin, Texas-based company surged toward an almost 10-year high, nearing a share price last seen in June 2011. 

“For over 10 years we’ve been doing basic research and early drug development with simufilam,” Remi Barbier, President and CEO of the company said in a statement. “We believe the underlying science is solid, the drug appears safe and the clinical roadmap makes sense. We’ve crossed the Rubicon.

Simufilam is a novel drug that targets “both neuroinflammation and neurodegeneration,” the statement said.

The discussion during the meeting with the FDA, which took place in January, was supported by years of scientific and clinical data. This included positive results from a previously completed phase two clinical program.

More than five million Americans are living with the disease, according to the Alzheimer’s Association.

Shares of Cassava Sciences traded at $59.07 at 12:20PM E.T. on Monday.

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