FDA’s Controversial Approval of Aducanumab for Alzheimer’s Disease

What’s happening – The FDA approved the first Alzheimer’s disease (AD) drug in 18 years, Biogen’s Aduhelm (aducanumab), earlier this month in a controversial decision that went against the advice of its expert advisory committee. None of the Peripheral and Central Nervous System Drugs Advisory Committee members recommended the drug for approval; 10 voted against it and one member was uncertain. The drug’s effectiveness and safety have not been established in the eyes of many in the scientific community, and the committee said aducanumab failed to demonstrate an ability to reduce cognitive symptoms in two of its clinical trials. Patients in both clinical trials of the drug experienced side effects of brain swelling and brain bleeding.

Aducanumab has been approved under the agency’s accelerated approval program, and Biogen has 9 years to complete another trial that will look at improving cognition by removing the beta-amyloid plaques associated with AD and dementia. Previous research is unclear about whether removing amyloid plaques improves cognitive symptoms.

Added to the questionable efficacy and the safety risks is the cost of the drug. The monthly infusion will reportedly cost $56,000 per year, in addition to the required brain imaging and monitoring of anyone taking it. Some worry about the effects of Medicare footing the bill. Demand is expected to be high for aducanumab as there are few treatments available for the nearly 6 million US patients with this devastating disease, but despite the desire for a new AD treatment, experts believe that the data did not indicate that the drug is effective or safe.

Committee members resign – Within days of the FDA’s decision, three members of the advisory committee resigned. One of them, Dr. Joel Perlmutter, a neurologist at Washington University in St. Louis, told Psycom Pro in an emailed statement explaining his rationale for resigning that, “Approval of a drug that is not effective has serious potential to impair future research into new treatments that may be effective for treating AD,” adding that he was “extraordinarily disappointed” that the committee’s review was not valued. Dr. Aaron Kesselheim, a professor at Harvard Medical School, wrote in his resignation letter that the approval was “probably the worst drug approval decision” in recent history. Dr. David Knopman, a neurologist at the Mayo Clinic, discussed the drug in a Mayo Clinic podcast.

Editor’s Note: See the FDA’s Indications and Usage update to aducanumab announced July 8, 2021.

Reports & Perspectives

  • FDA officials wrote an opinion article in the Washington Post this week explaining their decision to approve aducanumab and why it was a good fit for the accelerated approval pathway. The agency also released documents earlier this week and discussed its decision with STAT news.
  • Clinicians and researchers have spoken out in opinion pieces since the approval, including one co-written by Dr. Kesselheim about the FDA’s “new low,” one in the Washington Post about the FDA’s “desperate need of some soul-searching,” and this one calling aducanumab a “lackluster drug.”
  • An opinion article by Drs. Reshma Ramacha​ndran and Joseph S. Ross (also co-authors on the Washington Post op-ed) explores the difficult position of clinicians who disagree with the FDA’s decision about the drug and must explain why they don’t recommend it to patients and families who have high hopes after aducanumab’s approval. More from Dr. Ramachandran in our Psy-Q below.
  • Many are hopeful about the possibilities of the drug, including the Alzheimer’s Association, which released statements supporting the FDA’s decision and calling for a lower price.
  • The American Geriatrics Society wrote a letter opposing the FDA’s approval several days before the decision was announced.
  • A panel of AD experts, who had differing opinions about the FDA’s approval of the drug, agreed this week that aducanumab should only be given to specific patients – those with early stage disease whose brains have high levels of amyloid plaques. This is contrary to the FDA’s approval, which was for anyone with AD.
  • The first dose of Aduhelm was administered last week.

Additional Conversation

  • @akesselheim (Dr. Aaron Kesselheim) tweeted several days before he resigned from FDA’s advisory committee, “Accelerated Approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval.”
  • @jsross119 (Dr. Joseph Ross) tweeted in a thread about his and Dr. Ramachandran’s opinion piece, “We need to clearly explain to patients that this drug is not a cure. At best, it marginally slows disease progression – but that finding is suspect and has not been confirmed.”
  • @reshmagar (Dr. Reshma Ramachandran, co-author of two recent opinion articles) tweeted about her co-authored Washington Post op-ed, “Today in @washingtonpost, @gregggonsalves, @cmorten2, @jsross119, & I write on what needs to change to revive & restore trust in @US_FDA after #aducanumab’s approval: more $$$, commitment to independence (not #Pharma), follow the science, & transparency.”
  • @FinancialTimes tweeted, “US medicines watchdog accused of cozy ties with Big Pharma” and linked to its article about increasing criticism of FDA Commissioner Janet Woodcock.

In Practice

Psy-Q Challenge

How to address questions from patients and families about the newly approved Alzheimer’s drug aducanumab, with Reshma Ramachandran MD, MPP.

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Schizophrenia and Bipolar I Have a New Treatment Option for Adults

What’s happening – Adults with schizophrenia have a new treatment option in Lybalvi (olanzapine and samidorphan), a once-daily, oral atypical antipsychotic manufactured by Alkermes and expected to be available later this year. FDA also approved the drug for the treatment of bipolar 1 disorder in adults, as a maintenance monotherapy or for the acute treatment of manic or mixed episodes, as monotherapy or an adjunct to lithium or valproate.

Lybalvi combines olanzapine, an antipsychotic that has been approved since 1996, with samidorphan, a new chemical entity and an opioid antagonist that is designed to reduce the weight gain typically associated with olanzapine. Gaining weight is a side effect of olanzapine that may cause some patients to limit its use, according to a company release. Participants taking Lybalvi in clinical trials gained less weight than those taking olanzapine alone.

Why it’s complicated – Because samidorphan is an opioid antagonist, Lybalvi is contraindicated in patients using opioids or who are undergoing opioid withdrawal. Patients should be opioid-free for 7 days for short-acting opioids or 14 days for long-acting opioids before starting the drug. In addition, Lybalvi has a boxed warning that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. The drug is not approved for the treatment of patients with dementia-related psychosis.

Reports & Perspectives

  • Two studies of Lybalvi were published last year, the ENLIGHTEN-1 trial by Potkin et al in the Journal of Clinical Psychiatry and the ENLIGHTEN-2 trial by Correll et al in the American Journal of Psychiatry.
  • Samidorphan was developed at the Rensselaer Polytechnic Institute, which published a brief history of the compound in light of Lybalvi’s approval.
  • @JCPjournal (Journal of Clinical Psychopharmacology) tweeted, “FDA has approved Alkermes Plc’s #LYBALVI (#olanzapine and #samidorphan) to treat adults with schizophrenia and adults with bipolar I disorder. The drug offers the antipsychotic efficacy of olanzapine with less weight gain.”
  • @rpi (Rensselaer Polytechnic Institute) tweeted, “The @US_FDA has approved a new drug for treating schizophrenia and bipolar I disorder that includes samidorphan, a new chemical entity discovered in Prof. Mark Wentland’s lab at #RPI. @Alkermes is planning a commercial launch for LYBALVI later this year.”

In Practice

Nutritional Psychiatry is Growing: Exploring the Food–Mood Relationship

What’s happening – It wouldn’t be called comfort food if it didn’t make us feel good but often, clinicians are asked whether these foods are the right choices for overall mental health. Thinking about food in terms of how it may affect moods and emotions is the realm of nutritional psychiatry, an emerging field that looks beyond dietary changes that aim to improve physical health and encompasses mental health improvements, too.

Examples of nutritional psychiatric research include investigating how the gut microbiome may affect major depressive disorder, dietary influences on anxiety, whether genetic studies can establish a link between diet and the prevention of mental disorders, and an mHealth intervention targeting diet and mood in people with depression, to name a few.

Why it’s complicated – Studying the gut-brain axis – the communication between the gut microbiome and the central nervous system (CNS) – is ongoing, with room for improvement when understanding causality. Researchers have observed that dietary changes can improve psychological well-being, and even reduce depression, but challenges remain for understanding the underlying mechanisms.

Reports & Perspectives

  • Uma Naidoo, MD, founder and director of the Nutritional and Lifestyle Psychiatry Program at Massachusetts General Hospital (the first such hospital-based clinical service in US), emphasizes avoiding processed foods, sugar, and artificial sweeteners, while eating more vegetables, fruits, fiber, and healthy fats to promote brain health in her book and interviews.
  • Recent articles on the topic have appeared in the New York Times, Bon Appétit, Cooking Light, and Today, which focused on brain fog due to long COVID and how food may help.
  • Check out two organizations working to advance nutritional psychiatry: the International Society for Nutritional Psychiatry Research and The Center for Nutritional Psychology
  • @DrUmaNaidoo tweeted, “As a Nutritional Psychiatrist, I advise a diet full of vegetables, fruits, legumes, nuts/seeds and healthy fats for optimal #mentalhealth. This is also an optimal diet for planetary health! What’s healthy for our brains is healthy for the Earth!”
  • @foodmoodcentre (The Food & Mood Centre, a collaborative research center led by Deakin University in Australia) shared a new post, “…Looking through the lens at how #food can improve our #mood.”
  • @nytimes tweeted, “The foods we crave when we most need comfort tend to be the sugary and high fat foods that may be least likely to boost our moods. An emerging field of study known as nutritional psychiatry may offer alternatives.”

In Practice

Last Updated: Aug 26, 2021