Controversy and Pending Approval of Alzheimer’s Drug Aduhelm

by Athina Sitou, Contributing Writer

Alzheimer’s disease can often have heartbreaking effects on families. It ceases to be abstract when we think about our grandma or grandpa or mom or dad or spouse living with this devastating disease. It becomes tangible when we reflect on the fleeting warm feeling of having a loved one remember our name unexpectedly. These are only an infinitesimal part of the experiences of over half a million Canadians who are suffering from dementia (1). This significant population has probably felt hopeless after hearing their doctor say: there is no cure for Alzheimer’s.  

Yet, in June 2021, the US Food and Drug Administration (FDA) approved a new medication, called Aduhelm, that sparked flickers of hope in Alzheimer’s patients and their caregivers. However, the novel drug – developed by Biogen – is causing a lot of controversy among scientists due to disagreement about Aduhelm’s efficacy and safety. This controversy will likely influence Health Canada’s pending approval decision of this flawed and ultimately not recommended drug. 

Doubts regarding Aduhelm’s efficacy arose during phase III of clinical trials, the last step before the approval application. According to FDA standards, at least two phase III studies must prove successful for a treatment to be considered beneficial. Aduhelm may have shown positive results in one of the two studies, but unfortunately failed to do so in the other (3). The trials were consequently halted in March 2019, disappointing countless patients and their families. Aduhelm’s efficacy has thus remained unclear as the trials were terminated before they could be completed due to the lack of beneficial results in one of the two trials. 

In addition to the lack of clarity concerning Aduhelm’s efficacy, adverse effects also arose during the last two clinical trials (3). Among those who received the highest dose of the medication, one in three individuals developed internal bleeding or fluid buildup around the brain, known as amyloid-related imaging abnormalities (ARIA). Other secondary effects included headaches and loss of balance. Scientists observed these side effects in participants who were actually healthier than the demographic predicted to receive the medication, indicating that it could have even stronger side effects “in real-world settings” (5).

Biogen surprised the public six months after the trials’ termination, when they turned the tables and announced that they had conducted further analyses despite the halting of the trials. These analyses claimed that the drug benefited a particular participant subgroup who received the highest dose (3). This claim seems problematic since the people treated with the highest dosage were also the ones who experienced the worst ARIA side effects. The company nevertheless applied for approval from the FDA, whose expert advisory committee justifiably opposed Aduhelm’s approval. The FDA, however, authorized the drug on the basis of unmet medical need and considered in its evaluation other markers that may predict drug efficacy (4).

Health Canada is now reviewing Aduhelm to decide whether to approve it or not. A consensus statement supported by seven Canadian organizations comprised of Alzheimer’s experts states that the negative response of the FDA’s committee should be perceived as a “major ‘red flag’ ” by the deciding bodies in Canada (2). This consensus statement and Knopman¹ et al. suggest that an additional phase III high-dose trial is necessary to determine the drug’s clinical efficacy and safety.

Some may argue that the increasing number of individuals affected by Alzheimer’s and the aggressive nature of the disease warrant this drug’s approval since certain trial results predict clinical benefit. The urgent need for an Alzheimer’s treatment is indisputable, but Aduhelm’s approval unfortunately cannot be justified when the current data are “clearly insufficient to support a claim of efficacy” (3). Approving a medication whose efficacy and safety are not yet proven would be ethically immoral, irresponsible and dangerous for patients. We expect physicians and scientists to keep the patients’ interests at heart and never consciously put them at risk; approving a potentially harmful drug would compromise these values, which are at the core of what we associate with pharmacological research.

Alzheimer’s ravaging effects are real, and the possibility of having a treatment such as Aduhelm has brought much-needed hope to patients. Nevertheless, this fact cannot be used to overlook Aduhelm’s efficacy and safety concerns. This remains a complex issue and each person makes the decisions concerning their own health, but Aduhelm’s approval cannot currently be scientifically justified. A further trial is essential for scientists to study this medication to the fullest extent and reach an accurate conclusion about its efficacy and safety: two aspects that government agencies should thoroughly consider before approving any drug. 

Edited by Laura Reumont

Footnote:
1. Dr. Knopman was a site investigator in the phase III clinical trials for Aduhelm.

References:

  1. Alzheimer’s Association [Internet]. 2021. [cited 2021 Nov 18]. Available from: https://www.alz.org/ca/dementia-alzheimers-canada.asp 
  2. Chertkow H, Rockwood K, Hogan D, Phillips N, Montero-Odasso M. 2021. Consensus statement regarding the application of Biogen to Health Canada for approval of aducanumab. [Internet]. [cited 2021 Nov 18]. Available from: https://ccna-ccnv.ca/wp-content/uploads/2021/08/Consensus-statement-on-aducanumab_VFINAL_ENG.pdf 
  3. Knopman DS, Jones DT, Greicius MD. 2020. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen. Alzheimer’s & Dementia [Internet]. [cited 2021 Nov 18]; Vol. 17:696– 701. Available from:  https://doi.org/10.1002/alz.12213  
  4. US Food and Drug Administration [Internet]. 2021. [cited 2021 Nov 19]. Available from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information 
  5. Watt JA, Marple R, Hemmelgarn B, Straus SE. 2021. Should Canadian patients look forward to aducanumab for Alzheimer disease? CMAJ [Internet]. [cited 2021 Nov 18]; Vol. 193,36: E1430-E1431. Available from: 10.1503/cmaj.211134

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